|
In vitro antagonistic activity against human androgen receptor (hAR) expressed in CV-1 cells
|
Homo sapiens
|
157.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Nonsteroidal androgen receptor agonists based on 4-(trifluoromethyl)-2H-pyrano[3,2-g]quinolin-2-one.
Year : 1999
Volume : 9
Issue : 7
First Page : 1003
Last Page : 1008
Authors : Edwards JP, Higuchi RI, Winn DT, Pooley CL, Caferro TR, Hamann LG, Zhi L, Marschke KB, Goldman ME, Jones TK.
Abstract : A series of 2H-pyrano[3,2-g]quinolin-2-ones was prepared and tested for the ability to modulate the transcriptional activity of the human androgen receptor (hAR). The parent compound, 4-(trifluoromethyl)-2H-pyrano[3,2-g]quinolin-2-one, displayed moderate interaction with hAR, but substituted analogues were potent hAR modulators in vitro as measured by an hAR cotransfection assay in CV-1 cells and bound to hAR with high affinity in a whole cell assay. Several analogues were able to activate hAR-mediated gene transcription more potently and efficaciously than dihydrotestosterone.
|
Antagonistic activity (IC50) against human androgen receptor (hAR) in co-transfected CV-1 cell
|
None
|
157.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New nonsteroidal androgen receptor modulators based on 4-(trifluoromethyl)-2(1H)-pyrrolidino[3,2-g] quinolinone.
Year : 1998
Volume : 8
Issue : 7
First Page : 745
Last Page : 750
Authors : Edwards JP, West SJ, Pooley CL, Marschke KB, Farmer LJ, Jones TK.
Abstract : A series of 2(1H)-pyrrolidino[3,2-g]quinolinones was prepared and tested for the ability to modulate the transcriptional activity of the human androgen receptor (hAR). The parent compound, 4-(trifluoromethyl)-2(1H)-pyrrolidino[3,2-g]quinolinone, displayed moderate interaction with hAR, but more substituted analogues, particularly 6,7-disubstituted compounds, were potent hAR agonists in vitro.
|
Antagonistic activity against human androgen receptor (hAR) in co-transfected CV-1 cells.
|
None
|
157.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of a novel series of nonsteroidal, peripherally selective androgen receptor antagonists derived from 1,2-dihydropyridono[5,6-g]quinolines.
Year : 1998
Volume : 41
Issue : 4
First Page : 623
Last Page : 639
Authors : Hamann LG, Higuchi RI, Zhi L, Edwards JP, Wang XN, Marschke KB, Kong JW, Farmer LJ, Jones TK.
Abstract : A new nonsteroidal antiandrogenic pharmacophore has been discovered using cell-based cotransfection assays with human androgen receptor (hAR). This series of AR antagonists is structurally characterized by a linear tricyclic 1,2-dihydropyridono[5,6-g]quinoline core. Analogues inhibit AR-mediated reporter gene expression and bind to AR as potently as or better than any known AR antagonists. Several analogues also showed excellent in vivo activity in classic rodent models of AR antagonism, inhibiting growth of rat ventral prostate and seminal vesicles, without accompanying increases in serum gonadotropin and testosterone levels, as is seen with other AR antagonists. Investigations of structure-activity relationships surrounding this pharmacophore resulted in molecules with complete specificity for AR, antagonist activity on an AR mutant commonly observed in prostate cancer patients, and improved in vivo efficacy. Molecules based on this series of compounds have the potential to provide unique and effective clinical opportunities for treatment of prostate cancer and other androgen-dependent diseases.
|
In vitro agonistic activity against human androgen receptor (hAR) expressed in CV-1 cells; not active
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Nonsteroidal androgen receptor agonists based on 4-(trifluoromethyl)-2H-pyrano[3,2-g]quinolin-2-one.
Year : 1999
Volume : 9
Issue : 7
First Page : 1003
Last Page : 1008
Authors : Edwards JP, Higuchi RI, Winn DT, Pooley CL, Caferro TR, Hamann LG, Zhi L, Marschke KB, Goldman ME, Jones TK.
