|
Inhibitory activity against rat heart Phosphodiesterase 1(PDE1)
|
None
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel, potent, and selective phosphodiesterase 5 inhibitors: synthesis and biological activities of a series of 4-aryl-1-isoquinolinone derivatives.
Year : 2001
Volume : 44
Issue : 13
First Page : 2204
Last Page : 2218
Authors : Ukita T, Nakamura Y, Kubo A, Yamamoto Y, Moritani Y, Saruta K, Higashijima T, Kotera J, Takagi M, Kikkawa K, Omori K.
Abstract : A novel class of potent and selective phosphodiesterase 5 (PDE5) inhibitors, 4-aryl-1-isoquinolinone derivatives, which have been designed by the comparison of the structure of cGMP and a previously reported 1-arylnaphthalene lignan, was disclosed. Among these compounds, methyl 2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate dihydrochloride (36a) exhibited potent PDE5 inhibitory activity (IC(50) = 1.0 nM) with high isozyme selectivities (IC(50) ratio: PDE1/PDE5 = 1300, PDE2/PDE5 > 10 000, PDE3/PDE5 > 10 000, PDE4/PDE5 = 4700, PDE6/PDE5 = 28). Compound 36a also showed the most potent relaxant effect on isolated rabbit corpus cavernosum (EC(30) = 7.9 nM). Compound 63 (T-1032), the sulfate form of 36a, was selected for further biological and pharmacological evaluation of erectile dysfunction.
|
Inhibitory activity against canine lung Phosphodiesterase 5 (PDE5)
|
Canis lupus familiaris
|
3.9
nM
|
|
Journal : J. Med. Chem.
Title : Novel, potent, and selective phosphodiesterase 5 inhibitors: synthesis and biological activities of a series of 4-aryl-1-isoquinolinone derivatives.
Year : 2001
Volume : 44
Issue : 13
First Page : 2204
Last Page : 2218
Authors : Ukita T, Nakamura Y, Kubo A, Yamamoto Y, Moritani Y, Saruta K, Higashijima T, Kotera J, Takagi M, Kikkawa K, Omori K.
Abstract : A novel class of potent and selective phosphodiesterase 5 (PDE5) inhibitors, 4-aryl-1-isoquinolinone derivatives, which have been designed by the comparison of the structure of cGMP and a previously reported 1-arylnaphthalene lignan, was disclosed. Among these compounds, methyl 2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate dihydrochloride (36a) exhibited potent PDE5 inhibitory activity (IC(50) = 1.0 nM) with high isozyme selectivities (IC(50) ratio: PDE1/PDE5 = 1300, PDE2/PDE5 > 10 000, PDE3/PDE5 > 10 000, PDE4/PDE5 = 4700, PDE6/PDE5 = 28). Compound 36a also showed the most potent relaxant effect on isolated rabbit corpus cavernosum (EC(30) = 7.9 nM). Compound 63 (T-1032), the sulfate form of 36a, was selected for further biological and pharmacological evaluation of erectile dysfunction.
|
Inhibition of PDE5 of human platelets
|
Homo sapiens
|
1.6
nM
|
|
Journal : J. Med. Chem.
Title : Substituted pyrazolopyridines as potent and selective PDE5 inhibitors: potential agents for treatment of erectile dysfunction.
Year : 2001
Volume : 44
Issue : 7
First Page : 1025
Last Page : 1027
Authors : Yu G, Mason HJ, Wu X, Wang J, Chong S, Dorough G, Henwood A, Pongrac R, Seliger L, He B, Normandin D, Adam L, Krupinski J, Macor JE.
|
Inhibitory activity against bovine PDE5 (phosphodiesterase-5).
|
None
|
6.0
nM
|
|
Journal : J. Med. Chem.
Title : The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 1: 5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione analogues.
Year : 2003
Volume : 46
Issue : 21
First Page : 4525
Last Page : 4532
Authors : Daugan A, Grondin P, Ruault C, Le Monnier de Gouville AC, Coste H, Kirilovsky J, Hyafil F, Labaudinière R.
Abstract : Starting from ethyl beta-carboline-3-carboxylate (beta-CCE), 1, a modest inhibitor of type 5 phosphodiesterase (PDE5), a series of functionalized tetrahydro-beta-carboline derivatives has been identified as a novel chemical class of potent and selective PDE5 inhibitors. Optimization of the side chain on the hydantoin ring of initial lead compound 2 and of the aromatic ring on position 5 led to the identification of compound 6e, a highly potent and selective PDE5 inhibitor, with greater selectivity for PDE5 vs PDE1-4 than sildenafil. Compound 6e demonstrated a long-lasting and significant blood pressure lowering effect after iv administration in the spontaneously hypertensive rat model but showed only moderate oral in vivo efficacy.
|
Inhibition of bovine aorta PDE5 (Phosphodiesterase 5)
|
Bos taurus
|
6.0
nM
|
|
Journal : J. Med. Chem.
Title : The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione analogues.
Year : 2003
Volume : 46
Issue : 21
First Page : 4533
Last Page : 4542
Authors : Daugan A, Grondin P, Ruault C, Le Monnier de Gouville AC, Coste H, Linget JM, Kirilovsky J, Hyafil F, Labaudinière R.
Abstract : Modification of the hydantoin ring in the previously described lead compound 2a has led to the discovery of compound 12a, tadalafil, a highly potent and highly selective PDE5 inhibitor. The replacement of the hydantoin in compound 2a by a piperazinedione ring led to compound cis-11a which showed similar PDE5 inhibitory potency. Introduction of a 3,4-methylenedioxy substitution on the phenyl ring in position 6 led to a potent PDE5 inhibitor cis-11c with increased cellular potency. Optimization of the chain on the piperazinedione ring led to the identification of the racemic cis-N-methyl derivative 11i. High diastereospecificity for PDE5 inhibition was observed in the piperazinedione series with the cis-(6R,12aR) enantiomer displaying the highest PDE5 inhibitory activity. The piperazinedione 12a, tadalafil (GF196960), has been identified as a highly potent PDE5 inhibitor (IC(50) = 5 nM) with high selectivity for PDE5 vs PDE1-4 and PDE6. Compound 12a displays 85-fold greater selectivity vs PDE6 than sildenafil 1. 12a showed profound and long-lasting blood pressure lowering activity (30 mmHg/>7 h) in the spontaneously hypertensive rat model after oral administration (5 mg/kg).
|
Inhibitory activity against phosphodiesterase 5 (PDE5) isolated from canine lung
|
Canis lupus familiaris
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1,7- and 2,7-naphthyridine derivatives as potent and highly specific PDE5 inhibitors.
Year : 2003
Volume : 13
Issue : 14
First Page : 2341
Last Page : 2345
Authors : Ukita T, Nakamura Y, Kubo A, Yamamoto Y, Moritani Y, Saruta K, Higashijima T, Kotera J, Fujishige K, Takagi M, Kikkawa K, Omori K.
Abstract : Novel 1,7- and 2,7-naphthyridine derivatives, designed by the introduction of nitrogen atom into the phenyl ring of previously reported 4-aryl-1-isoquinolinone derivatives, were disclosed as a new structural class of potent and specific PDE5 inhibitors. Among them, 2,7-naphthyridine 4c showed potent PDE5 inhibition (IC(50)=0.23 nM) and one of the best PDE5 specificities against PDEs1-4,6 (>100,000-fold selective versus PDE1-4, 240-fold selective vs PDE6). This compound showed more potent relaxant effects on isolated rabbit corpus cavernosum (EC(30)=5.0 nM) than Sildenafil (EC(30)=8.7 nM). The compound 4c (T-0156) was selected for further biological and pharmacological evaluation of erectile dysfunction.
|
In vitro inhibitory concentration against human platelet Phosphodiesterase 5 was determined
|
None
|
1.6
nM
|
|
Journal : J. Med. Chem.
Title : Optimization of substituted N-3-benzylimidazoquinazolinone sulfonamides as potent and selective PDE5 inhibitors.
Year : 2000
Volume : 43
Issue : 26
First Page : 5037
Last Page : 5043
Authors : Rotella DP, Sun Z, Zhu Y, Krupinski J, Pongrac R, Seliger L, Normandin D, Macor JE.
Abstract : A previous report from these laboratories identified the N-3-benzylimidazoquinazolinone nucleus as a more selective PDE5 inhibitor template compared to the pyrazolopyrimidine of sildenafil. This paper describes in detail the structure-activity relationships of a set of sulfonamide analogues, several of which are both more potent and more selective PDE5 inhibitors in vitro than sildenafil. The synthesis, in vitro enzyme activity and selectivity, and in vitro functional and preclinical pharmacokinetic assessment of molecules in this series are described.
|
Inhibition of PDE5 from human platelets
|
Homo sapiens
|
1.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The discovery of novel, potent and selective PDE5 inhibitors.
Year : 2001
Volume : 11
Issue : 18
First Page : 2461
Last Page : 2464
Authors : Bi Y, Stoy P, Adam L, He B, Krupinski J, Normandin D, Pongrac R, Seliger L, Watson A, Macor JE.
Abstract : The design and synthesis of a novel scaffold for potent and selective PDE5 inhibitors are described. Compound 3a was more potent (PDE5 IC50=0.31 nM) and selective (>10,000-fold vs PDE1 and 160-fold selective vs PDE6) PDE5 inhibitor than sildenafil.
|
Inhibition of phosphodiesterase 5 from human platelets
|
Homo sapiens
|
1.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Quinolines as extremely potent and selective PDE5 inhibitors as potential agents for treatment of erectile dysfunction.
Year : 2004
Volume : 14
Issue : 6
First Page : 1577
Last Page : 1580
Authors : Bi Y, Stoy P, Adam L, He B, Krupinski J, Normandin D, Pongrac R, Seliger L, Watson A, Macor JE.
Abstract : In a continuing effort to discover novel chemotypes as potent and selective PDE5 inhibitors for the treatment of male erectile dysfunction (ED), we have found that 4-benzylaminoquinoline derivatives are very potent and selective PDE5 inhibitors. Some compounds in this series had PDE5 IC(50)'s as low as 50 pM. While an electron withdrawing group at the C6-position of the quinoline substantially improved PDE5 potency, an ethyl group at the C8-position not only improved the PDE5 potency but also the isozyme selectivity. Substitutents at the C3-position can incorporate a variety of different groups. The synthesis and primary structure-activity relationship of this new series of potent PDE5 inhibitors are described.
|
Inhibition of Phosphodiesterase 5 from human corpus cavernosum
|
Homo sapiens
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sildenafil (VIAGRATM), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction
Year : 1996
Volume : 6
Issue : 15
First Page : 1819
Last Page : 1824
Authors : Terrett NK, Bell AS, Brown D, Ellis P
|
Inhibitory concentration against human phosphodiesterase 5 (PDE5) enzyme
|
None
|
3.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : SAR development of polycyclic guanine derivatives targeted to the discovery of a selective PDE5 inhibitor for treatment of erectile dysfunction.
Year : 2004
Volume : 14
Issue : 5
First Page : 1291
Last Page : 1294
Authors : Pissarnitski DA, Asberom T, Boyle CD, Chackalamannil S, Chintala M, Clader JW, Greenlee WJ, Hu Y, Kurowski S, Myers J, Palamanda J, Stamford AW, Vemulapalli S, Wang Y, Wang P, Wu P, Xu R.
Abstract : Development of structure-activity relationship of cyclic guanines I lead us to discovery of a potent and selective series of phosphodiesterase 5 inhibitors 52-59 (IC50=1.3-11.0 nM, PDE6/5=116-600).
|
Inhibition of Phosphodiesterase 5 from human platelets
|
Homo sapiens
|
1.6
nM
|
|
Journal : J. Med. Chem.
Title : Substituted pyrazolopyridopyridazines as orally bioavailable potent and selective PDE5 inhibitors: potential agents for treatment of erectile dysfunction.
Year : 2003
Volume : 46
Issue : 4
First Page : 457
Last Page : 460
Authors : Yu G, Mason H, Wu X, Wang J, Chong S, Beyer B, Henwood A, Pongrac R, Seliger L, He B, Normandin D, Ferrer P, Zhang R, Adam L, Humphrey WG, Krupinski J, Macor JE.
Abstract : Novel pyrazolopyridopyridazine derivatives have been prepared as potent and selective PDE5 inhibitors. Compound 6 has been identified as a more potent and selective PDE5 inhibitor than sildenafil (1). It is as efficacious as sildenafil in in vitro and in vivo PDE5 inhibition models, and it is orally bioavailable in rats and dogs. The superior isozyme selectivity of 6 is expected to exert less adverse effects in humans when used for erectile dysfunction treatment.
|
Inhibitory concentration against phosphodiesterase 5 (PDE5) from human platelet
|
None
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of purine inhibitors of phosphodiesterase 7 (PDE7).
Year : 2004
Volume : 14
Issue : 11
First Page : 2955
Last Page : 2958
Authors : Pitts WJ, Vaccaro W, Huynh T, Leftheris K, Roberge JY, Barbosa J, Guo J, Brown B, Watson A, Donaldson K, Starling GC, Kiener PA, Poss MA, Dodd JH, Barrish JC.
Abstract : A series of purine based inhibitors of PDE7 has been derived from screening lead 1a. The synthesis, structure-activity relationships (SAR), and selectivity against several other PDE family members are described.
|
Inhibition of Phosphodiesterase 5
|
Homo sapiens
|
6.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Imidazo[5,1-f]triazin-4(3H)-ones, a new class of potent PDE 5 inhibitors.
Year : 2002
Volume : 12
Issue : 6
First Page : 865
Last Page : 868
Authors : Haning H, Niewöhner U, Schenke T, Es-Sayed M, Schmidt G, Lampe T, Bischoff E.
Abstract : 2-aryl-substituted imidazo[5,1-f][1,2,4]triazin-4(3H)-ones represent a new class of potent cGMP-PDE 5 inhibitors that prove to be superior to other purine-isosteric inhibitors. Subnanomolar inhibitors of PDE 5 with activity in in vivo models for erectile dysfunction have been identified. BAY 38-9456 (Vardenafil-hydrochloride) has been selected for clinical studies in the indication of erectile dysfunction.
|
Inhibition of phosphodiesterase type 5 (PDE5) of human platelets
|
Homo sapiens
|
1.6
nM
|
|
Journal : J. Med. Chem.
Title : N-3-substituted imidazoquinazolinones: potent and selective PDE5 inhibitors as potential agents for treatment of erectile dysfunction.
Year : 2000
Volume : 43
Issue : 7
First Page : 1257
Last Page : 1263
Authors : Rotella DP, Sun Z, Zhu Y, Krupinski J, Pongrac R, Seliger L, Normandin D, Macor JE.
Abstract : Phosphodiesterase type 5 (PDE5) inhibitors with improved PDE isozyme selectivity relative to sildenafil may result in agents for the treatment of male erectile dysfunction (MED) with a lower incidence of PDE-associated adverse effects. This paper describes the discovery of 14, a PDE5 inhibitor with improved potency and selectivity in vitro compared to sildenafil. This compound shows activity in a functional assay of erectile function comparable to that of sildenafil.
|
Phosphodiesterase 5 activity of human corpus cavernosum
|
Homo sapiens
|
1.87
nM
|
|
Journal : J. Med. Chem.
Title : Pyrimidinylpyrroloquinolones as highly potent and selective PDE5 inhibitors for treatment of erectile dysfunction.
Year : 2002
Volume : 45
Issue : 19
First Page : 4094
Last Page : 4096
Authors : Sui Z, Guan J, Macielag MJ, Jiang W, Zhang S, Qiu Y, Kraft P, Bhattacharjee S, John TM, Haynes-Johnson D, Clancy J.
Abstract : A series of N-pyrimidinylpyrroloquinolones were discovered as extremely potent and selective PDE5 inhibitors. Representative compounds demonstrated in vivo efficacy in dog erectile dysfunction models and are orally bioavailable.
|
Inhibitory activity against PDE5 from human corpus cavernosum
|
None
|
1.87
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological activities of novel beta-carbolines as PDE5 inhibitors.
Year : 2003
Volume : 13
Issue : 4
First Page : 761
Last Page : 765
Authors : Sui Z, Guan J, Macielag MJ, Jiang W, Qiu Y, Kraft P, Bhattacharjee S, John TM, Craig E, Haynes-Johnson D, Clancy J.
Abstract : A series of N(2)-furoyl and N(2)pyrimidinyl beta-carbolines was discovered to possess potent inhibitory activity against PDE5. During the synthesis we developed a tandem resin quenching protocol, which allowed us to synthesize large number of target compounds in a rapid fashion. Representative compounds exhibit superior selectivity to sildenafil versus other isozymes of PDEs, and demonstrated in vivo efficacy in increasing introcavernosal pressure in dogs.
|
Inhibitory activity against human Phosphodiesterase 5
|
None
|
1.91
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships of N-acyl pyrroloquinolone PDE-5 inhibitors.
Year : 2004
Volume : 47
Issue : 3
First Page : 656
Last Page : 662
Authors : Lanter JC, Sui Z, Macielag MJ, Fiordeliso JJ, Jiang W, Qiu Y, Bhattacharjee S, Kraft P, John TM, Haynes-Johnson D, Craig E, Clancy J.
Abstract : The discovery of the potent and selective PDE-5 inhibitory activity of a pyrroloquinolone scaffold prompted us to explore the SAR of its acyl derivatives. During the course of these studies, three structural series were found with K(i) values for PDE-5 in the subnanomolar range. Systematic modification of one of these leads produced a compound with excellent selectivity for PDE-5 over other phosphodiesterases and oral bioavailability of 15% in male rats. This compound also displayed in vivo efficacy in an anesthetized canine model of erection when dosed intravenously.
|
Inhibition of phosphodiesterase 5 of rabbit platelets
|
Oryctolagus cuniculus
|
1.78
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and phosphodiesterase 5 inhibitory activity of new sildenafil analogues containing a phosphonate group in the 5(')-sulfonamide moiety of phenyl ring.
Year : 2004
Volume : 14
Issue : 9
First Page : 2099
Last Page : 2103
Authors : Kim DK, Young Lee J, Park HJ, Minh Thai K.