Abstract : A series of 2H-pyrano[3,2-g]quinolin-2-ones was prepared and tested for the ability to modulate the transcriptional activity of the human androgen receptor (hAR). The parent compound, 4-(trifluoromethyl)-2H-pyrano[3,2-g]quinolin-2-one, displayed moderate interaction with hAR, but substituted analogues were potent hAR modulators in vitro as measured by an hAR cotransfection assay in CV-1 cells and bound to hAR with high affinity in a whole cell assay. Several analogues were able to activate hAR-mediated gene transcription more potently and efficaciously than dihydrotestosterone.
|
In vitro binding affinity at human androgen receptor transfected into COS cells.
|
None
|
117.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Nonsteroidal androgen receptor agonists based on 4-(trifluoromethyl)-2H-pyrano[3,2-g]quinolin-2-one.
Year : 1999
Volume : 9
Issue : 7
First Page : 1003
Last Page : 1008
Authors : Edwards JP, Higuchi RI, Winn DT, Pooley CL, Caferro TR, Hamann LG, Zhi L, Marschke KB, Goldman ME, Jones TK.
Abstract : A series of 2H-pyrano[3,2-g]quinolin-2-ones was prepared and tested for the ability to modulate the transcriptional activity of the human androgen receptor (hAR). The parent compound, 4-(trifluoromethyl)-2H-pyrano[3,2-g]quinolin-2-one, displayed moderate interaction with hAR, but substituted analogues were potent hAR modulators in vitro as measured by an hAR cotransfection assay in CV-1 cells and bound to hAR with high affinity in a whole cell assay. Several analogues were able to activate hAR-mediated gene transcription more potently and efficaciously than dihydrotestosterone.
|
Inhibitory concentration against human androgen receptor (AR) dependent transcriptional activity in co-transfected mammalian CV-1 cells
|
None
|
338.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Effects of isosteric pyridone replacements in androgen receptor antagonists based on 1,2-dihydro- and 1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-8-pyridono[5,6-g]quin olines.
Year : 2000
Volume : 10
Issue : 5
First Page : 411
Last Page : 414
Authors : Kong JW, Hamann LG, Ruppar DA, Edwards JP, Marschke KB, Jones TK.
Abstract : A series of nonsteroidal human androgen receptor (hAR) antagonists based on 8-substituted 1,2-dihydro- and 1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethylpyrido[3,2-g]quin olines was synthesized. Compounds in this series were tested for the ability to bind to hAR and inhibit hAR-dependent transcription in a mammalian cellular background.
|
Binding affinity against Androgen receptor transfected into COS cells
|
None
|
82.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New nonsteroidal androgen receptor modulators based on 4-(trifluoromethyl)-2(1H)-pyrrolidino[3,2-g] quinolinone.
Year : 1998
Volume : 8
Issue : 7
First Page : 745
Last Page : 750
Authors : Edwards JP, West SJ, Pooley CL, Marschke KB, Farmer LJ, Jones TK.
Abstract : A series of 2(1H)-pyrrolidino[3,2-g]quinolinones was prepared and tested for the ability to modulate the transcriptional activity of the human androgen receptor (hAR). The parent compound, 4-(trifluoromethyl)-2(1H)-pyrrolidino[3,2-g]quinolinone, displayed moderate interaction with hAR, but more substituted analogues, particularly 6,7-disubstituted compounds, were potent hAR agonists in vitro.
|
Binding affinity for human androgen receptor transfected into mammalian COS-1 cells
|
None
|
117.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Effects of isosteric pyridone replacements in androgen receptor antagonists based on 1,2-dihydro- and 1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-8-pyridono[5,6-g]quin olines.
Year : 2000
Volume : 10
Issue : 5
First Page : 411
Last Page : 414
Authors : Kong JW, Hamann LG, Ruppar DA, Edwards JP, Marschke KB, Jones TK.