Abstract : Synthesis of new sildenafil analogues containing a phosphonate group in the 5(')-sulfonamide moiety of the phenyl ring, 12a-e, 13a-d, and 14a-d, and evaluation of their in vitro PDE5 inhibitory activity are disclosed. Enzyme assays revealed that maximum 10-fold increase in PDE5 inhibitory activity, compared with sildenafil, was achieved by introducing a phosphonate group in the 5(')-sulfonamide moiety. Docking model of (PDE5: 12d) complex shows that the PDE5-bound conformation of 12d matches completely with that of sildenafil, while 12d is partially overlapped with cGMP with ethyl phosphonate group of 12d superimposed onto the cyclic phosphate group of cGMP.
|
Inhibition of Phosphodiesterase 5 from rabbit platelets
|
Oryctolagus cuniculus
|
3.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sildenafil (VIAGRATM), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction
Year : 1996
Volume : 6
Issue : 15
First Page : 1819
Last Page : 1824
Authors : Terrett NK, Bell AS, Brown D, Ellis P
|
Relaxant effect mediated by PDE5 inhibition in rabbit corpus cavernosum
|
Oryctolagus cuniculus
|
19.0
nM
|
|
Journal : J. Med. Chem.
Title : Substituted pyrazolopyridopyridazines as orally bioavailable potent and selective PDE5 inhibitors: potential agents for treatment of erectile dysfunction.
Year : 2003
Volume : 46
Issue : 4
First Page : 457
Last Page : 460
Authors : Yu G, Mason H, Wu X, Wang J, Chong S, Beyer B, Henwood A, Pongrac R, Seliger L, He B, Normandin D, Ferrer P, Zhang R, Adam L, Humphrey WG, Krupinski J, Macor JE.
Abstract : Novel pyrazolopyridopyridazine derivatives have been prepared as potent and selective PDE5 inhibitors. Compound 6 has been identified as a more potent and selective PDE5 inhibitor than sildenafil (1). It is as efficacious as sildenafil in in vitro and in vivo PDE5 inhibition models, and it is orally bioavailable in rats and dogs. The superior isozyme selectivity of 6 is expected to exert less adverse effects in humans when used for erectile dysfunction treatment.
|
Inhibition of Phosphodiesterase 5 from rat diaphragm
|
Rattus norvegicus
|
0.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A prenylated flavonol, sophoflavescenol: a potent and selective inhibitor of cGMP phosphodiesterase 5.
Year : 2002
Volume : 12
Issue : 17
First Page : 2313
Last Page : 2316
Authors : Shin HJ, Kim HJ, Kwak JH, Chun HO, Kim JH, Park H, Kim DH, Lee YS.
Abstract : During the search for naturally occurring cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) inhibitors, it was found that the extracts from Sophora flavescens exhibit potent inhibitory activity against cGMP PDE5 prepared from rat diaphragm. Therefore, the inhibitory activities of five flavonoids, kushenol H (1), kushenol K (2), kurarinol (3), sophoflavescenol (4) and kuraridine (5), isolated from S. flavescens were measured against cGMP PDE5 to identify potent cGMP PDE5 inhibitory constituents. Among tested compounds, sophoflavescenol (4), a C-8 prenylated flavonol, showed the most potent inhibitory activity (IC(50)=0.013 microM) against cGMP PDE5 with 31.5- and 196.2-fold selectivity over PDE3 and PDE4, respectively. Kinetic analysis revealed that sophoflavescenol was a mixed inhibitor of PDE5 with a K(i) value of 0.005 microM.
|
Inhibitory activity against Phosphodiesterase 5 (PDE5) was evaluated
|
None
|
1.91
nM
|
|
Journal : J. Med. Chem.
Title : Furoyl and benzofuroyl pyrroloquinolones as potent and selective PDE5 inhibitors for treatment of erectile dysfunction.
Year : 2003
Volume : 46
Issue : 3
First Page : 441
Last Page : 444
Authors : Jiang W, Sui Z, Macielag MJ, Walsh SP, Fiordeliso JJ, Lanter JC, Guan J, Qiu Y, Kraft P, Bhattacharjee S, Craig E, Haynes-Johnson D, John TM, Clancy J.
Abstract : Synthesis of furoyl and benzofuroyl pyrroloquinolones as potent and selective PDE5 inhibitors was reported. Their in vitro potencies in inhibiting PDE5 and selectivity in inhibiting other PDE isozymes (PDE1-4 and PDE6) were evaluated. Some of these compounds are more potent than sildenafil with better selectivity toward PDE1 and PDE6. Incorporation of solublizing groups resulted in bioavailable analogues. Selected compounds showed in vivo efficacy in anesthetized dog model for penile erection.
|
Inhibition of bovine retina PDE6 (Phosphodiesterase 6)
|
Bos taurus
|
74.0
nM
|
|
Journal : J. Med. Chem.
Title : The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione analogues.
Year : 2003
Volume : 46
Issue : 21
First Page : 4533
Last Page : 4542
Authors : Daugan A, Grondin P, Ruault C, Le Monnier de Gouville AC, Coste H, Linget JM, Kirilovsky J, Hyafil F, Labaudinière R.
Abstract : Modification of the hydantoin ring in the previously described lead compound 2a has led to the discovery of compound 12a, tadalafil, a highly potent and highly selective PDE5 inhibitor. The replacement of the hydantoin in compound 2a by a piperazinedione ring led to compound cis-11a which showed similar PDE5 inhibitory potency. Introduction of a 3,4-methylenedioxy substitution on the phenyl ring in position 6 led to a potent PDE5 inhibitor cis-11c with increased cellular potency. Optimization of the chain on the piperazinedione ring led to the identification of the racemic cis-N-methyl derivative 11i. High diastereospecificity for PDE5 inhibition was observed in the piperazinedione series with the cis-(6R,12aR) enantiomer displaying the highest PDE5 inhibitory activity. The piperazinedione 12a, tadalafil (GF196960), has been identified as a highly potent PDE5 inhibitor (IC(50) = 5 nM) with high selectivity for PDE5 vs PDE1-4 and PDE6. Compound 12a displays 85-fold greater selectivity vs PDE6 than sildenafil 1. 12a showed profound and long-lasting blood pressure lowering activity (30 mmHg/>7 h) in the spontaneously hypertensive rat model after oral administration (5 mg/kg).
|
Inhibition of phosphodiesterase 6 from bovine retina
|
Bos taurus
|
19.77
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and phosphodiesterase 5 inhibitory activity of new sildenafil analogues containing a phosphonate group in the 5(')-sulfonamide moiety of phenyl ring.
Year : 2004
Volume : 14
Issue : 9
First Page : 2099
Last Page : 2103
Authors : Kim DK, Young Lee J, Park HJ, Minh Thai K.
Abstract : Synthesis of new sildenafil analogues containing a phosphonate group in the 5(')-sulfonamide moiety of the phenyl ring, 12a-e, 13a-d, and 14a-d, and evaluation of their in vitro PDE5 inhibitory activity are disclosed. Enzyme assays revealed that maximum 10-fold increase in PDE5 inhibitory activity, compared with sildenafil, was achieved by introducing a phosphonate group in the 5(')-sulfonamide moiety. Docking model of (PDE5: 12d) complex shows that the PDE5-bound conformation of 12d matches completely with that of sildenafil, while 12d is partially overlapped with cGMP with ethyl phosphonate group of 12d superimposed onto the cyclic phosphate group of cGMP.
|
Inhibitory activity against Phosphodiesterase 6 isolated from bovine retina
|
None
|
28.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1,7- and 2,7-naphthyridine derivatives as potent and highly specific PDE5 inhibitors.
Year : 2003
Volume : 13
Issue : 14
First Page : 2341
Last Page : 2345
Authors : Ukita T, Nakamura Y, Kubo A, Yamamoto Y, Moritani Y, Saruta K, Higashijima T, Kotera J, Fujishige K, Takagi M, Kikkawa K, Omori K.
Abstract : Novel 1,7- and 2,7-naphthyridine derivatives, designed by the introduction of nitrogen atom into the phenyl ring of previously reported 4-aryl-1-isoquinolinone derivatives, were disclosed as a new structural class of potent and specific PDE5 inhibitors. Among them, 2,7-naphthyridine 4c showed potent PDE5 inhibition (IC(50)=0.23 nM) and one of the best PDE5 specificities against PDEs1-4,6 (>100,000-fold selective versus PDE1-4, 240-fold selective vs PDE6). This compound showed more potent relaxant effects on isolated rabbit corpus cavernosum (EC(30)=5.0 nM) than Sildenafil (EC(30)=8.7 nM). The compound 4c (T-0156) was selected for further biological and pharmacological evaluation of erectile dysfunction.
|
Concentration required to inhibit phosphodiesterase type 5 (PDE5) isolated from corpus cavernosum by 50% was determined
|
None
|
3.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of xanthine analogues as potent and selective PDE5 inhibitors.
Year : 2002
Volume : 12
Issue : 21
First Page : 3149
Last Page : 3152
Authors : Wang Y, Chackalamannil S, Hu Z, Boyle CD, Lankin CM, Xia Y, Xu R, Asberom T, Pissarnitski D, Stamford AW, Greenlee WJ, Skell J, Kurowski S, Vemulapalli S, Palamanda J, Chintala M, Wu P, Myers J, Wang P.
Abstract : We have discovered potent and selective xanthine PDE5 inhibitors. Compound 25 (PDE5 IC(50)=0.6 nM, PDE6/PDE5=101) demonstrated similar functional efficacy and PK profile to Sildenafil (PDE5 IC(50)=3.5 nM, PDE6/PDE5=7).
|
Inhibition of phosphodiesterase 1 from bovine heart
|
Bos taurus
|
739.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and phosphodiesterase 5 inhibitory activity of new sildenafil analogues containing a phosphonate group in the 5(')-sulfonamide moiety of phenyl ring.
Year : 2004
Volume : 14
Issue : 9
First Page : 2099
Last Page : 2103
Authors : Kim DK, Young Lee J, Park HJ, Minh Thai K.
Abstract : Synthesis of new sildenafil analogues containing a phosphonate group in the 5(')-sulfonamide moiety of the phenyl ring, 12a-e, 13a-d, and 14a-d, and evaluation of their in vitro PDE5 inhibitory activity are disclosed. Enzyme assays revealed that maximum 10-fold increase in PDE5 inhibitory activity, compared with sildenafil, was achieved by introducing a phosphonate group in the 5(')-sulfonamide moiety. Docking model of (PDE5: 12d) complex shows that the PDE5-bound conformation of 12d matches completely with that of sildenafil, while 12d is partially overlapped with cGMP with ethyl phosphonate group of 12d superimposed onto the cyclic phosphate group of cGMP.
|
Inhibition of Phosphodiesterase 1
|
Bos taurus
|
400.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Imidazo[5,1-f]triazin-4(3H)-ones, a new class of potent PDE 5 inhibitors.
Year : 2002
Volume : 12
Issue : 6
First Page : 865
Last Page : 868
Authors : Haning H, Niewöhner U, Schenke T, Es-Sayed M, Schmidt G, Lampe T, Bischoff E.
Abstract : 2-aryl-substituted imidazo[5,1-f][1,2,4]triazin-4(3H)-ones represent a new class of potent cGMP-PDE 5 inhibitors that prove to be superior to other purine-isosteric inhibitors. Subnanomolar inhibitors of PDE 5 with activity in in vivo models for erectile dysfunction have been identified. BAY 38-9456 (Vardenafil-hydrochloride) has been selected for clinical studies in the indication of erectile dysfunction.
|
Inhibitory activity against phosphodiesterase-1 (PDE1) isolated from canine lung
|
Canis lupus familiaris
|
270.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1,7- and 2,7-naphthyridine derivatives as potent and highly specific PDE5 inhibitors.
Year : 2003
Volume : 13
Issue : 14
First Page : 2341
Last Page : 2345
Authors : Ukita T, Nakamura Y, Kubo A, Yamamoto Y, Moritani Y, Saruta K, Higashijima T, Kotera J, Fujishige K, Takagi M, Kikkawa K, Omori K.
Abstract : Novel 1,7- and 2,7-naphthyridine derivatives, designed by the introduction of nitrogen atom into the phenyl ring of previously reported 4-aryl-1-isoquinolinone derivatives, were disclosed as a new structural class of potent and specific PDE5 inhibitors. Among them, 2,7-naphthyridine 4c showed potent PDE5 inhibition (IC(50)=0.23 nM) and one of the best PDE5 specificities against PDEs1-4,6 (>100,000-fold selective versus PDE1-4, 240-fold selective vs PDE6). This compound showed more potent relaxant effects on isolated rabbit corpus cavernosum (EC(30)=5.0 nM) than Sildenafil (EC(30)=8.7 nM). The compound 4c (T-0156) was selected for further biological and pharmacological evaluation of erectile dysfunction.
|
Inhibition of Phosphodiesterase 1 from rat liver
|
Rattus norvegicus
|
260.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sildenafil (VIAGRATM), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction
Year : 1996
Volume : 6
Issue : 15
First Page : 1819
Last Page : 1824
Authors : Terrett NK, Bell AS, Brown D, Ellis P
|
Inhibition of Phosphodiesterase 3
|
None
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Imidazo[5,1-f]triazin-4(3H)-ones, a new class of potent PDE 5 inhibitors.
Year : 2002
Volume : 12
Issue : 6
First Page : 865
Last Page : 868
Authors : Haning H, Niewöhner U, Schenke T, Es-Sayed M, Schmidt G, Lampe T, Bischoff E.
Abstract : 2-aryl-substituted imidazo[5,1-f][1,2,4]triazin-4(3H)-ones represent a new class of potent cGMP-PDE 5 inhibitors that prove to be superior to other purine-isosteric inhibitors. Subnanomolar inhibitors of PDE 5 with activity in in vivo models for erectile dysfunction have been identified. BAY 38-9456 (Vardenafil-hydrochloride) has been selected for clinical studies in the indication of erectile dysfunction.
|
Inhibition of Phosphodiesterase 4
|
None
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Imidazo[5,1-f]triazin-4(3H)-ones, a new class of potent PDE 5 inhibitors.
Year : 2002
Volume : 12
Issue : 6
First Page : 865
Last Page : 868
Authors : Haning H, Niewöhner U, Schenke T, Es-Sayed M, Schmidt G, Lampe T, Bischoff E.
Abstract : 2-aryl-substituted imidazo[5,1-f][1,2,4]triazin-4(3H)-ones represent a new class of potent cGMP-PDE 5 inhibitors that prove to be superior to other purine-isosteric inhibitors. Subnanomolar inhibitors of PDE 5 with activity in in vivo models for erectile dysfunction have been identified. BAY 38-9456 (Vardenafil-hydrochloride) has been selected for clinical studies in the indication of erectile dysfunction.
|
Relaxant effect on rabbit corpus cavernosum
|
Oryctolagus cuniculus
|
7.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1,7- and 2,7-naphthyridine derivatives as potent and highly specific PDE5 inhibitors.
Year : 2003
Volume : 13
Issue : 14
First Page : 2341
Last Page : 2345
Authors : Ukita T, Nakamura Y, Kubo A, Yamamoto Y, Moritani Y, Saruta K, Higashijima T, Kotera J, Fujishige K, Takagi M, Kikkawa K, Omori K.
Abstract : Novel 1,7- and 2,7-naphthyridine derivatives, designed by the introduction of nitrogen atom into the phenyl ring of previously reported 4-aryl-1-isoquinolinone derivatives, were disclosed as a new structural class of potent and specific PDE5 inhibitors. Among them, 2,7-naphthyridine 4c showed potent PDE5 inhibition (IC(50)=0.23 nM) and one of the best PDE5 specificities against PDEs1-4,6 (>100,000-fold selective versus PDE1-4, 240-fold selective vs PDE6). This compound showed more potent relaxant effects on isolated rabbit corpus cavernosum (EC(30)=5.0 nM) than Sildenafil (EC(30)=8.7 nM). The compound 4c (T-0156) was selected for further biological and pharmacological evaluation of erectile dysfunction.
|
Relaxant effect on rabbit corpus cavernosal tissue strips
|
Oryctolagus cuniculus
|
42.0
nM
|
|
Journal : J. Med. Chem.
Title : Substituted pyrazolopyridines as potent and selective PDE5 inhibitors: potential agents for treatment of erectile dysfunction.
Year : 2001
Volume : 44
Issue : 7
First Page : 1025
Last Page : 1027
Authors : Yu G, Mason HJ, Wu X, Wang J, Chong S, Dorough G, Henwood A, Pongrac R, Seliger L, He B, Normandin D, Adam L, Krupinski J, Macor JE.
|
Relaxant effect on isolated rabbit corpus cavernosum
|
Oryctolagus cuniculus
|
8.7
nM
|
|
Journal : J. Med. Chem.
Title : Novel, potent, and selective phosphodiesterase 5 inhibitors: synthesis and biological activities of a series of 4-aryl-1-isoquinolinone derivatives.
Year : 2001
Volume : 44
Issue : 13
First Page : 2204
Last Page : 2218
Authors : Ukita T, Nakamura Y, Kubo A, Yamamoto Y, Moritani Y, Saruta K, Higashijima T, Kotera J, Takagi M, Kikkawa K, Omori K.
Abstract : A novel class of potent and selective phosphodiesterase 5 (PDE5) inhibitors, 4-aryl-1-isoquinolinone derivatives, which have been designed by the comparison of the structure of cGMP and a previously reported 1-arylnaphthalene lignan, was disclosed. Among these compounds, methyl 2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate dihydrochloride (36a) exhibited potent PDE5 inhibitory activity (IC(50) = 1.0 nM) with high isozyme selectivities (IC(50) ratio: PDE1/PDE5 = 1300, PDE2/PDE5 > 10 000, PDE3/PDE5 > 10 000, PDE4/PDE5 = 4700, PDE6/PDE5 = 28). Compound 36a also showed the most potent relaxant effect on isolated rabbit corpus cavernosum (EC(30) = 7.9 nM). Compound 63 (T-1032), the sulfate form of 36a, was selected for further biological and pharmacological evaluation of erectile dysfunction.
|
Inhibition of human phosphodiesterase 5
|
Homo sapiens
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : The next generation of phosphodiesterase inhibitors: structural clues to ligand and substrate selectivity of phosphodiesterases.