Abstract : A series of nonsteroidal human androgen receptor (hAR) antagonists based on 8-substituted 1,2-dihydro- and 1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethylpyrido[3,2-g]quin olines was synthesized. Compounds in this series were tested for the ability to bind to hAR and inhibit hAR-dependent transcription in a mammalian cellular background.
|
Binding affinity for human androgen receptor in transiently-transfected COS-1 cells.
|
None
|
117.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological activity of a novel series of nonsteroidal, peripherally selective androgen receptor antagonists derived from 1,2-dihydropyridono[5,6-g]quinolines.
Year : 1998
Volume : 41
Issue : 4
First Page : 623
Last Page : 639
Authors : Hamann LG, Higuchi RI, Zhi L, Edwards JP, Wang XN, Marschke KB, Kong JW, Farmer LJ, Jones TK.
Abstract : A new nonsteroidal antiandrogenic pharmacophore has been discovered using cell-based cotransfection assays with human androgen receptor (hAR). This series of AR antagonists is structurally characterized by a linear tricyclic 1,2-dihydropyridono[5,6-g]quinoline core. Analogues inhibit AR-mediated reporter gene expression and bind to AR as potently as or better than any known AR antagonists. Several analogues also showed excellent in vivo activity in classic rodent models of AR antagonism, inhibiting growth of rat ventral prostate and seminal vesicles, without accompanying increases in serum gonadotropin and testosterone levels, as is seen with other AR antagonists. Investigations of structure-activity relationships surrounding this pharmacophore resulted in molecules with complete specificity for AR, antagonist activity on an AR mutant commonly observed in prostate cancer patients, and improved in vivo efficacy. Molecules based on this series of compounds have the potential to provide unique and effective clinical opportunities for treatment of prostate cancer and other androgen-dependent diseases.
|
In vivo binding affinity for rat ventral prostate androgen receptor by displacement of [3H]R-1881
|
Rattus norvegicus
|
330.0
nM
|
|
Journal : J. Med. Chem.
Title : Antiandrogenic steroidal sulfonyl heterocycles. Utility of electrostatic complementarity in defining bioisosteric sulfonyl heterocycles.
Year : 1992
Volume : 35
Issue : 10
First Page : 1663
Last Page : 1670
Authors : Mallamo JP, Pilling GM, Wetzel JR, Kowalczyk PJ, Bell MR, Kullnig RK, Batzold FH, Juniewicz PE, Winneker RC, Luss HR.
Abstract : Complementarity of electrostatic potential surface maps was utilized in defining bioisosteric steroidal androgen receptor antagonists. Semiempirical and ab initio level calculations performed on a series of methanesulfonyl heterocycles indicated the requirement for a partial negative charge at the heteroatom attached to C-3 of the steroid nucleus to attain androgen receptor affinity. Synthesis and testing of six heterocycle A-ring-fused dihydroethisterone derivatives support this hypothesis, and we have identified two new androgen receptor antagonists of this class.
|
Binding affinity for androgen receptor in human MDA-453 cells
|
Homo sapiens
|
64.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure based approach to the design of bicyclic-1H-isoindole-1,3(2H)-dione based androgen receptor antagonists.
Year : 2005
Volume : 15
Issue : 2
First Page : 271
Last Page : 276
Authors : Salvati ME, Balog A, Shan W, Wei DD, Pickering D, Attar RM, Geng J, Rizzo CA, Gottardis MM, Weinmann R, Krystek SR, Sack J, An Y, Kish K.
Abstract : A novel series of isoindoledione based compounds were identified as potent antagonists of the androgen receptor (AR). Co-crystallization of members of this family of inhibitors was successfully accomplished with the T877A AR LBD. A working model of how this class of compounds functions to antagonize the AR was created. Based on this model, it was proposed that expanding the bicyclic portion of the molecule should result in analogs which function as effective antagonists against a variety of AR isoforms. In contrast to what was predicted by the model, SAR around this new series was dictated by the aniline portion rather than the bicyclic portion of the molecule.
|
Inhibition of [3H]DHT binding to androgen receptor of MDA-453 cells
|
Homo sapiens
|
64.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of a novel class of androgen receptor antagonists based on the bicyclic-1H-isoindole-1,3(2H)-dione nucleus.