Year : 2005
Volume : 48
Issue : 10
First Page : 3449
Last Page : 3462
Authors : Manallack DT, Hughes RA, Thompson PE.
|
Inhibition of human phosphodiesterase 6
|
Homo sapiens
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : The next generation of phosphodiesterase inhibitors: structural clues to ligand and substrate selectivity of phosphodiesterases.
Year : 2005
Volume : 48
Issue : 10
First Page : 3449
Last Page : 3462
Authors : Manallack DT, Hughes RA, Thompson PE.
|
Inhibition of phosphodiesterase 5 in rat fetal lung fibroblast (RFL-6) cells
|
Rattus norvegicus
|
1.8
nM
|
|
Journal : J. Med. Chem.
Title : Pyrroloquinolone PDE5 inhibitors with improved pharmaceutical profiles for clinical studies on erectile dysfunction.
Year : 2005
Volume : 48
Issue : 6
First Page : 2126
Last Page : 2133
Authors : Jiang W, Guan J, Macielag MJ, Zhang S, Qiu Y, Kraft P, Bhattacharjee S, John TM, Haynes-Johnson D, Lundeen S, Sui Z.
Abstract : We previously reported a series of potent and selective pyrimidinyl pyrroloquinolone PDE5 inhibitors such as 2a for potential use in male erectile dysfunction (MED) (Sui, Z.; Guan, J.; Macielag, M. J.; Jiang, W.; Zhang, S.; Qiu, Y.; Kraft, P., Bhattacharjee, S.; John, T. M.; Craig, E.; Haynes-Johnson, D.; Clancy, J. J. Med. Chem. 2002, 45, 4094-4096). Unfortunately, the low aqueous solubility and poor oral bioavailability rendered them undesirable development candidates. To address this issue, we designed a series of analogues using two approaches: increasing the overall basicity and reducing molecular weight of the lead. Through earlier SAR studies, we discovered that the PDE5 potency of the pyrroloquinolones is insensitive to substitution on the pyrrole nitrogen. Basic functional groups such as pyridines and benzimidazoles were appended via the aromatic ring connected to the pyrrole nitrogen. Several truncated analogues were also designed and synthesized to improve oral absorption. These modifications allowed us to identify analogues with good oral bioavailability in rats, dogs, and monkeys while the high potency against PDE5 and desirable selectivity versus other PDE isozymes were maintained. Compounds R-11e and R-11l were selected as development candidates for MED and other indications.
|
Inhibition of bovine Phosphodiesterase 6 (n=2-3)
|
Bos taurus
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones as potent and selective PDE5 inhibitors.
Year : 2005
Volume : 15
Issue : 9
First Page : 2381
Last Page : 2384
Authors : Feixas J, Giovannoni MP, Vergelli C, Gavaldà A, Cesari N, Graziano A, Dal Piaz V.
Abstract : A series of potent PDE5 inhibitors with high selectivity versus PDE6 isoenzymes was identified.
|
Inhibition of human Phosphodiesterase 5 (n=2-3)
|
Homo sapiens
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones as potent and selective PDE5 inhibitors.
Year : 2005
Volume : 15
Issue : 9
First Page : 2381
Last Page : 2384
Authors : Feixas J, Giovannoni MP, Vergelli C, Gavaldà A, Cesari N, Graziano A, Dal Piaz V.
Abstract : A series of potent PDE5 inhibitors with high selectivity versus PDE6 isoenzymes was identified.
|
Inhibition of phosphodiesterase 1
|
None
|
400.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Comparison of different heterocyclic scaffolds as substrate analog PDE5 inhibitors.
Year : 2005
Volume : 15
Issue : 17
First Page : 3900
Last Page : 3907
Authors : Haning H, Niewöhner U, Schenke T, Lampe T, Hillisch A, Bischoff E.
Abstract : Several different heterocyclic systems were compared as PDE5 inhibitor scaffolds. In addition to the known 3H-imidazo[5,1-f][1,2,4]triazin-4-ones and pyrazolopyrimidinones, isomeric imidazo[1,5-a][1,3,5]triazin-4(3H)-ones were also shown to be potent and selective PDE inhibitor scaffolds with in vivo activity. SAR trends were elucidated for sulfonamide derivatives with generality across different scaffolds.
|
Inhibition of human phosphodiesterase 1
|
Homo sapiens
|
350.0
nM
|
|
Journal : J. Med. Chem.
Title : The next generation of phosphodiesterase inhibitors: structural clues to ligand and substrate selectivity of phosphodiesterases.
Year : 2005
Volume : 48
Issue : 10
First Page : 3449
Last Page : 3462
Authors : Manallack DT, Hughes RA, Thompson PE.
|
Inhibition of phosphodiesterase 5
|
None
|
6.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Comparison of different heterocyclic scaffolds as substrate analog PDE5 inhibitors.
Year : 2005
Volume : 15
Issue : 17
First Page : 3900
Last Page : 3907
Authors : Haning H, Niewöhner U, Schenke T, Lampe T, Hillisch A, Bischoff E.
Abstract : Several different heterocyclic systems were compared as PDE5 inhibitor scaffolds. In addition to the known 3H-imidazo[5,1-f][1,2,4]triazin-4-ones and pyrazolopyrimidinones, isomeric imidazo[1,5-a][1,3,5]triazin-4(3H)-ones were also shown to be potent and selective PDE inhibitor scaffolds with in vivo activity. SAR trends were elucidated for sulfonamide derivatives with generality across different scaffolds.
|
Inhibition of human phosphodiesterase 5
|
Homo sapiens
|
3.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of purine based PDE1/PDE5 inhibitors to a potent and selective PDE5 inhibitor for the treatment of male ED.
Year : 2005
Volume : 15
Issue : 9
First Page : 2365
Last Page : 2369
Authors : Boyle CD, Xu R, Asberom T, Chackalamannil S, Clader JW, Greenlee WJ, Guzik H, Hu Y, Hu Z, Lankin CM, Pissarnitski DA, Stamford AW, Wang Y, Skell J, Kurowski S, Vemulapalli S, Palamanda J, Chintala M, Wu P, Myers J, Wang P.
Abstract : In search of a PDE5 inhibitor for erectile dysfunction, an SAR was developed from a PDE1/PDE5 purine series of leads, which had modest PDE5 potency and poor isozyme selectivity. A compound (41) with PDE5 inhibition and in vivo activity similar to sildenafil was discovered from this effort. In addition, purine 41 demonstrated superior overall PDE isozyme selectivity when compared to the approved PDE5 inhibitors sildenafil, vardenafil, and tadalafil, which may result in a more favorable side-effect profile.
|
Inhibition of human phosphodiesterase 6
|
Homo sapiens
|
25.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of purine based PDE1/PDE5 inhibitors to a potent and selective PDE5 inhibitor for the treatment of male ED.
Year : 2005
Volume : 15
Issue : 9
First Page : 2365
Last Page : 2369
Authors : Boyle CD, Xu R, Asberom T, Chackalamannil S, Clader JW, Greenlee WJ, Guzik H, Hu Y, Hu Z, Lankin CM, Pissarnitski DA, Stamford AW, Wang Y, Skell J, Kurowski S, Vemulapalli S, Palamanda J, Chintala M, Wu P, Myers J, Wang P.
Abstract : In search of a PDE5 inhibitor for erectile dysfunction, an SAR was developed from a PDE1/PDE5 purine series of leads, which had modest PDE5 potency and poor isozyme selectivity. A compound (41) with PDE5 inhibition and in vivo activity similar to sildenafil was discovered from this effort. In addition, purine 41 demonstrated superior overall PDE isozyme selectivity when compared to the approved PDE5 inhibitors sildenafil, vardenafil, and tadalafil, which may result in a more favorable side-effect profile.
|
Inhibition of phosphodiesterase 1 isolated from bovine heart
|
Bos taurus
|
561.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and phosphodiesterase 5 inhibitory activity of novel pyrido[1,2-e]purin-4(3H)-one derivatives.
Year : 2005
Volume : 15
Issue : 11
First Page : 2790
Last Page : 2794
Authors : Xia G, Li J, Peng A, Lai S, Zhang S, Shen J, Liu Z, Chen X, Ji R.
Abstract : Synthesis and primary SAR of a novel series of 2-phenylpyrido[1,2-e]purin-4(3H)-one derivatives with piperazinyl sulfonamide substituents were described herein. As potential PDE5 inhibitors for erectile dysfunction (ED) treatment, representative compounds exhibit improved selectivity versus PDE1 and PDE6. Meanwhile, compound 3e demonstrated functional efficacy on rabbit corpus cavernosum strip in vitro.
|
Inhibition of phosphodiesterase 6 isolated from bovine retina
|
Bos taurus
|
25.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and phosphodiesterase 5 inhibitory activity of novel pyrido[1,2-e]purin-4(3H)-one derivatives.
Year : 2005
Volume : 15
Issue : 11
First Page : 2790
Last Page : 2794
Authors : Xia G, Li J, Peng A, Lai S, Zhang S, Shen J, Liu Z, Chen X, Ji R.
Abstract : Synthesis and primary SAR of a novel series of 2-phenylpyrido[1,2-e]purin-4(3H)-one derivatives with piperazinyl sulfonamide substituents were described herein. As potential PDE5 inhibitors for erectile dysfunction (ED) treatment, representative compounds exhibit improved selectivity versus PDE1 and PDE6. Meanwhile, compound 3e demonstrated functional efficacy on rabbit corpus cavernosum strip in vitro.
|
Inhibition of Phosphodiesterase 5
|
None
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Fused pyrimidine based inhibitors of phosphodiesterase 7 (PDE7): synthesis and initial structure-activity relationships.
Year : 2005
Volume : 15
Issue : 7
First Page : 1829
Last Page : 1833
Authors : Kempson J, Pitts WJ, Barbosa J, Guo J, Omotoso O, Watson A, Stebbins K, Starling GC, Dodd JH, Barrish JC, Felix R, Fischer K.
Abstract : A series of fused pyrimidine based inhibitors of PDE7 have been derived from an earlier screening lead 1. The synthesis, structure-activity relationships (SAR) and selectivity against several other PDE family members are described.
|
Inhibition of phosphodiesterase 5 isolated from human platelets
|
Homo sapiens
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and phosphodiesterase 5 inhibitory activity of novel pyrido[1,2-e]purin-4(3H)-one derivatives.
Year : 2005
Volume : 15
Issue : 11
First Page : 2790
Last Page : 2794
Authors : Xia G, Li J, Peng A, Lai S, Zhang S, Shen J, Liu Z, Chen X, Ji R.
Abstract : Synthesis and primary SAR of a novel series of 2-phenylpyrido[1,2-e]purin-4(3H)-one derivatives with piperazinyl sulfonamide substituents were described herein. As potential PDE5 inhibitors for erectile dysfunction (ED) treatment, representative compounds exhibit improved selectivity versus PDE1 and PDE6. Meanwhile, compound 3e demonstrated functional efficacy on rabbit corpus cavernosum strip in vitro.
|
Inhibition of human corpus cavernosum PDE5
|
Homo sapiens
|
3.5
nM
|
|
Journal : J. Med. Chem.
Title : A novel series of potent and selective PDE5 inhibitors with potential for high and dose-independent oral bioavailability.
Year : 2006
Volume : 49
Issue : 12
First Page : 3581
Last Page : 3594
Authors : Allerton CM, Barber CG, Beaumont KC, Brown DG, Cole SM, Ellis D, Lane CA, Maw GN, Mount NM, Rawson DJ, Robinson CM, Street SD, Summerhill NW.
Abstract : Sildenafil (5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one), a potent and selective phosphodiesterase type 5 (PDE5) inhibitor, provided the first oral treatment for male erectile dysfunction. The objective of the work reported in this paper was to combine high levels of PDE5 potency and selectivity with high and dose-independent oral bioavailability, to minimize the impact on the C(max) of any interactions with coadministered drugs in the clinic. This goal was achieved through identification of a lower clearance series with a high absorption profile, by replacing the 5'-piperazine sulfonamide in the sildenafil template with a 5'-methyl ketone. This novel series provided compounds with low metabolism in human hepatocytes, excellent caco-2 flux, and the potential for good aqueous solubility. The in vivo oral and iv pharmacokinetic profiles of example compounds confirmed the high oral bioavailability predicted from these in vitro screens. 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2) was selected for progression into the clinic.
|
Inhibition of bovine cone PDE6
|
Bos taurus
|
33.0
nM
|
|
Journal : J. Med. Chem.
Title : A novel series of potent and selective PDE5 inhibitors with potential for high and dose-independent oral bioavailability.
Year : 2006
Volume : 49
Issue : 12
First Page : 3581
Last Page : 3594
Authors : Allerton CM, Barber CG, Beaumont KC, Brown DG, Cole SM, Ellis D, Lane CA, Maw GN, Mount NM, Rawson DJ, Robinson CM, Street SD, Summerhill NW.
Abstract : Sildenafil (5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one), a potent and selective phosphodiesterase type 5 (PDE5) inhibitor, provided the first oral treatment for male erectile dysfunction. The objective of the work reported in this paper was to combine high levels of PDE5 potency and selectivity with high and dose-independent oral bioavailability, to minimize the impact on the C(max) of any interactions with coadministered drugs in the clinic. This goal was achieved through identification of a lower clearance series with a high absorption profile, by replacing the 5'-piperazine sulfonamide in the sildenafil template with a 5'-methyl ketone. This novel series provided compounds with low metabolism in human hepatocytes, excellent caco-2 flux, and the potential for good aqueous solubility. The in vivo oral and iv pharmacokinetic profiles of example compounds confirmed the high oral bioavailability predicted from these in vitro screens. 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2) was selected for progression into the clinic.
|
Inhibition of PDE5
|
Homo sapiens
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel pyrazolopyrimidopyridazinones with potent and selective phosphodiesterase 5 (PDE5) inhibitory activity as potential agents for treatment of erectile dysfunction.
Year : 2006
Volume : 49
Issue : 17
First Page : 5363
Last Page : 5371
Authors : Giovannoni MP, Vergelli C, Biancalani C, Cesari N, Graziano A, Biagini P, Gracia J, Gavaldà A, Dal Piaz V.
Abstract : Pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones and their analogues, potentially useful for the treatment of erectile dysfunction, were synthesized and evaluated as inhibitors of phosphodiesterase 5 (PDE5). Several compounds showed IC50 values in the low nanomolar range, and in particular, compound 5r, displaying high potency toward PDE5 (IC50 = 8.3 nM) and high selectivity versus PDE6 (240-fold) appeared to be a very promising new lead both in comparison with the potent but not selective sildenafil and in comparison with some analogues previously reported by us. SAR studies in this triheterocyclic scaffold led us to conclude that the best arranged groups are a methyl in position 1, a benzyl in position 3, a phenyl in position 9, and a linear four-carbon chain in position 6.
|
Inhibition of PDE6
|
Homo sapiens
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel pyrazolopyrimidopyridazinones with potent and selective phosphodiesterase 5 (PDE5) inhibitory activity as potential agents for treatment of erectile dysfunction.
Year : 2006
Volume : 49
Issue : 17
First Page : 5363
Last Page : 5371
Authors : Giovannoni MP, Vergelli C, Biancalani C, Cesari N, Graziano A, Biagini P, Gracia J, Gavaldà A, Dal Piaz V.
Abstract : Pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones and their analogues, potentially useful for the treatment of erectile dysfunction, were synthesized and evaluated as inhibitors of phosphodiesterase 5 (PDE5). Several compounds showed IC50 values in the low nanomolar range, and in particular, compound 5r, displaying high potency toward PDE5 (IC50 = 8.3 nM) and high selectivity versus PDE6 (240-fold) appeared to be a very promising new lead both in comparison with the potent but not selective sildenafil and in comparison with some analogues previously reported by us. SAR studies in this triheterocyclic scaffold led us to conclude that the best arranged groups are a methyl in position 1, a benzyl in position 3, a phenyl in position 9, and a linear four-carbon chain in position 6.
|
Inhibition of human recombinant PDE5A1 expressed in COS7 cells
|
Homo sapiens
|
75.0
nM
|
|
Journal : J. Nat. Prod.
Title : Potent inhibition of human phosphodiesterase-5 by icariin derivatives.
Year : 2008
Volume : 71
Issue : 9
First Page : 1513
Last Page : 1517
Authors : Dell'Agli M, Galli GV, Dal Cero E, Belluti F, Matera R, Zironi E, Pagliuca G, Bosisio E.
Abstract : Plant extracts traditionally used for male impotence (Tribulus terrestris, Ferula hermonis, Epimedium brevicornum, Cinnamomum cassia), and the individual compounds cinnamaldehyde, ferutinin, and icariin, were screened against phosphodiesterase-5A1 (PDE5A1) activity. Human recombinant PDE5A1 was used as the enzyme source. Only E. brevicornum extract (80% inhibition at 50 microg/mL) and its active principle icariin (1) (IC50 5.9 microM) were active. To improve its inhibitory activity, 1 was subjected to various structural modifications. Thus, 3,7-bis(2-hydroxyethyl)icaritin (5), where both sugars in 1 were replaced with hydroxyethyl residues, potently inhibited PDE5A1 with an IC50 very close to that of sildenafil (IC50 75 vs 74 nM). Thus, 5 was 80 times more potent than 1, and its selectivity versus phosphodiesterase-6 (PDE6) and cyclic adenosine monophosphate-phosphodiesterase (cAMP-PDE) was much higher in comparison with sildenafil. The improved pharmacodynamic profile and lack of cytotoxicity on human fibroblasts make compound 5 a promising candidate for further development.
|
Inhibition of human PDE6C
|
Homo sapiens
|
160.0
nM
|
|
Journal : J. Nat. Prod.
Title : Potent inhibition of human phosphodiesterase-5 by icariin derivatives.
Year : 2008
Volume : 71
Issue : 9
First Page : 1513
Last Page : 1517
Authors : Dell'Agli M, Galli GV, Dal Cero E, Belluti F, Matera R, Zironi E, Pagliuca G, Bosisio E.
Abstract : Plant extracts traditionally used for male impotence (Tribulus terrestris, Ferula hermonis, Epimedium brevicornum, Cinnamomum cassia), and the individual compounds cinnamaldehyde, ferutinin, and icariin, were screened against phosphodiesterase-5A1 (PDE5A1) activity. Human recombinant PDE5A1 was used as the enzyme source. Only E. brevicornum extract (80% inhibition at 50 microg/mL) and its active principle icariin (1) (IC50 5.9 microM) were active. To improve its inhibitory activity, 1 was subjected to various structural modifications. Thus, 3,7-bis(2-hydroxyethyl)icaritin (5), where both sugars in 1 were replaced with hydroxyethyl residues, potently inhibited PDE5A1 with an IC50 very close to that of sildenafil (IC50 75 vs 74 nM). Thus, 5 was 80 times more potent than 1, and its selectivity versus phosphodiesterase-6 (PDE6) and cyclic adenosine monophosphate-phosphodiesterase (cAMP-PDE) was much higher in comparison with sildenafil. The improved pharmacodynamic profile and lack of cytotoxicity on human fibroblasts make compound 5 a promising candidate for further development.
|
Inhibition of PDE5
|
None
|
6.607
nM
|
|
Inhibition of PDE5
|
None
|
3.631
nM
|
|
Journal : Bioorg. Med. Chem.
Title : In silico prediction of novel phosphodiesterase type-5 inhibitors derived from Sildenafil, Vardenafil and Tadalafil.
Year : 2008
Volume : 16
Issue : 16
First Page : 7599
Last Page : 7606
Authors : Antunes JE, Freitas MP, da Cunha EF, Ramalho TC, Rittner R.
Abstract : A series of drug-like compounds derived from Sildenafil, Vardenafil and Tadalafil analogues were modelled through the MIA-QSAR (multivariate image analysis applied to quantitative structure-activity relationships) ligand-based approach. A highly predictive model was achieved and novel compounds, miscellany of substructures of these three representative phosphodiesterase type-5 (PDE-5) inhibitors were predicted using the calibration parameters obtained through partial least squares (PLS) regression. The high bioactivities of eight promising compounds were corroborated by docking evaluation. Calculated ADME-Tox (absorption, distribution, metabolism, excretion and toxicity) profiles for such compounds suggest advantages of some of them over the currently available, most common drugs used for the treatment of erectile dysfunction.
|
Inhibition of PDE5 in human platelets after 5 mins by LC-MS/MS analysis
|
Homo sapiens
|
53.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological evaluations of sildenafil analogues for treatment of erectile dysfunction.
Year : 2008
Volume : 51
Issue : 9
First Page : 2807
Last Page : 2815
Authors : Flores Toque HA, Priviero FB, Teixeira CE, Perissutti E, Fiorino F, Severino B, Frecentese F, Lorenzetti R, Baracat JS, Santagada V, Caliendo G, Antunes E, De Nucci G.
Abstract : The 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one, sildenafil, is a cGMP-specific phosphodiesterase-5 (PDE5) inhibitor used for penile erectile dysfunction. In the search for more potent and selective PDE5 inhibitors, new sildenafil analogues (6a-v), characterized by the presence on the sulfonyl group in the 5' position of novel N-4-substituted piperazines or ethylenediamine moiety, were prepared by traditional and microwave-assisted synthesis and tested in rabbit isolated aorta and corpus cavernosum. Similarly to sildenafil, several analogues showed IC50 values in the nanomolar range. In the in vitro studies, all the tested compounds caused concentration-dependent relaxations in both rabbit isolated aorta and corpus cavernosum. All sildenafil analogues potentiated the nitric oxide-dependent vasodilation in endothelium-intact rabbit aorta. Compound 6f exhibited great pEC50 value in corpus cavernosum, and compounds 6r and 6u in isolated aorta were found as potent as sildenafil for inhibiting PDE5. Because several analogues were significantly more lipophilic than sildenafil, these compounds may offer a new lead for development of new sildenafil analogues.
|
Inhibition of phenylephrine-induced contraction of smooth muscles in New Zealand white rabbit corpus cavernosum
|
Oryctolagus cuniculus
|
169.82
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological evaluations of sildenafil analogues for treatment of erectile dysfunction.
Year : 2008
Volume : 51
Issue : 9
First Page : 2807
Last Page : 2815
Authors : Flores Toque HA, Priviero FB, Teixeira CE, Perissutti E, Fiorino F, Severino B, Frecentese F, Lorenzetti R, Baracat JS, Santagada V, Caliendo G, Antunes E, De Nucci G.
Abstract : The 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one, sildenafil, is a cGMP-specific phosphodiesterase-5 (PDE5) inhibitor used for penile erectile dysfunction. In the search for more potent and selective PDE5 inhibitors, new sildenafil analogues (6a-v), characterized by the presence on the sulfonyl group in the 5' position of novel N-4-substituted piperazines or ethylenediamine moiety, were prepared by traditional and microwave-assisted synthesis and tested in rabbit isolated aorta and corpus cavernosum. Similarly to sildenafil, several analogues showed IC50 values in the nanomolar range. In the in vitro studies, all the tested compounds caused concentration-dependent relaxations in both rabbit isolated aorta and corpus cavernosum. All sildenafil analogues potentiated the nitric oxide-dependent vasodilation in endothelium-intact rabbit aorta. Compound 6f exhibited great pEC50 value in corpus cavernosum, and compounds 6r and 6u in isolated aorta were found as potent as sildenafil for inhibiting PDE5. Because several analogues were significantly more lipophilic than sildenafil, these compounds may offer a new lead for development of new sildenafil analogues.
|
Inhibition of phenylephrine-induced contraction of smooth muscles in New Zealand white rabbit endothelium-intact aorta
|
Oryctolagus cuniculus
|
56.23
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological evaluations of sildenafil analogues for treatment of erectile dysfunction.
Year : 2008
Volume : 51
Issue : 9
First Page : 2807
Last Page : 2815
Authors : Flores Toque HA, Priviero FB, Teixeira CE, Perissutti E, Fiorino F, Severino B, Frecentese F, Lorenzetti R, Baracat JS, Santagada V, Caliendo G, Antunes E, De Nucci G.
Abstract : The 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one, sildenafil, is a cGMP-specific phosphodiesterase-5 (PDE5) inhibitor used for penile erectile dysfunction. In the search for more potent and selective PDE5 inhibitors, new sildenafil analogues (6a-v), characterized by the presence on the sulfonyl group in the 5' position of novel N-4-substituted piperazines or ethylenediamine moiety, were prepared by traditional and microwave-assisted synthesis and tested in rabbit isolated aorta and corpus cavernosum. Similarly to sildenafil, several analogues showed IC50 values in the nanomolar range. In the in vitro studies, all the tested compounds caused concentration-dependent relaxations in both rabbit isolated aorta and corpus cavernosum. All sildenafil analogues potentiated the nitric oxide-dependent vasodilation in endothelium-intact rabbit aorta. Compound 6f exhibited great pEC50 value in corpus cavernosum, and compounds 6r and 6u in isolated aorta were found as potent as sildenafil for inhibiting PDE5. Because several analogues were significantly more lipophilic than sildenafil, these compounds may offer a new lead for development of new sildenafil analogues.
|
Inhibition of phenylephrine-induced contraction of smooth muscles in New Zealand white rabbit denuded aorta
|
Oryctolagus cuniculus
|
269.15
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and pharmacological evaluations of sildenafil analogues for treatment of erectile dysfunction.
Year : 2008
Volume : 51
Issue : 9
First Page : 2807
Last Page : 2815
Authors : Flores Toque HA, Priviero FB, Teixeira CE, Perissutti E, Fiorino F, Severino B, Frecentese F, Lorenzetti R, Baracat JS, Santagada V, Caliendo G, Antunes E, De Nucci G.
Abstract : The 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one, sildenafil, is a cGMP-specific phosphodiesterase-5 (PDE5) inhibitor used for penile erectile dysfunction. In the search for more potent and selective PDE5 inhibitors, new sildenafil analogues (6a-v), characterized by the presence on the sulfonyl group in the 5' position of novel N-4-substituted piperazines or ethylenediamine moiety, were prepared by traditional and microwave-assisted synthesis and tested in rabbit isolated aorta and corpus cavernosum. Similarly to sildenafil, several analogues showed IC50 values in the nanomolar range. In the in vitro studies, all the tested compounds caused concentration-dependent relaxations in both rabbit isolated aorta and corpus cavernosum. All sildenafil analogues potentiated the nitric oxide-dependent vasodilation in endothelium-intact rabbit aorta. Compound 6f exhibited great pEC50 value in corpus cavernosum, and compounds 6r and 6u in isolated aorta were found as potent as sildenafil for inhibiting PDE5. Because several analogues were significantly more lipophilic than sildenafil, these compounds may offer a new lead for development of new sildenafil analogues.
|
Inhibition of human corpus cavernosum PDE5 by scintillation proximity assay
|
Homo sapiens
|
3.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Highly potent and selective chiral inhibitors of PDE5: an illustration of Pfeiffer's rule.
Year : 2008
Volume : 18
Issue : 23
First Page : 6033
Last Page : 6036
Authors : Bunnage ME, Mathias JP, Wood A, Miller D, Street SD.
Abstract : A series of potent chiral PDE5 inhibitors are described that are based on the sildenafil architecture but exhibit much greater selectivity over PDE6. Eudismic analysis of the SAR in this series provided a clear illustration of Pfeiffer's rule and indicated that the chiral motif was involved in a highly-stereoselective interaction with PDE5. This PDE5 specificity translated to levels of selectivity over PDE6 that were hitherto unprecedented in the sildenafil scaffold. UK-371,800 (compound 8) was identified as a development candidate from this series that married sildenafil-like molecular properties with high selectivity over PDE6. Clinical data confirm that UK-371,800 has markedly superior human pharmacokinetics to a previously-described higher molecular weight achiral analogue in this template (compound 1).
|
Inhibition of bovine PDE5
|
Bos taurus
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Quinazolines as potent and highly selective PDE5 inhibitors as potential therapeutics for male erectile dysfunction.
Year : 2008
Volume : 18
Issue : 23
First Page : 6279
Last Page : 6282
Authors : Kim YH, Choi H, Lee J, Hwang IC, Moon SK, Kim SJ, Lee HW, Im DS, Lee SS, Ahn SK, Kim SW, Han CK, Yoon JH, Lee KJ, Choi NS.
Abstract : In an effort to minimize side effects associated with low selectivity against PDE isozymes, we have successfully identified a series of 6,7,8-substituted quinzaolines as potent inhibitors of PDE5 with high level of isozyme selectivity, especially against PDE6 and PDE11. PDE5 potency and isozyme selectivity of quinazolines were greatly improved with substitutions both at 6- and 8-position. The synthesis, structure-activity relationships and in vivo efficacy of this novel series of potent PDE5 inhibitors are described.
|
Inhibition of bovine PDE6
|
Bos taurus
|
140.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Quinazolines as potent and highly selective PDE5 inhibitors as potential therapeutics for male erectile dysfunction.
Year : 2008
Volume : 18
Issue : 23
First Page : 6279
Last Page : 6282
Authors : Kim YH, Choi H, Lee J, Hwang IC, Moon SK, Kim SJ, Lee HW, Im DS, Lee SS, Ahn SK, Kim SW, Han CK, Yoon JH, Lee KJ, Choi NS.
Abstract : In an effort to minimize side effects associated with low selectivity against PDE isozymes, we have successfully identified a series of 6,7,8-substituted quinzaolines as potent inhibitors of PDE5 with high level of isozyme selectivity, especially against PDE6 and PDE11. PDE5 potency and isozyme selectivity of quinazolines were greatly improved with substitutions both at 6- and 8-position. The synthesis, structure-activity relationships and in vivo efficacy of this novel series of potent PDE5 inhibitors are described.
|
Inhibition of rabbit platelet PDE5 by scintillation proximity assay
|
Oryctolagus cuniculus
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Phenylquinazolin-4(3H)-one, a class of potent PDE5 inhibitors with high selectivity versus PDE6.
Year : 2009
Volume : 19
Issue : 10
First Page : 2777
Last Page : 2779
Authors : Duan H, Zheng J, Lai Q, Liu Z, Tian G, Wang Z, Li J, Shen J.
Abstract : In our efforts to minimize the side effects associated with low selectivity against the other PDE isozymes, a novel class of 2-phenylquinazolin-4(3H)-one derivatives were designed and prepared as potent PDE5 inhibitors with high selectivity against PDE6. The syntheses and SAR studies of such molecules were reported.
|
Inhibition of bovine retina PDE6 by scintillation proximity assay
|
Bos taurus
|
30.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Phenylquinazolin-4(3H)-one, a class of potent PDE5 inhibitors with high selectivity versus PDE6.
Year : 2009
Volume : 19
Issue : 10
First Page : 2777
Last Page : 2779
Authors : Duan H, Zheng J, Lai Q, Liu Z, Tian G, Wang Z, Li J, Shen J.
Abstract : In our efforts to minimize the side effects associated with low selectivity against the other PDE isozymes, a novel class of 2-phenylquinazolin-4(3H)-one derivatives were designed and prepared as potent PDE5 inhibitors with high selectivity against PDE6. The syntheses and SAR studies of such molecules were reported.
|
Selectivity ratio of IC50 for bovine retina PDE6 to IC50 for rabbit platelet PDE5
|
None
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Phenylquinazolin-4(3H)-one, a class of potent PDE5 inhibitors with high selectivity versus PDE6.
Year : 2009
Volume : 19
Issue : 10
First Page : 2777
Last Page : 2779
Authors : Duan H, Zheng J, Lai Q, Liu Z, Tian G, Wang Z, Li J, Shen J.
Abstract : In our efforts to minimize the side effects associated with low selectivity against the other PDE isozymes, a novel class of 2-phenylquinazolin-4(3H)-one derivatives were designed and prepared as potent PDE5 inhibitors with high selectivity against PDE6. The syntheses and SAR studies of such molecules were reported.
|
Inhibition of PDE5
|
None
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Phenylquinazolin-4(3H)-one, a class of potent PDE5 inhibitors with high selectivity versus PDE6.
Year : 2009
Volume : 19
Issue : 10
First Page : 2777
Last Page : 2779
Authors : Duan H, Zheng J, Lai Q, Liu Z, Tian G, Wang Z, Li J, Shen J.
Abstract : In our efforts to minimize the side effects associated with low selectivity against the other PDE isozymes, a novel class of 2-phenylquinazolin-4(3H)-one derivatives were designed and prepared as potent PDE5 inhibitors with high selectivity against PDE6. The syntheses and SAR studies of such molecules were reported.
|
Inhibition of bovine retina PDE6
|
Bos taurus
|
140.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of potent, selective, and orally bioavailable PDE5 inhibitor: Methyl-4-(3-chloro-4-methoxybenzylamino)-8-(2-hydroxyethyl)-7-methoxyquinazolin-6-ylmethylcarbamate (CKD 533).
Year : 2010
Volume : 20
Issue : 1
First Page : 383
Last Page : 386
Authors : Choi H, Lee J, Kim YH, Im DS, Hwang IC, Kim SJ, Moon SK, Lee HW, Lee SS, Ahn SK, Kim SW, Choi NS, Lee KJ.
Abstract : In a continuing effort to discover novel PDE5 inhibitors, we have successfully found quinazolines with 4-benzylamino substitution as potent and selective PDE5 inhibitors. Initial lead compound (1) was found to be easily metabolized when incubated with human liver microsomes mainly through C6 amide hydrolysis. Blocking of this metabolic hot spot led to discovery of 10 (CKD533) which is highly potent, selective and orally efficacious in conscious rabbit model for erectile dysfunction and now is undergoing preclinical toxicology study.
|
Inhibition of bovine platelet PDE5
|
Bos taurus
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of potent, selective, and orally bioavailable PDE5 inhibitor: Methyl-4-(3-chloro-4-methoxybenzylamino)-8-(2-hydroxyethyl)-7-methoxyquinazolin-6-ylmethylcarbamate (CKD 533).
Year : 2010
Volume : 20
Issue : 1
First Page : 383
Last Page : 386
Authors : Choi H, Lee J, Kim YH, Im DS, Hwang IC, Kim SJ, Moon SK, Lee HW, Lee SS, Ahn SK, Kim SW, Choi NS, Lee KJ.
Abstract : In a continuing effort to discover novel PDE5 inhibitors, we have successfully found quinazolines with 4-benzylamino substitution as potent and selective PDE5 inhibitors. Initial lead compound (1) was found to be easily metabolized when incubated with human liver microsomes mainly through C6 amide hydrolysis. Blocking of this metabolic hot spot led to discovery of 10 (CKD533) which is highly potent, selective and orally efficacious in conscious rabbit model for erectile dysfunction and now is undergoing preclinical toxicology study.
|
Inhibition of PDE5
|
None
|
3.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1-(2-(2,2,2-trifluoroethoxy)ethyl-1H-pyrazolo[4,3-d]pyrimidines as potent phosphodiesterase 5 (PDE5) inhibitors.
Year : 2010
Volume : 20
Issue : 10
First Page : 3125
Last Page : 3128
Authors : Tollefson MB, Acker BA, Jacobsen EJ, Hughes RO, Walker JK, Fox DN, Palmer MJ, Freeman SK, Yu Y, Bond BR.
Abstract : 1H-Pyrazolo[4,3-d]pyrimidines were previously disclosed as a potent second generation class of phosphodiesterase 5 (PDE5) inhibitors. This work explores the advancement of more selective and potent PDE5 inhibitors resulting from the substitution of 2-(2,2,2-trifluoroethoxy)ethyl at the 1 position in the so-called alkoxy pocket.
|
Inhibition of PDE6
|
None
|
30.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1-(2-(2,2,2-trifluoroethoxy)ethyl-1H-pyrazolo[4,3-d]pyrimidines as potent phosphodiesterase 5 (PDE5) inhibitors.
Year : 2010
Volume : 20
Issue : 10
First Page : 3125
Last Page : 3128
Authors : Tollefson MB, Acker BA, Jacobsen EJ, Hughes RO, Walker JK, Fox DN, Palmer MJ, Freeman SK, Yu Y, Bond BR.