Year : 2005
Volume : 15
Issue : 2
First Page : 389
Last Page : 393
Authors : Salvati ME, Balog A, Wei DD, Pickering D, Attar RM, Geng J, Rizzo CA, Hunt JT, Gottardis MM, Weinmann R, Martinez R.
Abstract : A novel series of isoindoledione based compounds were identified as potent antagonists of the androgen receptor (AR). SAR around this series revealed dramatic differences in binding and function in mutant variants (MT) of the AR as compared to the wild type (WT) receptor. Optimization of the aniline portion revealed substitution patterns, which yielded potent antagonist activity against the WT AR as well as the MT AR found in the LNCaP and PCa2b human prostate tumor cell lines.
|
Inhibition of [3H]-DHT binding to T877A androgen receptor of LNCaP cells
|
Homo sapiens
|
35.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of a novel class of androgen receptor antagonists based on the bicyclic-1H-isoindole-1,3(2H)-dione nucleus.
Year : 2005
Volume : 15
Issue : 2
First Page : 389
Last Page : 393
Authors : Salvati ME, Balog A, Wei DD, Pickering D, Attar RM, Geng J, Rizzo CA, Hunt JT, Gottardis MM, Weinmann R, Martinez R.
Abstract : A novel series of isoindoledione based compounds were identified as potent antagonists of the androgen receptor (AR). SAR around this series revealed dramatic differences in binding and function in mutant variants (MT) of the AR as compared to the wild type (WT) receptor. Optimization of the aniline portion revealed substitution patterns, which yielded potent antagonist activity against the WT AR as well as the MT AR found in the LNCaP and PCa2b human prostate tumor cell lines.
|
Displacement of [3H]DHT from androgen receptor of human MDA-453 cells
|
Homo sapiens
|
65.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis and evaluation of [2.2.1]-bicycloazahydantoins as androgen receptor antagonists.
Year : 2004
Volume : 14
Issue : 24
First Page : 6107
Last Page : 6111
Authors : Balog A, Salvati ME, Shan W, Mathur A, Leith LW, Wei DD, Attar RM, Geng J, Rizzo CA, Wang C, Krystek SR, Tokarski JS, Hunt JT, Gottardis M, Weinmann R.
Abstract : A novel series of [2.2.1]-azahydantoins has been designed and synthesized in an enantiospecific manner. The ability of these compounds to act as antagonists to the androgen receptor was investigated and several were found to have potent activity in vitro.
|
Inhibition of androgen receptor in human MDA-453 cells
|
Homo sapiens
|
173.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure based approach to the design of bicyclic-1H-isoindole-1,3(2H)-dione based androgen receptor antagonists.
Year : 2005
Volume : 15
Issue : 2
First Page : 271
Last Page : 276
Authors : Salvati ME, Balog A, Shan W, Wei DD, Pickering D, Attar RM, Geng J, Rizzo CA, Gottardis MM, Weinmann R, Krystek SR, Sack J, An Y, Kish K.
Abstract : A novel series of isoindoledione based compounds were identified as potent antagonists of the androgen receptor (AR). Co-crystallization of members of this family of inhibitors was successfully accomplished with the T877A AR LBD. A working model of how this class of compounds functions to antagonize the AR was created. Based on this model, it was proposed that expanding the bicyclic portion of the molecule should result in analogs which function as effective antagonists against a variety of AR isoforms. In contrast to what was predicted by the model, SAR around this new series was dictated by the aniline portion rather than the bicyclic portion of the molecule.
|
Displacement of [3H]R-1881 from Androgen receptor of LNCaP cells
|
Homo sapiens
|
940.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model.
Year : 2005
Volume : 48
Issue : 8
First Page : 2972
Last Page : 2984
Authors : Handratta VD, Vasaitis TS, Njar VC, Gediya LK, Kataria R, Chopra P, Newman D, Farquhar R, Guo Z, Qiu Y, Brodie AM.