Abstract : 1H-Pyrazolo[4,3-d]pyrimidines were previously disclosed as a potent second generation class of phosphodiesterase 5 (PDE5) inhibitors. This work explores the advancement of more selective and potent PDE5 inhibitors resulting from the substitution of 2-(2,2,2-trifluoroethoxy)ethyl at the 1 position in the so-called alkoxy pocket.
|
DRUGMATRIX: Phosphodiesterase PDE5 enzyme inhibition (substrate: [3H]cGMP + cGMP)
|
Homo sapiens
|
4.577
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Adenosine A1 radioligand binding (ligand: DPCPX)
|
None
|
871.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Adenosine A2A radioligand binding (ligand: AB-MECA)
|
None
|
253.0
nM
|
|
DRUGMATRIX: Adenosine A2A radioligand binding (ligand: AB-MECA)
|
None
|
142.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Alpha-1B adrenergic receptor radioligand binding (ligand: prazosin)
|
Rattus norvegicus
|
806.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Inhibition of rabbit platelet PDE5 using [3H]cGMP as substrate after 30 mins by scintillation proximity assay
|
Oryctolagus cuniculus
|
3.3
nM
|
|
Journal : J. Med. Chem.
Title : Utilization of halogen bond in lead optimization: a case study of rational design of potent phosphodiesterase type 5 (PDE5) inhibitors.
Year : 2011
Volume : 54
Issue : 15
First Page : 5607
Last Page : 5611
Authors : Xu Z, Liu Z, Chen T, Chen T, Wang Z, Tian G, Shi J, Wang X, Lu Y, Yan X, Wang G, Jiang H, Chen K, Wang S, Xu Y, Shen J, Zhu W.
Abstract : For proof-of-concept of halogen bonding in drug design, a series of halogenated compounds were designed based on a lead structure as new inhibitors of phosphodiesterase type 5. Bioassay results revealed a good correlation between the measured bioactivity and the calculated halogen bond energy. Our X-ray crystal structures verified the existence of the predicted halogen bonds, demonstrating that the halogen bond is an applicable tool in drug design and should be routinely considered in lead optimization.
|
Inhibition of Trypanosoma brucei PDEB1 at 100 uM
|
Trypanosoma brucei
|
51.5
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. Part 1. Sildenafil analogs.
Year : 2012
Volume : 22
Issue : 7
First Page : 2579
Last Page : 2581
Authors : Wang C, Ashton TD, Gustafson A, Bland ND, Ochiana SO, Campbell RK, Pollastri MP.
Abstract : Parasitic diseases, such as African sleeping sickness, have a significant impact on the health and well-being in the poorest regions of the world. Pragmatic drug discovery efforts are needed to find new therapeutic agents. In this Letter we describe target repurposing efforts focused on trypanosomal phosphodiesterases. We outline the synthesis and biological evaluation of analogs of sildenafil (1), a human PDE5 inhibitor, for activities against trypanosomal PDEB1 (TbrPDEB1). We find that, while low potency analogs can be prepared, this chemical class is a sub-optimal starting point for further development of TbrPDE inhibitors.
|
Inhibition of bovine platelet PDE5
|
Bos taurus
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of chalcones as potent and selective PDE5A1 inhibitors.
Year : 2012
Volume : 22
Issue : 12
First Page : 3983
Last Page : 3987
Authors : Nam KY, Choi NS, Han CK, Ahn SK.
Abstract : Chalcones have an affinity for many receptors, enzymes, and transcription factors as flavonoid analogues. Their most studied pharmacological action is that of vasodilatation due to inhibition of phosphodiesterase 5A1 (PDE5A1). To this end, we have established a recursive partitioning model with 3 chemical descriptors for the prediction of compounds that can inhibit PDE5A1. This model was able to predict active compounds with an accuracy of 82.8%. Compound 4 was found to be a potent and selective inhibitor, with a relatively low IC(50) value. The binding mechanism of this compound was also investigated through molecular docking studies.
|
Inhibition of rabbit corpus cavernosum PDE6
|
Oryctolagus cuniculus
|
100.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of chalcones as potent and selective PDE5A1 inhibitors.
Year : 2012
Volume : 22
Issue : 12
First Page : 3983
Last Page : 3987
Authors : Nam KY, Choi NS, Han CK, Ahn SK.
Abstract : Chalcones have an affinity for many receptors, enzymes, and transcription factors as flavonoid analogues. Their most studied pharmacological action is that of vasodilatation due to inhibition of phosphodiesterase 5A1 (PDE5A1). To this end, we have established a recursive partitioning model with 3 chemical descriptors for the prediction of compounds that can inhibit PDE5A1. This model was able to predict active compounds with an accuracy of 82.8%. Compound 4 was found to be a potent and selective inhibitor, with a relatively low IC(50) value. The binding mechanism of this compound was also investigated through molecular docking studies.
|
Inhibition of ABCC5 in human erythrocytes assessed as inhibition of ATP-mediated [3H]cGMP uptake in inside-out vesicles at 32 uM after 60 mins by liquid scintillation counting
|
Homo sapiens
|
85.0
%
|
|
Journal : J. Med. Chem.
Title : Novel cGMP efflux inhibitors identified by virtual ligand screening (VLS) and confirmed by experimental studies.
Year : 2012
Volume : 55
Issue : 7
First Page : 3049
Last Page : 3057
Authors : Sager G, Ørvoll EØ, Lysaa RA, Kufareva I, Abagyan R, Ravna AW.
Abstract : Elevated intracellular levels of cyclic guanosine monophosphate (cGMP) may induce apoptosis, and at least some cancer cells seem to escape this effect by increased efflux of cGMP, as clinical studies have shown that extracellular cGMP levels are elevated in various types of cancer. The human ATP binding cassette (ABC) transporter ABCC5 transports cGMP out of cells, and inhibition of ABCC5 may have cytotoxic effects. Sildenafil inhibits cGMP efflux by binding to ABCC5, and in order to search for potential novel ABCC5 inhibitors, we have identified sildenafil derivates using structural and computational guidance and tested them for the cGMP efflux effect. Eleven compounds from virtual ligand screening (VLS) were tested in vitro, using inside-out vesicles (IOV), for inhibition of cGMP efflux. Seven of 11 compounds predicted by VLS to bind to ABCC5 were more potent than sildenafil, and the two most potent showed K(i) of 50-100 nM.
|
Displacement of [3H]ZM241385 from human AA2AR expressed in HEK293T cells after 2 hrs by liquid scintillation counter
|
Homo sapiens
|
199.53
nM
|
|
Journal : J. Med. Chem.
Title : A prospective cross-screening study on G-protein-coupled receptors: lessons learned in virtual compound library design.
Year : 2012
Volume : 55
Issue : 11
First Page : 5311
Last Page : 5325
Authors : Sanders MP, Roumen L, van der Horst E, Lane JR, Vischer HF, van Offenbeek J, de Vries H, Verhoeven S, Chow KY, Verkaar F, Beukers MW, McGuire R, Leurs R, Ijzerman AP, de Vlieg J, de Esch IJ, Zaman GJ, Klomp JP, Bender A, de Graaf C.
Abstract : We present the systematic prospective evaluation of a protein-based and a ligand-based virtual screening platform against a set of three G-protein-coupled receptors (GPCRs): the β-2 adrenoreceptor (ADRB2), the adenosine A(2A) receptor (AA2AR), and the sphingosine 1-phosphate receptor (S1PR1). Novel bioactive compounds were identified using a consensus scoring procedure combining ligand-based (frequent substructure ranking) and structure-based (Snooker) tools, and all 900 selected compounds were screened against all three receptors. A striking number of ligands showed affinity/activity for GPCRs other than the intended target, which could be partly attributed to the fuzziness and overlap of protein-based pharmacophore models. Surprisingly, the phosphodiesterase 5 (PDE5) inhibitor sildenafil was found to possess submicromolar affinity for AA2AR. Overall, this is one of the first published prospective chemogenomics studies that demonstrate the identification of novel cross-pharmacology between unrelated protein targets. The lessons learned from this study can be used to guide future virtual ligand design efforts.
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
22.2
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
30.8
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
45.9
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human recombinant PDE6C at 1 uM by [3H]cGMP based tritium scintillation proximity assay
|
Homo sapiens
|
39.2
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and pharmacological evaluation of monocyclic pyrimidinones as novel inhibitors of PDE5.
Year : 2012
Volume : 55
Issue : 23
First Page : 10540
Last Page : 10550
Authors : Wang G, Liu Z, Chen T, Wang Z, Yang H, Zheng M, Ren J, Tian G, Yang X, Li L, Li J, Suo J, Zhang R, Jiang X, Terrett NK, Shen J, Xu Y, Jiang H.
Abstract : Cyclic nucleotide phosphodiesterase type 5 (PDE5) is a prime drug target for treating the diseases associated with a lower level of the cyclic guanosine monophosphate (cGMP), which is a specific substrate for PDE5 hydrolysis. Here we report a series of novel PDE5 inhibitors with the new scaffold of the monocyclic pyrimidin-4(3H)-one ring developed using the structure-based discovery strategy. In total, 37 derivatives of the pyrimidin-4(3H)-ones, were designed, synthesized, and evaluated for their inhibitory activities to PDE5, resulting in 25 compounds with IC50 ranging from 1 to 100 nM and 11 compounds with IC50 ranging from 1 to 10 nM. Compound 5, 5,6-diethyl-2-[2-n-propoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]pyrimid-4(3H)-one, the most potent compound, has an excellent IC50 (1.6 nM) in vitro and a good efficacy in a rat model of erection. It thus provides a potential candidate for the further development into a new drug targeting PDE5.
|
Inhibition of rat brain PDE1 by [3H]cGMP based tritium scintillation proximity assay
|
Rattus norvegicus
|
230.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and pharmacological evaluation of monocyclic pyrimidinones as novel inhibitors of PDE5.
Year : 2012
Volume : 55
Issue : 23
First Page : 10540
Last Page : 10550
Authors : Wang G, Liu Z, Chen T, Wang Z, Yang H, Zheng M, Ren J, Tian G, Yang X, Li L, Li J, Suo J, Zhang R, Jiang X, Terrett NK, Shen J, Xu Y, Jiang H.
Abstract : Cyclic nucleotide phosphodiesterase type 5 (PDE5) is a prime drug target for treating the diseases associated with a lower level of the cyclic guanosine monophosphate (cGMP), which is a specific substrate for PDE5 hydrolysis. Here we report a series of novel PDE5 inhibitors with the new scaffold of the monocyclic pyrimidin-4(3H)-one ring developed using the structure-based discovery strategy. In total, 37 derivatives of the pyrimidin-4(3H)-ones, were designed, synthesized, and evaluated for their inhibitory activities to PDE5, resulting in 25 compounds with IC50 ranging from 1 to 100 nM and 11 compounds with IC50 ranging from 1 to 10 nM. Compound 5, 5,6-diethyl-2-[2-n-propoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]pyrimid-4(3H)-one, the most potent compound, has an excellent IC50 (1.6 nM) in vitro and a good efficacy in a rat model of erection. It thus provides a potential candidate for the further development into a new drug targeting PDE5.
|
Inhibition of human recombinant PDE5A by [3H]cGMP based tritium scintillation proximity assay
|
Homo sapiens
|
3.9
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and pharmacological evaluation of monocyclic pyrimidinones as novel inhibitors of PDE5.
Year : 2012
Volume : 55
Issue : 23
First Page : 10540
Last Page : 10550
Authors : Wang G, Liu Z, Chen T, Wang Z, Yang H, Zheng M, Ren J, Tian G, Yang X, Li L, Li J, Suo J, Zhang R, Jiang X, Terrett NK, Shen J, Xu Y, Jiang H.
Abstract : Cyclic nucleotide phosphodiesterase type 5 (PDE5) is a prime drug target for treating the diseases associated with a lower level of the cyclic guanosine monophosphate (cGMP), which is a specific substrate for PDE5 hydrolysis. Here we report a series of novel PDE5 inhibitors with the new scaffold of the monocyclic pyrimidin-4(3H)-one ring developed using the structure-based discovery strategy. In total, 37 derivatives of the pyrimidin-4(3H)-ones, were designed, synthesized, and evaluated for their inhibitory activities to PDE5, resulting in 25 compounds with IC50 ranging from 1 to 100 nM and 11 compounds with IC50 ranging from 1 to 10 nM. Compound 5, 5,6-diethyl-2-[2-n-propoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]pyrimid-4(3H)-one, the most potent compound, has an excellent IC50 (1.6 nM) in vitro and a good efficacy in a rat model of erection. It thus provides a potential candidate for the further development into a new drug targeting PDE5.
|
Inhibition of mouse Ido2 transfected in HEK293T cells using L-tryptophan as substrate assessed as kynurenine formation at 20 uM after 45 mins by spectrophotometric analysis relative to control
|
Mus musculus
|
55.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of selective inhibitors of indoleamine 2,3-dioxygenase 2.
Year : 2012
Volume : 22
Issue : 24
First Page : 7641
Last Page : 7646
Authors : Bakmiwewa SM, Fatokun AA, Tran A, Payne RJ, Hunt NH, Ball HJ.
Abstract : The kynurenine pathway is responsible for the breakdown of the majority of the essential amino acid, tryptophan (Trp). The first and rate-limiting step of the kynurenine pathway can be independently catalysed by tryptophan 2,3-dioxygenase (Tdo2), indoleamine 2,3-dioxygenase 1 (Ido1) or indoleamine 2,3-dioxygenase 2 (Ido2). Tdo2 or Ido1 enzymatic activity has been implicated in a number of actions of the kynurenine pathway, including immune evasion by tumors. IDO2 is expressed in several human pancreatic cancer cell lines, suggesting it also may play a role in tumorigenesis. Although Ido2 was originally suggested to be a target of the chemotherapeutic agent dextro-1-methyl-tryptophan, subsequent studies suggest this compound does not inhibit Ido2 activity. The development of selective Ido2 inhibitors could provide valuable tools for investigating its activity in tumor development and normal physiology. In this study, a library of Food and Drug Administration-approved drugs was screened for inhibition of mouse Ido2 enzymatic activity. A number of candidates were identified and IC(50) values of each compound for Ido1 and Ido2 were estimated. The Ido2 inhibitors were also tested for inhibition of Tdo2 activity. Our results showed that compounds from a class of drugs used to inhibit proton pumps were the most potent and selective Ido2 inhibitors identified in the library screen. These included tenatoprazole, which exhibited an IC(50) value of 1.8μM for Ido2 with no inhibition of Ido1 or Tdo2 activity detected at a concentration of 100μM tenatoprazole. These highly-selective Ido2 inhibitors will be useful for defining the distinct biological roles of the three Trp-catabolizing enzymes.
|
Inhibition of PDE6 (unknown origin) using FAM-cGMP as substrate after 60 mins by fluorescence assay
|
Homo sapiens
|
0.5
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis of quinoline derivatives: discovery of a potent and selective phosphodiesterase 5 inhibitor for the treatment of Alzheimer's disease.
Year : 2013
Volume : 60
First Page : 285
Last Page : 294
Authors : Fiorito J, Saeed F, Zhang H, Staniszewski A, Feng Y, Francis YI, Rao S, Thakkar DM, Deng SX, Landry DW, Arancio O.
Abstract : Phosphodiesterase type 5 (PDE5) mediates the degradation of cGMP in a variety of tissues including brain. Recent studies have demonstrated the importance of the nitric oxide/cGMP/cAMP-responsive element-binding protein (CREB) pathway to the process of learning and memory. Thus, PDE5 inhibitors (PDE5Is) are thought to be promising new therapeutic agents for the treatment of Alzheimer's disease (AD), a neurodegenerative disorder characterized by memory loss. To explore this possibility, a series of quinoline derivatives were synthesized and evaluated. We found that compound 7a selectively inhibits PDE5 with an IC(50) of 0.27 nM and readily crosses the blood brain barrier. In an in vivo mouse model of AD, compound 7a rescues synaptic and memory defects. Quinoline-based, CNS-permeant PDE5Is have potential for AD therapeutic development.
|
Inhibition of PDE5 (unknown origin) using FAM-cGMP as substrate after 60 mins by fluorescence assay
|
Homo sapiens
|
2.2
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis of quinoline derivatives: discovery of a potent and selective phosphodiesterase 5 inhibitor for the treatment of Alzheimer's disease.
Year : 2013
Volume : 60
First Page : 285
Last Page : 294
Authors : Fiorito J, Saeed F, Zhang H, Staniszewski A, Feng Y, Francis YI, Rao S, Thakkar DM, Deng SX, Landry DW, Arancio O.
Abstract : Phosphodiesterase type 5 (PDE5) mediates the degradation of cGMP in a variety of tissues including brain. Recent studies have demonstrated the importance of the nitric oxide/cGMP/cAMP-responsive element-binding protein (CREB) pathway to the process of learning and memory. Thus, PDE5 inhibitors (PDE5Is) are thought to be promising new therapeutic agents for the treatment of Alzheimer's disease (AD), a neurodegenerative disorder characterized by memory loss. To explore this possibility, a series of quinoline derivatives were synthesized and evaluated. We found that compound 7a selectively inhibits PDE5 with an IC(50) of 0.27 nM and readily crosses the blood brain barrier. In an in vivo mouse model of AD, compound 7a rescues synaptic and memory defects. Quinoline-based, CNS-permeant PDE5Is have potential for AD therapeutic development.
|
Inhibition of PDE5 (unknown origin)
|
Homo sapiens
|
1.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of novel 5-(3,4,5-trimethoxybenzoyl)-4-aminopyrimidine derivatives as potent and selective phosphodiesterase 5 inhibitors: scaffold hopping using a pseudo-ring by intramolecular hydrogen bond formation.
Year : 2014
Volume : 24
Issue : 22
First Page : 5175
Last Page : 5180
Authors : Sakamoto T, Koga Y, Hikota M, Matsuki K, Murakami M, Kikkawa K, Fujishige K, Kotera J, Omori K, Morimoto H, Yamada K.
Abstract : 5-(3,4,5-Trimethoxybenzoyl)-4-amimopyrimidine derivatives were found as a novel chemical class of potent and highly selective phosphodiesterase 5 inhibitors. A pseudo-ring formed by an intramolecular hydrogen bond constrained the conformation of 3-chloro-4-methoxybenzylamino and 3,4,5-trimethoxybenzoyl substituents and led to the discovery of T-6932 (19a) with a potent PDE5 inhibitory activity (IC50 = 0.13 nM) and a high selectivity over PDE6 (IC50 ratio: PDE6/PDE5 = 2400). Further modification at the 2-position of T-6932 resulted in the finding of 26, which exhibited potent relaxant effects on isolated rabbit corpus cavernosum (EC30 = 11 nM) with a high PDE5 selectivity over PDE6 (IC50 ratio: PDE6/PDE5 = 2800).
|
Inhibition of rabbit platelet PDE5A using [3H]cGMP as substrate at 1 uM after 30 mins by scintillation proximity assay
|
Oryctolagus cuniculus
|
98.9
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of pyrazolo[4,3-e][1,2,4]triazine sulfonamides, novel Sildenafil analogs with tyrosinase inhibitory activity.
Year : 2014
Volume : 22
Issue : 23
First Page : 6616
Last Page : 6624
Authors : Mojzych M, Dolashki A, Voelter W.
Abstract : Tyrosinase is a multifunctional, glycosylated and copper-containing oxidase which catalyzes the first two steps in mammalian melanogenesis and is responsible for enzymatic browning reactions in damaged fruits during post-harvest handling and processing. Neither hyperpigmentation in human skin nor enzymatic browning in fruits are desirable. These phenomena have encouraged researchers to seek new potent tyrosinase inhibitors for use in foods and cosmetics. This article surveys tyrosinase inhibitors, newly discovered from natural and synthetic sources. The inhibitory strength is comparable to that of the standard inhibitor kojic acid. Also their inhibitory mechanisms are discussed. The new obtained compounds were also tested as PDE5 inhibitors and did not show significant inhibitory effect.
|
Inhibition of human PDE5A1 expressed in baculovirus in sf9 cells by PDE Glo phosphodiesterase assay
|
Homo sapiens
|
5.6
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of novel pyrazolopyrimidinone analogs as potent inhibitors of phosphodiesterase type-5.
Year : 2015
Volume : 23
Issue : 9
First Page : 2121
Last Page : 2128
Authors : Sawant SD, Lakshma Reddy G, Dar MI, Srinivas M, Gupta G, Sahu PK, Mahajan P, Nargotra A, Singh S, Sharma SC, Tikoo M, Singh G, Vishwakarma RA, Syed SH.
Abstract : Cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type-5 (PDE5), a clinically proven target to treat erectile dysfunction and diseases associated with lower cGMP levels in humans, is present in corpus cavernosum, heart, lung, platelets, prostate, urethra, bladder, liver, brain, and stomach. Sildenafil, vardenafil, tadalafil and avanafil are FDA approved drugs in market as PDE5 inhibitors for treating erectile dysfunction. In the present study a lead molecule 4-ethoxy-N-(6-hydroxyhexyl)-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonamide, that is, compound-4a, an analog of pyrazolopyrimidinone scaffold has been identified as selective PDE5 inhibitor. A series of compounds was synthesized by replacing N-methylpiperazine moiety (ring-C) of sildenafil structure with different N-substitutions towards sulfonamide end. Compound-4a showed lower IC₅₀ value (1.5 nM) against PDE5 than parent sildenafil (5.6 nM) in in vitro enzyme assay. The isoform selectivity of the compound-4a against other PDE isoforms was similar to that of the Sildenafil. In corroboration with the in vitro data, this molecule showed better efficacy in in vivo studies using the conscious rabbit model. Also compound-4a exhibited good physicochemical properties like solubility, caco-2 permeability, cLogP along with optimal PK profile having no significant CYP enzyme inhibitory liabilities. Discovery of these novel bioactive compounds may open a new alternative for developing novel preclinical candidates based on this drugable scaffold.
|
Inhibition of PDE1A1 (unknown origin) using fluorescently labeled cAMP substrate by fluorescence polarization assay
|
Homo sapiens
|
600.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of novel pyrazolopyrimidinone analogs as potent inhibitors of phosphodiesterase type-5.
Year : 2015
Volume : 23
Issue : 9
First Page : 2121
Last Page : 2128
Authors : Sawant SD, Lakshma Reddy G, Dar MI, Srinivas M, Gupta G, Sahu PK, Mahajan P, Nargotra A, Singh S, Sharma SC, Tikoo M, Singh G, Vishwakarma RA, Syed SH.
Abstract : Cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type-5 (PDE5), a clinically proven target to treat erectile dysfunction and diseases associated with lower cGMP levels in humans, is present in corpus cavernosum, heart, lung, platelets, prostate, urethra, bladder, liver, brain, and stomach. Sildenafil, vardenafil, tadalafil and avanafil are FDA approved drugs in market as PDE5 inhibitors for treating erectile dysfunction. In the present study a lead molecule 4-ethoxy-N-(6-hydroxyhexyl)-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonamide, that is, compound-4a, an analog of pyrazolopyrimidinone scaffold has been identified as selective PDE5 inhibitor. A series of compounds was synthesized by replacing N-methylpiperazine moiety (ring-C) of sildenafil structure with different N-substitutions towards sulfonamide end. Compound-4a showed lower IC₅₀ value (1.5 nM) against PDE5 than parent sildenafil (5.6 nM) in in vitro enzyme assay. The isoform selectivity of the compound-4a against other PDE isoforms was similar to that of the Sildenafil. In corroboration with the in vitro data, this molecule showed better efficacy in in vivo studies using the conscious rabbit model. Also compound-4a exhibited good physicochemical properties like solubility, caco-2 permeability, cLogP along with optimal PK profile having no significant CYP enzyme inhibitory liabilities. Discovery of these novel bioactive compounds may open a new alternative for developing novel preclinical candidates based on this drugable scaffold.
|
Inhibition of PDE5A1 (unknown origin)
|
Homo sapiens
|
5.6
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of novel pyrazolopyrimidinone analogs as potent inhibitors of phosphodiesterase type-5.
Year : 2015
Volume : 23
Issue : 9
First Page : 2121
Last Page : 2128
Authors : Sawant SD, Lakshma Reddy G, Dar MI, Srinivas M, Gupta G, Sahu PK, Mahajan P, Nargotra A, Singh S, Sharma SC, Tikoo M, Singh G, Vishwakarma RA, Syed SH.
Abstract : Cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type-5 (PDE5), a clinically proven target to treat erectile dysfunction and diseases associated with lower cGMP levels in humans, is present in corpus cavernosum, heart, lung, platelets, prostate, urethra, bladder, liver, brain, and stomach. Sildenafil, vardenafil, tadalafil and avanafil are FDA approved drugs in market as PDE5 inhibitors for treating erectile dysfunction. In the present study a lead molecule 4-ethoxy-N-(6-hydroxyhexyl)-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonamide, that is, compound-4a, an analog of pyrazolopyrimidinone scaffold has been identified as selective PDE5 inhibitor. A series of compounds was synthesized by replacing N-methylpiperazine moiety (ring-C) of sildenafil structure with different N-substitutions towards sulfonamide end. Compound-4a showed lower IC₅₀ value (1.5 nM) against PDE5 than parent sildenafil (5.6 nM) in in vitro enzyme assay. The isoform selectivity of the compound-4a against other PDE isoforms was similar to that of the Sildenafil. In corroboration with the in vitro data, this molecule showed better efficacy in in vivo studies using the conscious rabbit model. Also compound-4a exhibited good physicochemical properties like solubility, caco-2 permeability, cLogP along with optimal PK profile having no significant CYP enzyme inhibitory liabilities. Discovery of these novel bioactive compounds may open a new alternative for developing novel preclinical candidates based on this drugable scaffold.
|
Inhibition of PDE6C (unknown origin)
|
Homo sapiens
|
24.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of novel pyrazolopyrimidinone analogs as potent inhibitors of phosphodiesterase type-5.
Year : 2015
Volume : 23
Issue : 9
First Page : 2121
Last Page : 2128
Authors : Sawant SD, Lakshma Reddy G, Dar MI, Srinivas M, Gupta G, Sahu PK, Mahajan P, Nargotra A, Singh S, Sharma SC, Tikoo M, Singh G, Vishwakarma RA, Syed SH.
Abstract : Cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type-5 (PDE5), a clinically proven target to treat erectile dysfunction and diseases associated with lower cGMP levels in humans, is present in corpus cavernosum, heart, lung, platelets, prostate, urethra, bladder, liver, brain, and stomach. Sildenafil, vardenafil, tadalafil and avanafil are FDA approved drugs in market as PDE5 inhibitors for treating erectile dysfunction. In the present study a lead molecule 4-ethoxy-N-(6-hydroxyhexyl)-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonamide, that is, compound-4a, an analog of pyrazolopyrimidinone scaffold has been identified as selective PDE5 inhibitor. A series of compounds was synthesized by replacing N-methylpiperazine moiety (ring-C) of sildenafil structure with different N-substitutions towards sulfonamide end. Compound-4a showed lower IC₅₀ value (1.5 nM) against PDE5 than parent sildenafil (5.6 nM) in in vitro enzyme assay. The isoform selectivity of the compound-4a against other PDE isoforms was similar to that of the Sildenafil. In corroboration with the in vitro data, this molecule showed better efficacy in in vivo studies using the conscious rabbit model. Also compound-4a exhibited good physicochemical properties like solubility, caco-2 permeability, cLogP along with optimal PK profile having no significant CYP enzyme inhibitory liabilities. Discovery of these novel bioactive compounds may open a new alternative for developing novel preclinical candidates based on this drugable scaffold.
|
Relaxation effect on phenylephrine-induced contractile response in isolated rabbit corpus cavernosum
|
Oryctolagus cuniculus
|
8.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 8-(3-chloro-4-methoxybenzyl)-8H-pyrido[2,3-d]pyrimidin-7-one derivatives as potent and selective phosphodiesterase 5 inhibitors.
Year : 2015
Volume : 25
Issue : 7
First Page : 1431
Last Page : 1435
Authors : Sakamoto T, Koga Y, Hikota M, Matsuki K, Mochida H, Kikkawa K, Fujishige K, Kotera J, Omori K, Morimoto H, Yamada K.
Abstract : A novel series of highly selective phosphodiesterase 5 (PDE5) inhibitors was found. 8H-Pyrido[2,3-d]pyrimidin-7-one derivatives bearing an (S)-2-(hydroxymethyl)pyrrolidin-1-yl group at the 2-position and a 3-chloro-4-methoxybenzyl group at the 8-position exhibited potent PDE5 inhibitory activities and high PDE5 selectivity over PDE6. Among the synthesized compounds, the 5-methyl analogue (5b) showed the most potent relaxant effect on isolated rabbit corpus cavernosum with an EC30 value of 0.85 nM.
|
Inhibition of recombinant human PDE5A
|
Homo sapiens
|
8.5
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of First-in-Class Dual Acting Histone Deacetylases (HDACs) and Phosphodiesterase 5 (PDE5) Inhibitors for the Treatment of Alzheimer's Disease.
Year : 2016
Volume : 59
Issue : 19
First Page : 8967
Last Page : 9004
Authors : Rabal O, Sánchez-Arias JA, Cuadrado-Tejedor M, de Miguel I, Pérez-González M, García-Barroso C, Ugarte A, Estella-Hermoso de Mendoza A, Sáez E, Espelosin M, Ursua S, Haizhong T, Wei W, Musheng X, Garcia-Osta A, Oyarzabal J.
Abstract : Simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylases (HDAC) has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). To further extend this concept, we designed and synthesized the first chemical series of dual acting PDE5 and HDAC inhibitors, and we validated this systems therapeutics approach. Following the implementation of structure- and knowledge-based approaches, initial hits were designed and were shown to validate our hypothesis of dual in vitro inhibition. Then, an optimization strategy was pursued to obtain a proper tool compound for in vivo testing in AD models. Initial hits were translated into molecules with adequate cellular functional responses (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation in the nanomolar range), an acceptable therapeutic window (>1 log unit), and the ability to cross the blood-brain barrier, leading to the identification of 7 as a candidate for in vivo proof-of-concept testing ( Cuadrado-Tejedor, M.; Garcia-Barroso, C.; Sánchez-Arias, J. A.; Rabal, O.; Mederos, S.; Ugarte, A.; Franco, R.; Segura, V.; Perea, G.; Oyarzabal, J.; Garcia-Osta, A. Neuropsychopharmacology 2016 , in press, doi: 10.1038/npp.2016.163 ).
|
Inhibition of full length recombinant human N-terminal GST-tagged PDE5A1 expressed in baculovirus infected Sf9 cells using cGMP as substrate after 30 mins by HTRF assay
|
Homo sapiens
|
4.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of First-in-Class Dual Acting Histone Deacetylases (HDACs) and Phosphodiesterase 5 (PDE5) Inhibitors for the Treatment of Alzheimer's Disease.
Year : 2016
Volume : 59
Issue : 19
First Page : 8967
Last Page : 9004
Authors : Rabal O, Sánchez-Arias JA, Cuadrado-Tejedor M, de Miguel I, Pérez-González M, García-Barroso C, Ugarte A, Estella-Hermoso de Mendoza A, Sáez E, Espelosin M, Ursua S, Haizhong T, Wei W, Musheng X, Garcia-Osta A, Oyarzabal J.
Abstract : Simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylases (HDAC) has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). To further extend this concept, we designed and synthesized the first chemical series of dual acting PDE5 and HDAC inhibitors, and we validated this systems therapeutics approach. Following the implementation of structure- and knowledge-based approaches, initial hits were designed and were shown to validate our hypothesis of dual in vitro inhibition. Then, an optimization strategy was pursued to obtain a proper tool compound for in vivo testing in AD models. Initial hits were translated into molecules with adequate cellular functional responses (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation in the nanomolar range), an acceptable therapeutic window (>1 log unit), and the ability to cross the blood-brain barrier, leading to the identification of 7 as a candidate for in vivo proof-of-concept testing ( Cuadrado-Tejedor, M.; Garcia-Barroso, C.; Sánchez-Arias, J. A.; Rabal, O.; Mederos, S.; Ugarte, A.; Franco, R.; Segura, V.; Perea, G.; Oyarzabal, J.; Garcia-Osta, A. Neuropsychopharmacology 2016 , in press, doi: 10.1038/npp.2016.163 ).
|
Inhibition of NorA in Staphylococcus aureus SA1199B harboring GrlA A116E mutant assessed as inhibition of ethidium bromide efflux at 50 uM measured after 5 mins by fluorometric method relative to control
|
Staphylococcus aureus
|
22.9
%
|
|
Journal : J Med Chem
Title : Pharmacophore-Based Repositioning of Approved Drugs as Novel Staphylococcus aureus NorA Efflux Pump Inhibitors.
Year : 2017
Volume : 60
Issue : 4
First Page : 1598
Last Page : 1604
Authors : Astolfi A, Felicetti T, Iraci N, Manfroni G, Massari S, Pietrella D, Tabarrini O, Kaatz GW, Barreca ML, Sabatini S, Cecchetti V.
Abstract : An intriguing opportunity to address antimicrobial resistance is represented by the inhibition of efflux pumps. Focusing on NorA, the most important efflux pump of Staphylococcus aureus, an efflux pump inhibitors (EPIs) library was used for ligand-based pharmacophore modeling studies. By exploitation of the obtained models, an in silico drug repositioning approach allowed for the identification of novel and potent NorA EPIs.
|
Inhibition of recombinant human full length PDE5A1 catalytic domain expressed in Escherichia coli BL21 using [3H]cGMP as substrate after 15 mins by liquid scintillation counting
|
Homo sapiens
|
2.2
nM
|
|
Journal : J Med Chem
Title : Novel Phosphodiesterase Inhibitors for Cognitive Improvement in Alzheimer's Disease.
Year : 2018
Volume : 61
Issue : 13
First Page : 5467
Last Page : 5483
Authors : Wu Y, Li Z, Huang YY, Wu D, Luo HB.
Abstract : Alzheimer's disease (AD) is one of the greatest public health challenges. Phosphodiesterases (PDEs) are a superenzyme family responsible for the hydrolysis of two second messengers: cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Since several PDE subfamilies are highly expressed in the human brain, the inhibition of PDEs is involved in neurodegenerative processes by regulating the concentration of cAMP and/or cGMP. Currently, PDEs are considered as promising targets for the treatment of AD since many PDE inhibitors have exhibited remarkable cognitive improvement effects in preclinical studies and over 15 of them have been subjected to clinical trials. The aim of this review is to summarize the outstanding progress that has been made by PDE inhibitors as anti-AD agents with encouraging results in preclinical studies and clinical trials. The binding affinity, pharmacokinetics, underlying mechanisms, and limitations of these PDE inhibitors in the treatment of AD are also reviewed and discussed.
|
Inhibition of PDE5 (unknown origin)
|
Homo sapiens
|
3.981
nM
|
|
Journal : J Med Chem
Title : Mapping the Efficiency and Physicochemical Trajectories of Successful Optimizations.
Year : 2018
Volume : 61
Issue : 15
First Page : 6421
Last Page : 6467
Authors : Young RJ, Leeson PD.
Abstract : The practices and tactics employed in successful optimizations are examined, judged from the trajectories of ligand efficiency and property evolution. A wide range of targets is analyzed, encompassing a variety of hit finding methods (HTS, fragments, encoded library technology) and types of molecules, including those beyond the rule of five. The wider employment of efficiency metrics and lipophilicity control is evident in contemporary practice and the impact on quality demonstrable. What is clear is that while targets are different, successful molecules are almost invariably among the most efficient for their target, even at the extremes. Trajectory mapping, based on principles rather than rules, is useful in assessing quality and progress in optimizations while benchmarking against competitors and assessing property-dependent risks.
|
Inhibition of N-terminal GST-tagged full length recombinant human PDE5A1 catalytic domain expressed in Baculovirus infected Sf9 insect cells at 100 nM using FAM-cGMP as substrate after 1 hr by fluorescence polarization assay relative to control
|
Homo sapiens
|
98.0
%
|
|
Journal : Eur J Med Chem
Title : Design and synthesis of furyl/thineyl pyrroloquinolones based on natural alkaloid perlolyrine, lead to the discovery of potent and selective PDE5 inhibitors.
Year : 2018
Volume : 150
First Page : 30
Last Page : 38
Authors : Zheng H, Li L, Sun B, Gao Y, Song W, Zhao X, Gao Y, Xie Z, Zhang N, Ji J, Yuan H, Lou H.
Abstract : Based on perlolyrine (1), a natural alkaloid with weak PDE5 potency from the traditional Chinese aphrodisiac plant Tribulus terrestris L., a series α-substituted tetrahydro-β-carboline (THβC) derivatives were synthesized via T+BF4--mediated oxidative C-H functionalization of N-aryl THβCs with diverse potassium trifluoroborates. Following Winterfeldt oxidation afforded the corresponding furyl/thienyl pyrroloquinolones, of which 5-ethylthiophene/ethylfuran derivatives 20a-b were identified as the most potent and selective PDE5 inhibitors. Among the enantiomers, (S)-20a and (S)-20b (IC50 = 0.52 and 0.39 nM) were found to be more effective than their (R)-antipode, display favorable pharmacokinetic profiles, exert in vitro vasorelaxant effects on the isolated thoracic aorta, and exhibit in vivo efficacy in the anesthetized rabbit erectile model.
|
Inhibition of N-terminal GST-tagged full length recombinant human PDE5A1 catalytic domain expressed in Baculovirus infected Sf9 insect cells at 10 nM using FAM-cGMP as substrate after 1 hr by fluorescence polarization assay relative to control
|
Homo sapiens
|
74.0
%
|
|
Journal : Eur J Med Chem
Title : Design and synthesis of furyl/thineyl pyrroloquinolones based on natural alkaloid perlolyrine, lead to the discovery of potent and selective PDE5 inhibitors.
Year : 2018
Volume : 150
First Page : 30
Last Page : 38
Authors : Zheng H, Li L, Sun B, Gao Y, Song W, Zhao X, Gao Y, Xie Z, Zhang N, Ji J, Yuan H, Lou H.
Abstract : Based on perlolyrine (1), a natural alkaloid with weak PDE5 potency from the traditional Chinese aphrodisiac plant Tribulus terrestris L., a series α-substituted tetrahydro-β-carboline (THβC) derivatives were synthesized via T+BF4--mediated oxidative C-H functionalization of N-aryl THβCs with diverse potassium trifluoroborates. Following Winterfeldt oxidation afforded the corresponding furyl/thienyl pyrroloquinolones, of which 5-ethylthiophene/ethylfuran derivatives 20a-b were identified as the most potent and selective PDE5 inhibitors. Among the enantiomers, (S)-20a and (S)-20b (IC50 = 0.52 and 0.39 nM) were found to be more effective than their (R)-antipode, display favorable pharmacokinetic profiles, exert in vitro vasorelaxant effects on the isolated thoracic aorta, and exhibit in vivo efficacy in the anesthetized rabbit erectile model.
|
Inhibition of N-terminal GST-tagged full length recombinant human PDE5A1 catalytic domain expressed in Baculovirus infected Sf9 insect cells using FAM-cGMP as substrate after 1 hr by fluorescence polarization assay
|
Homo sapiens
|
3.65
nM
|
|
Journal : Eur J Med Chem
Title : Design and synthesis of furyl/thineyl pyrroloquinolones based on natural alkaloid perlolyrine, lead to the discovery of potent and selective PDE5 inhibitors.
Year : 2018
Volume : 150
First Page : 30
Last Page : 38
Authors : Zheng H, Li L, Sun B, Gao Y, Song W, Zhao X, Gao Y, Xie Z, Zhang N, Ji J, Yuan H, Lou H.
Abstract : Based on perlolyrine (1), a natural alkaloid with weak PDE5 potency from the traditional Chinese aphrodisiac plant Tribulus terrestris L., a series α-substituted tetrahydro-β-carboline (THβC) derivatives were synthesized via T+BF4--mediated oxidative C-H functionalization of N-aryl THβCs with diverse potassium trifluoroborates. Following Winterfeldt oxidation afforded the corresponding furyl/thienyl pyrroloquinolones, of which 5-ethylthiophene/ethylfuran derivatives 20a-b were identified as the most potent and selective PDE5 inhibitors. Among the enantiomers, (S)-20a and (S)-20b (IC50 = 0.52 and 0.39 nM) were found to be more effective than their (R)-antipode, display favorable pharmacokinetic profiles, exert in vitro vasorelaxant effects on the isolated thoracic aorta, and exhibit in vivo efficacy in the anesthetized rabbit erectile model.
|
Inhibition of PDE5A (unknown origin)
|
Homo sapiens
|
8.5
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, biological evaluation and in vivo testing of dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors for the treatment of Alzheimer's disease.
Year : 2018
Volume : 150
First Page : 506
Last Page : 524
Authors : Rabal O, Sánchez-Arias JA, Cuadrado-Tejedor M, de Miguel I, Pérez-González M, García-Barroso C, Ugarte A, Estella-Hermoso de Mendoza A, Sáez E, Espelosin M, Ursua S, Haizhong T, Wei W, Musheng X, Garcia-Osta A, Oyarzabal J.
Abstract : We have identified chemical probes that act as dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors (>1 log unit difference versus class I HDACs) to decipher the contribution of HDAC isoforms to the positive impact of dual-acting PDE5 and HDAC inhibitors on mouse models of Alzheimer's disease (AD) and fine-tune this systems therapeutics approach. Structure- and knowledge-based approaches led to the design of first-in-class molecules with the desired target compound profile: dual PDE5 and HDAC6-selective inhibitors. Compound 44b, which fulfilled the biochemical, functional and ADME-Tox profiling requirements and exhibited adequate pharmacokinetic properties, was selected as pharmacological tool compound and tested in a mouse model of AD (Tg2576) in vivo.
|
Inhibition of human PDE5A1 catalytic domain (535 to 860 residues) expressed in Escherichia coli BL21 using 3H-cGMP as substrate after 15 mins by liquid scintillation counting
|
Homo sapiens
|
5.1
nM
|
|
Journal : J Med Chem
Title : Optimization of Chromeno[2,3- c]pyrrol-9(2 H)-ones as Highly Potent, Selective, and Orally Bioavailable PDE5 Inhibitors: Structure-Activity Relationship, X-ray Crystal Structure, and Pharmacodynamic Effect on Pulmonary Arterial Hypertension.
Year : 2018
Volume : 61
Issue : 18
First Page : 8468
Last Page : 8473
Authors : Wu D, Huang Y, Chen Y, Huang YY, Geng H, Zhang T, Zhang C, Li Z, Guo L, Chen J, Luo HB.
Abstract : To further explore the structure-activity relationship around the chromeno[2,3- c]pyrrol-9(2 H)-one scaffold, 19 derivatives as inhibitors against PDE5 were discovered. The most potent inhibitor 3 has an IC50 of 0.32 nM with remarkable selectivity and druglike profile. Oral administration of 3 (1.25 mg/kg) caused comparable therapeutic effects to sildenafil (10.0 mg/kg) against pulmonary arterial hypertension. Further, different binding patterns from sildenafil were revealed in cocrystal structures, which provide structural templates for discovery of highly potent PDE5 inhibitors.
|
Inhibition of PDE5 (unknown origin)
|
Homo sapiens
|
5.0
nM
|
|
Journal : Eur J Med Chem
Title : Inhibitors of phosphodiesterase as cancer therapeutics.
Year : 2018
Volume : 150
First Page : 742
Last Page : 756
Authors : Peng T, Gong J, Jin Y, Zhou Y, Tong R, Wei X, Bai L, Shi J.
Abstract : Phosphodiesterases (PDEs) are a class of enzymes that hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which is involved in many physiological processes including visual transduction, cell proliferation and differentiation, cell-cycle regulation, gene expression, inflammation, apoptosis, and metabolic function. PDEs are composed of 11 different families and each family contains different subtypes. The distribution, expression, regulation mode and sensitivity to inhibitors of each subtype are different, and they are involved in cancer, inflammation, asthma, depression, erectile dysfunction and other pathological processes of development. A large number of studies have shown that PDEs play an important role in the development of tumors by affecting the intracellular level of cAMP and/or cGMP and PDEs could become diagnostic markers or therapeutic targets. This review will give a brief overview of the expression and regulation of PDE families in the process of tumorigenesis and their anti-tumor inhibitors, which may guide the design of novel therapeutic drugs targeting PDEs for anticancer agent.
|
Inhibition of PDE5 (unknown origin)
|
Homo sapiens
|
1.6
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of furyl/thienyl β-carboline derivatives as potent and selective PDE5 inhibitors with excellent vasorelaxant effect.
Year : 2018
Volume : 158
First Page : 767
Last Page : 780
Authors : Zheng H, Wu Y, Sun B, Cheng C, Qiao Y, Jiang Y, Zhao S, Xie Z, Tan J, Lou H.
Abstract : Based on our previous studies and predictive docking results, furans and thiophenes were introduced to the privileged tetrahydro-β-carboline scaffold to generate more potent and selective PDE5 inhibitors. A total of 66 novel furyl/thienyl tetrahydro-β-carboline derivatives were designed, synthesized and evaluated for PDE5 inhibition. Tetrahydro-β-carboline-piperazinedione 19f and tetrahydro-β-carboline-hydantoin 26b with optimized pendant 5-ethylfuran/5-ethylthiophene were identified as the most potent PDE5 inhibitors, and showed high selectivity towards PDE5 versus other PDE isozymes, especially PDE6 and PDE11. Further vasorelaxant activity assessments revealed that these PDE5 inhibitors also exhibited significant angiectasis on the norepinephrine-precontracted 3rd-order mesenteric arteries (110-150 μm) via NO-sGC-cGMP pathway, implying their further application for the treatment of vascular diseases.
|
Inhibition of rat lung PDE5 using [3H]cGMP as substrate measured after 10 mins by scintillation counting method
|
Rattus norvegicus
|
2.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and evaluation of N<sup>2</sup>,N<sup>4</sup>-diaminoquinazoline based inhibitors of phosphodiesterase type 5.
Year : 2019
Volume : 29
Issue : 2
First Page : 267
Last Page : 270
Authors : Pobsuk N, Paracha TU, Chaichamnong N, Salaloy N, Suphakun P, Hannongbua S, Choowongkomon K, Pekthong D, Chootip K, Ingkaninan K, Gleeson MP.
Abstract : We describe the design, synthesis and evaluation of a series of N<sup>2</sup>,N<sup>4</sup>-diaminoquinazoline analogs as PDE5 inhibitors. Twenty compounds were prepared and these were assessed in terms of their PDE5 and PDE6 activity, ex-vivo vasodilation response, mammalian cytotoxicity and aqueous solubility. Molecular docking was used to determine the binding mode of the series and this was demonstrated to be consistent with the observed SAR. Compound 15 was the most active PDE5 inhibitor (IC<sub>50</sub> = 0.072 ± 0.008 µM) and exhibited 4.6-fold selectivity over PDE6. Ex-vivo assessment of 15 and 22 in a rat pulmonary artery vasodilation model demonstrated EC<sub>50</sub>s of 1.63 ± 0.72 µM and 2.28 ± 0.74 µM respectively.
|
Inhibition of histone activated chicken PDE6 using [3H]cGMP as substrate measured after 10 mins by scintillation counting method
|
Gallus gallus
|
13.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and evaluation of N<sup>2</sup>,N<sup>4</sup>-diaminoquinazoline based inhibitors of phosphodiesterase type 5.
Year : 2019
Volume : 29
Issue : 2
First Page : 267
Last Page : 270
Authors : Pobsuk N, Paracha TU, Chaichamnong N, Salaloy N, Suphakun P, Hannongbua S, Choowongkomon K, Pekthong D, Chootip K, Ingkaninan K, Gleeson MP.
Abstract : We describe the design, synthesis and evaluation of a series of N<sup>2</sup>,N<sup>4</sup>-diaminoquinazoline analogs as PDE5 inhibitors. Twenty compounds were prepared and these were assessed in terms of their PDE5 and PDE6 activity, ex-vivo vasodilation response, mammalian cytotoxicity and aqueous solubility. Molecular docking was used to determine the binding mode of the series and this was demonstrated to be consistent with the observed SAR. Compound 15 was the most active PDE5 inhibitor (IC<sub>50</sub> = 0.072 ± 0.008 µM) and exhibited 4.6-fold selectivity over PDE6. Ex-vivo assessment of 15 and 22 in a rat pulmonary artery vasodilation model demonstrated EC<sub>50</sub>s of 1.63 ± 0.72 µM and 2.28 ± 0.74 µM respectively.
|
Vasorelaxant activity in Wistar rat endothelium intact pulmonary artery rings assessed as inhibition of phenylephrine-induced contraction
|
Rattus norvegicus
|
140.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and evaluation of N<sup>2</sup>,N<sup>4</sup>-diaminoquinazoline based inhibitors of phosphodiesterase type 5.
Year : 2019
Volume : 29
Issue : 2
First Page : 267
Last Page : 270
Authors : Pobsuk N, Paracha TU, Chaichamnong N, Salaloy N, Suphakun P, Hannongbua S, Choowongkomon K, Pekthong D, Chootip K, Ingkaninan K, Gleeson MP.
Abstract : We describe the design, synthesis and evaluation of a series of N<sup>2</sup>,N<sup>4</sup>-diaminoquinazoline analogs as PDE5 inhibitors. Twenty compounds were prepared and these were assessed in terms of their PDE5 and PDE6 activity, ex-vivo vasodilation response, mammalian cytotoxicity and aqueous solubility. Molecular docking was used to determine the binding mode of the series and this was demonstrated to be consistent with the observed SAR. Compound 15 was the most active PDE5 inhibitor (IC<sub>50</sub> = 0.072 ± 0.008 µM) and exhibited 4.6-fold selectivity over PDE6. Ex-vivo assessment of 15 and 22 in a rat pulmonary artery vasodilation model demonstrated EC<sub>50</sub>s of 1.63 ± 0.72 µM and 2.28 ± 0.74 µM respectively.
|
Inhibition of N-terminal GST-tagged human PDE5A1 expressed in baculovirus infected sf9 cells using [3H]cGMP as substrate measured after 30 mins by scintillation proximity assay
|
Homo sapiens
|
4.31
nM
|
|
Journal : J Med Chem
Title : Pharmacokinetics-Driven Optimization of 4(3 H)-Pyrimidinones as Phosphodiesterase Type 5 Inhibitors Leading to TPN171, a Clinical Candidate for the Treatment of Pulmonary Arterial Hypertension.
Year : 2019
Volume : 62
Issue : 10
First Page : 4979
Last Page : 4990
Authors : Wang Z, Jiang X, Zhang X, Tian G, Yang R, Wu J, Zou X, Liu Z, Yang X, Wu C, Shi J, Li J, Suo J, Wang Y, Zhang R, Xu Z, Gong X, He Y, Zhu W, Aisa HA, Jiang H, Xu Y, Shen J.
Abstract : Phosphodiesterase type 5 (PDE5) inhibitors are first-line therapy for pulmonary arterial hypertension (PAH) and erectile dysfunction. As a continuing work to improve the terminal half-lives and oral bioavailabilities of our previously reported 4(3 H)-pyrimidones, a pharmacokinetics-driven optimization focusing on the terminal substituent is described. Two major congeneric series of 4(3 H)-pyrimidones, the aminosulfonylphenylpyrimidones and acylaminophenylpyrimidones, were designed, synthesized, and pharmacologically assessed in vitro and in vivo. Among them, compound 15 (TPN171) with subnanomolar potency for PDE5 and good selectivity over PDE6 was finally recognized as a potential drug candidate, and its pharmacokinetic profiles in rats and dogs are significantly improved compared to the starting compound (3). Moreover, TPN171 was proven to exert a longer lasting effect than sildenafil in animal models, providing a foundation for a once-daily oral administration for its clinical use. TPN171 is currently being investigated in a phase II clinical trial for the treatment of PAH.
|
Inhibition of N-terminal GST-tagged human PDE1 expressed in baculovirus infected sf9 cells using [3H]cAMP as substrate measured after 30 mins by scintillation proximity assay
|
Homo sapiens
|
819.0
nM
|
|
Journal : J Med Chem
Title : Pharmacokinetics-Driven Optimization of 4(3 H)-Pyrimidinones as Phosphodiesterase Type 5 Inhibitors Leading to TPN171, a Clinical Candidate for the Treatment of Pulmonary Arterial Hypertension.
Year : 2019
Volume : 62
Issue : 10
First Page : 4979
Last Page : 4990
Authors : Wang Z, Jiang X, Zhang X, Tian G, Yang R, Wu J, Zou X, Liu Z, Yang X, Wu C, Shi J, Li J, Suo J, Wang Y, Zhang R, Xu Z, Gong X, He Y, Zhu W, Aisa HA, Jiang H, Xu Y, Shen J.
Abstract : Phosphodiesterase type 5 (PDE5) inhibitors are first-line therapy for pulmonary arterial hypertension (PAH) and erectile dysfunction. As a continuing work to improve the terminal half-lives and oral bioavailabilities of our previously reported 4(3 H)-pyrimidones, a pharmacokinetics-driven optimization focusing on the terminal substituent is described. Two major congeneric series of 4(3 H)-pyrimidones, the aminosulfonylphenylpyrimidones and acylaminophenylpyrimidones, were designed, synthesized, and pharmacologically assessed in vitro and in vivo. Among them, compound 15 (TPN171) with subnanomolar potency for PDE5 and good selectivity over PDE6 was finally recognized as a potential drug candidate, and its pharmacokinetic profiles in rats and dogs are significantly improved compared to the starting compound (3). Moreover, TPN171 was proven to exert a longer lasting effect than sildenafil in animal models, providing a foundation for a once-daily oral administration for its clinical use. TPN171 is currently being investigated in a phase II clinical trial for the treatment of PAH.
|
Inhibition of N-terminal GST-tagged human PDE6C expressed in baculovirus infected sf9 cells using [3H]cGMP as substrate measured after 30 mins by scintillation proximity assay
|
Homo sapiens
|
36.42
nM
|
|
Journal : J Med Chem
Title : Pharmacokinetics-Driven Optimization of 4(3 H)-Pyrimidinones as Phosphodiesterase Type 5 Inhibitors Leading to TPN171, a Clinical Candidate for the Treatment of Pulmonary Arterial Hypertension.
Year : 2019
Volume : 62
Issue : 10
First Page : 4979
Last Page : 4990
Authors : Wang Z, Jiang X, Zhang X, Tian G, Yang R, Wu J, Zou X, Liu Z, Yang X, Wu C, Shi J, Li J, Suo J, Wang Y, Zhang R, Xu Z, Gong X, He Y, Zhu W, Aisa HA, Jiang H, Xu Y, Shen J.
Abstract : Phosphodiesterase type 5 (PDE5) inhibitors are first-line therapy for pulmonary arterial hypertension (PAH) and erectile dysfunction. As a continuing work to improve the terminal half-lives and oral bioavailabilities of our previously reported 4(3 H)-pyrimidones, a pharmacokinetics-driven optimization focusing on the terminal substituent is described. Two major congeneric series of 4(3 H)-pyrimidones, the aminosulfonylphenylpyrimidones and acylaminophenylpyrimidones, were designed, synthesized, and pharmacologically assessed in vitro and in vivo. Among them, compound 15 (TPN171) with subnanomolar potency for PDE5 and good selectivity over PDE6 was finally recognized as a potential drug candidate, and its pharmacokinetic profiles in rats and dogs are significantly improved compared to the starting compound (3). Moreover, TPN171 was proven to exert a longer lasting effect than sildenafil in animal models, providing a foundation for a once-daily oral administration for its clinical use. TPN171 is currently being investigated in a phase II clinical trial for the treatment of PAH.
|
Inhibition of human platelets PDE5
|
Homo sapiens
|
1.0
nM
|
|
Journal : Eur J Med Chem
Title : Design and synthesis of 3-aminophthalazine derivatives and structural analogues as PDE5 inhibitors: anti-allodynic effect against neuropathic pain in a mouse model.
Year : 2019
Volume : 177
First Page : 269
Last Page : 290
Authors : Bollenbach M, Lugnier C, Kremer M, Salvat E, Megat S, Bihel F, Bourguignon JJ, Barrot M, Schmitt M.
Abstract : Neuropathic pain is a chronic pain caused by a lesion or disease affecting the somatosensory nervous system. To date, no specific treatment has been developed to cure this pain. Antidepressants and anticonvulsant drugs are used, but they do not demonstrate universal efficacy, and they often cause detrimental adverse effects. Some studies highlighted the efficacy of sildenafil, a well-known inhibitor of phosphodiesterase 5 (PDE5, (IC<sub>50</sub> = 3.3 nM)), in models of pain. Based on these results, we focused our attention on MY 5445, another known PDE5 inhibitor. Homologues, isosteres and structural analogues of MY 5445 were designed and all synthesized compounds were evaluated for their inhibitory activity toward PDE5. Selectivity profiles towards other PDE1-4 isoenzymes, water solubility and stability in acidic medium of the most potent PDE5 inhibitors were determined and the aminophthalazine 16h and its mimetic 41n (3-aminoindazole) were evaluated in comparison to MY 5445 (4b) in vivo in a model of neuropathic pain induced by sciatic nerve cuffing in mice (3 and 0.5 mg/kg, ip twice a day). Both compounds showed the same efficacy on neuropathic allodynia as MY 5445, and thus produced a significant relief of mechanical hypersensitivity after 12 days of treatment.
|
Inhibition of bovine aortic smooth muscle PDE5 at 1 uM using cGMP as substrate incubated for 30 mins in presence of EGTA and [3H]cGMP by liquid scintillation counting method relative to control
|
Bos taurus
|
98.0
%
|
|
Journal : Eur J Med Chem
Title : Design and synthesis of 3-aminophthalazine derivatives and structural analogues as PDE5 inhibitors: anti-allodynic effect against neuropathic pain in a mouse model.
Year : 2019
Volume : 177
First Page : 269
Last Page : 290
Authors : Bollenbach M, Lugnier C, Kremer M, Salvat E, Megat S, Bihel F, Bourguignon JJ, Barrot M, Schmitt M.
Abstract : Neuropathic pain is a chronic pain caused by a lesion or disease affecting the somatosensory nervous system. To date, no specific treatment has been developed to cure this pain. Antidepressants and anticonvulsant drugs are used, but they do not demonstrate universal efficacy, and they often cause detrimental adverse effects. Some studies highlighted the efficacy of sildenafil, a well-known inhibitor of phosphodiesterase 5 (PDE5, (IC<sub>50</sub> = 3.3 nM)), in models of pain. Based on these results, we focused our attention on MY 5445, another known PDE5 inhibitor. Homologues, isosteres and structural analogues of MY 5445 were designed and all synthesized compounds were evaluated for their inhibitory activity toward PDE5. Selectivity profiles towards other PDE1-4 isoenzymes, water solubility and stability in acidic medium of the most potent PDE5 inhibitors were determined and the aminophthalazine 16h and its mimetic 41n (3-aminoindazole) were evaluated in comparison to MY 5445 (4b) in vivo in a model of neuropathic pain induced by sciatic nerve cuffing in mice (3 and 0.5 mg/kg, ip twice a day). Both compounds showed the same efficacy on neuropathic allodynia as MY 5445, and thus produced a significant relief of mechanical hypersensitivity after 12 days of treatment.
|
Inhibition of human His-tagged PDE5A catalytic domain expressed in Escherichia coli BL21-CodonPlus(DE3) cells using [3H]cAMP or [3H]cGMP as substrate incubated for 30 mins by scintillation counting method
|
Homo sapiens
|
2.2
nM
|
|
Journal : J Med Chem
Title : PDEStrIAn: A Phosphodiesterase Structure and Ligand Interaction Annotated Database As a Tool for Structure-Based Drug Design.
Year : 2016
Volume : 59
Issue : 15
First Page : 7029
Last Page : 7065
Authors : Jansen C, Kooistra AJ, Kanev GK, Leurs R, de Esch IJ, de Graaf C.
Abstract : A systematic analysis is presented of the 220 phosphodiesterase (PDE) catalytic domain crystal structures present in the Protein Data Bank (PDB) with a focus on PDE-ligand interactions. The consistent structural alignment of 57 PDE ligand binding site residues enables the systematic analysis of PDE-ligand interaction fingerprints (IFPs), the identification of subtype-specific PDE-ligand interaction features, and the classification of ligands according to their binding modes. We illustrate how systematic mining of this phosphodiesterase structure and ligand interaction annotated (PDEStrIAn) database provides new insights into how conserved and selective PDE interaction hot spots can accommodate the large diversity of chemical scaffolds in PDE ligands. A substructure analysis of the cocrystallized PDE ligands in combination with those in the ChEMBL database provides a toolbox for scaffold hopping and ligand design. These analyses lead to an improved understanding of the structural requirements of PDE binding that will be useful in future drug discovery studies.
|
Inhibition of human PDE5A
|
Homo sapiens
|
2.2
nM
|
|
Journal : J Med Chem
Title : PDEStrIAn: A Phosphodiesterase Structure and Ligand Interaction Annotated Database As a Tool for Structure-Based Drug Design.
Year : 2016
Volume : 59
Issue : 15
First Page : 7029
Last Page : 7065
Authors : Jansen C, Kooistra AJ, Kanev GK, Leurs R, de Esch IJ, de Graaf C.
Abstract : A systematic analysis is presented of the 220 phosphodiesterase (PDE) catalytic domain crystal structures present in the Protein Data Bank (PDB) with a focus on PDE-ligand interactions. The consistent structural alignment of 57 PDE ligand binding site residues enables the systematic analysis of PDE-ligand interaction fingerprints (IFPs), the identification of subtype-specific PDE-ligand interaction features, and the classification of ligands according to their binding modes. We illustrate how systematic mining of this phosphodiesterase structure and ligand interaction annotated (PDEStrIAn) database provides new insights into how conserved and selective PDE interaction hot spots can accommodate the large diversity of chemical scaffolds in PDE ligands. A substructure analysis of the cocrystallized PDE ligands in combination with those in the ChEMBL database provides a toolbox for scaffold hopping and ligand design. These analyses lead to an improved understanding of the structural requirements of PDE binding that will be useful in future drug discovery studies.
|
Inhibition of recombinant human PDE5A1 catalytic domain (535 to 860 residues) expressed in baculovirus infected sf9 cells using [3H]cGMP as substrate incubated for 15 mins by liquid scintillation counting method
|
Homo sapiens
|
2.2
nM
|
|
Journal : J Med Chem
Title : PDEStrIAn: A Phosphodiesterase Structure and Ligand Interaction Annotated Database As a Tool for Structure-Based Drug Design.
Year : 2016
Volume : 59
Issue : 15
First Page : 7029
Last Page : 7065
Authors : Jansen C, Kooistra AJ, Kanev GK, Leurs R, de Esch IJ, de Graaf C.
Abstract : A systematic analysis is presented of the 220 phosphodiesterase (PDE) catalytic domain crystal structures present in the Protein Data Bank (PDB) with a focus on PDE-ligand interactions. The consistent structural alignment of 57 PDE ligand binding site residues enables the systematic analysis of PDE-ligand interaction fingerprints (IFPs), the identification of subtype-specific PDE-ligand interaction features, and the classification of ligands according to their binding modes. We illustrate how systematic mining of this phosphodiesterase structure and ligand interaction annotated (PDEStrIAn) database provides new insights into how conserved and selective PDE interaction hot spots can accommodate the large diversity of chemical scaffolds in PDE ligands. A substructure analysis of the cocrystallized PDE ligands in combination with those in the ChEMBL database provides a toolbox for scaffold hopping and ligand design. These analyses lead to an improved understanding of the structural requirements of PDE binding that will be useful in future drug discovery studies.
|
Inhibition of recombinant human His6-tagged PDE5A (535 to 786 residues)/PDE6C expressed in Escherichia coli BL21-CodonPlus cells using [3H]cGMP as substrate
|
Homo sapiens
|
25.0
nM
|
|
Journal : J Med Chem
Title : PDEStrIAn: A Phosphodiesterase Structure and Ligand Interaction Annotated Database As a Tool for Structure-Based Drug Design.
Year : 2016
Volume : 59
Issue : 15
First Page : 7029
Last Page : 7065
Authors : Jansen C, Kooistra AJ, Kanev GK, Leurs R, de Esch IJ, de Graaf C.
Abstract : A systematic analysis is presented of the 220 phosphodiesterase (PDE) catalytic domain crystal structures present in the Protein Data Bank (PDB) with a focus on PDE-ligand interactions. The consistent structural alignment of 57 PDE ligand binding site residues enables the systematic analysis of PDE-ligand interaction fingerprints (IFPs), the identification of subtype-specific PDE-ligand interaction features, and the classification of ligands according to their binding modes. We illustrate how systematic mining of this phosphodiesterase structure and ligand interaction annotated (PDEStrIAn) database provides new insights into how conserved and selective PDE interaction hot spots can accommodate the large diversity of chemical scaffolds in PDE ligands. A substructure analysis of the cocrystallized PDE ligands in combination with those in the ChEMBL database provides a toolbox for scaffold hopping and ligand design. These analyses lead to an improved understanding of the structural requirements of PDE binding that will be useful in future drug discovery studies.
|
Inhibition of PDE5A1 catalytic domain (535 to 860 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) at 2 nM using [3H]cGMP as substrate after 15 mins by liquid scintillation counting method relative to control
|
Homo sapiens
|
54.9
%
|
|
Journal : J Med Chem
Title : Discovery of Novel Pyrazolo[3,4-b] Pyridine Derivatives with Dual Activities of Vascular Remodeling Inhibition and Vasodilation for the Treatment of Pulmonary Arterial Hypertension.
Year : 2020
Volume : 63
Issue : 19
First Page : 11215
Last Page : 11234
Authors : Hu L,Li L,Chang Q,Fu S,Qin J,Chen Z,Li X,Liu Q,Hu G,Li Q
Abstract : Current pulmonary arterial hypertension (PAH) therapeutic strategies mainly focus on vascular relaxation with less emphasis on vascular remodeling, which results in poor prognosis. Hence, dual pathway regulators with vasodilation effect via soluble guanylate cyclase (sGC) stimulation and vascular remodeling regulation effect by AMP-activated protein kinase (AMPK) inhibition provide more advantages and potentialities. Herein, we designed and synthesized a series of novel pyrazolo[3,4-b] pyridine derivatives based on sGC stimulator and AMPK inhibitor scaffolds. In vitro, 2 exhibited moderate vasodilation activity and higher proliferation and migration suppressive effects compared to riociguat. In vivo, 2 significantly decreased right ventricular systolic pressure (RVSP), attenuated pulmonary artery medial thickness (PAMT), and right ventricular hypertrophy (RVH) in hypoxia-induced PAH rat models (i.g.). Given the unique advantages of significant vascular remodeling inhibition and moderate vascular relaxation based on the dual pathway regulation, we proposed 2 as a promising lead for anti-PAH drug discovery.
|
Inhibition of PDE5 in human platelets at 10 uM incubated for 30 mins using cGMP as substrate by HPLC analysis relative to control
|
Homo sapiens
|
100.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design and synthesis of pyrazolo[3,4-d]pyrimidinone derivatives: Discovery of selective phosphodiesterase-5 inhibitors.
Year : 2020
Volume : 30
Issue : 16
First Page : 127337
Last Page : 127337
Authors : Shaaban MA,Elshaier YAMM,Hammad AH,Farag NA,Hassan Haredy H,AbdEl-Ghany AA,Mohamed KO
Abstract : A novel series of 1,6-disubstituted pyrazolo[3,4-d]pyrimidin-7-one derivatives, 2a-h, 4a-d, 5 and 6, were successfully synthesized, which showed promising, and potent inhibition of phosphodiesterase 5 (PDE5). The inhibitory activities of 5, 4b, 2a, 2d, 2f, 4d and 4a against PDE5 were similar to that of sildenafil (100%). These compounds exhibited potent relaxant effects on isolated rat cavernosum tissue with pEC values ranging from 8.31 to 5.16 µM. Pyrazolo[3,4-d]pyrimidin-7-one scaffolds have been rationally designed via consecutive molecular modelling studies prior to their synthesis and biological evaluation. In addition, the results of the pharmacophore-based virtual screening revealed that 1v0p_PVB might have promising activity as a PDE-5 inhibitor.
|
Inhibition of human PDE5A1 (535-860 residues) expressed in Escherichia coli BL21 incubated for 15 mins using [3H]-cGMP as substrate by liquid scintillation counting method
|
Homo sapiens
|
5.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Evodiamine Derivatives as Highly Selective PDE5 Inhibitors Targeting a Unique Allosteric Pocket.
Year : 2020
Volume : 63
Issue : 17
First Page : 9828
Last Page : 9837
Authors : Zhang T,Lai Z,Yuan S,Huang YY,Dong G,Sheng C,Ke H,Luo HB
Abstract : Clinical use of phosphodiesterase-5 (PDE5) inhibitors is limited by several side effects due to weak isoform selectivity. Herein, a unique allosteric pocket of PDE5 is identified by molecular modeling and structural biology, which enables the discovery of highly selective PDE5 inhibitors from natural product evodiamine (EVO). The crystal structure of PDE5 with bound EVO derivative ( S )-7e revealed that binding of ( S )-7e to the novel allosteric pocket induced dramatic conformation changes in the H-loop with a maximum 24 Å movement of their Cα atoms. This movement directly blocks the binding of substrate/inhibitors to the PDE5 active site, which is different from all traditional PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil. These derivatives showed >570-fold selectivity over PDE6C and PDE11A and achieved potent efficacy for the effective treatment of pulmonary hypertension in vivo.
|
Inhibition of human PDE5A1 D563A mutant expressed in Escherichia coli BL21 incubated for 15 mins using [3H]-cGMP as substrate by liquid scintillation counting method
|
Homo sapiens
|
1.2
nM
|
|
Journal : J Med Chem
Title : Discovery of Evodiamine Derivatives as Highly Selective PDE5 Inhibitors Targeting a Unique Allosteric Pocket.
Year : 2020
Volume : 63
Issue : 17
First Page : 9828
Last Page : 9837
Authors : Zhang T,Lai Z,Yuan S,Huang YY,Dong G,Sheng C,Ke H,Luo HB
Abstract : Clinical use of phosphodiesterase-5 (PDE5) inhibitors is limited by several side effects due to weak isoform selectivity. Herein, a unique allosteric pocket of PDE5 is identified by molecular modeling and structural biology, which enables the discovery of highly selective PDE5 inhibitors from natural product evodiamine (EVO). The crystal structure of PDE5 with bound EVO derivative ( S )-7e revealed that binding of ( S )-7e to the novel allosteric pocket induced dramatic conformation changes in the H-loop with a maximum 24 Å movement of their Cα atoms. This movement directly blocks the binding of substrate/inhibitors to the PDE5 active site, which is different from all traditional PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil. These derivatives showed >570-fold selectivity over PDE6C and PDE11A and achieved potent efficacy for the effective treatment of pulmonary hypertension in vivo.
|
Inhibition of human PDE5A1 catalytic domain (Glu535 to Gln860 residues) expressed in Escherichia coli BL21 using [3H]-cGMP as substrate preincubated for 15 mins followed by snake venom 5'-nucleotidase and further incubated for 10 mins by scintillation counting method
|
Homo sapiens
|
4.9
nM
|
|
|
Inhibition of human full length His-tagged PDE5A1 expressed in baculovirus infected Sf9 insect cells using [3H]-cGMP as substrate preincubated for 15 mins followed by snake venom 5'-nucleotidase and further incubated for 10 mins by scintillation counting method
|
Homo sapiens
|
3.0
nM
|
|
|
Inhibition of recombinant full length GST-tagged PDE5A1 (unknown origin) expressed in baculovirus infected Sf9 insect cells using TAMRA-cGMP as substrate incubated for 1.5 hrs by IMAP-FP assay
|
Homo sapiens
|
3.0
nM
|
|