Abstract : New chemical entities, steroidal C-17 benzoazoles (5, 6, 9 and 10) and pyrazines (14 and 15) were rationally designed and synthesized. The key reaction for synthesis of the benzoazoles involved the nucleophilic vinylic "addition-elimination" substitution reaction of 3beta-acetoxy-17-chloro-16-formylandrosta-5,16-diene (2) and benzoazole nucleophiles, while that for synthesis of pyrazines involved palladium-catalyzed cross-coupling reaction of 17-iodoandrosta-5,16-dien-3beta-ol (13) with tributylstannyl diazines. Some of the compounds were shown to be potent inhibitors of human CYP17 enzyme as well as potent antagonist of both wild type and mutant androgen receptors (AR). The most potent CYP17 inhibitors were 3beta-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (5, code named VN/124-1), 3beta-hydroxy-17-(5(1)-pyrimidyl)androsta-5,16-diene (15) and 17-(1H-benzimidazole-1-yl)androsta-4,16-dien-3-one (6), with IC(50) values of 300, 500 and 915 nM, respectively. Compounds 5, 6, 14 and 15 were effective at preventing binding of (3)H-R1881 (methyltrienolone, a stable synthetic androgen) to both the mutant LNCaP AR and the wild-type AR, but with a 2.2- to 5-fold higher binding efficiency to the latter. Compounds 5 and 6 were also shown to be potent pure AR antagonists. The cell growth studies showed that 5 and 6 inhibit the growth of DHT-stimulated LNCaP and LAPC4 prostate cancer cells with IC(50) values in the low micromolar range (i.e., <10 microM). Their inhibitory potencies were comparable to that of casodex but remarkably superior to that of flutamide. The pharmacokinetics of compounds 5 and 6 in mice were investigated. Following s.c. administration of 50 mg/kg of 5 and 6, peak plasma levels of 16.82 and 5.15 ng/mL, respectively, occurred after 30 to 60 min, both compounds were cleared rapidly from plasma (terminal half-lives of 44.17 and 39.93 min, respectively), and neither was detectable at 8 h. Remarkably, compound 5 was rapidly converted into a metabolite tentatively identified as 17-(1H-benzimidazol-1-yl)androsta-3-one. When tested in vivo, 5 proved to be very effective at inhibiting the growth of androgen-dependent LAPC4 human prostate tumor xenograft, while 6 was ineffective. Compound 5 (50 mg/kg/twice daily) resulted in a 93.8% reduction (P = 0.00065) in the mean final tumor volume compared with controls, and it was also significantly more effective than castration. To our knowledge, this is the first example of an antihormonal agent (an inhibitor of androgen synthesis (CYP17 inhibitor)/antiandrogen) that is significantly more effective than castration in suppression of androgen-dependent prostate tumor growth. In view of these impressive anticancer properties, compound 5 is a strong candidate for development for the treatment of human prostate cancer.
|
In vitro antagonistic activity against androgen receptor of MDA-453 cells
|
Homo sapiens
|
170.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis and evaluation of [2.2.1]-bicycloazahydantoins as androgen receptor antagonists.
Year : 2004
Volume : 14
Issue : 24
First Page : 6107
Last Page : 6111
Authors : Balog A, Salvati ME, Shan W, Mathur A, Leith LW, Wei DD, Attar RM, Geng J, Rizzo CA, Wang C, Krystek SR, Tokarski JS, Hunt JT, Gottardis M, Weinmann R.
Abstract : A novel series of [2.2.1]-azahydantoins has been designed and synthesized in an enantiospecific manner. The ability of these compounds to act as antagonists to the androgen receptor was investigated and several were found to have potent activity in vitro.
|
In vitro antagonistic activity against mutant androgen receptor of LNCap cells
|
Homo sapiens
|
400.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis and evaluation of [2.2.1]-bicycloazahydantoins as androgen receptor antagonists.
Year : 2004
Volume : 14
Issue : 24
First Page : 6107
Last Page : 6111
Authors : Balog A, Salvati ME, Shan W, Mathur A, Leith LW, Wei DD, Attar RM, Geng J, Rizzo CA, Wang C, Krystek SR, Tokarski JS, Hunt JT, Gottardis M, Weinmann R.
Abstract : A novel series of [2.2.1]-azahydantoins has been designed and synthesized in an enantiospecific manner. The ability of these compounds to act as antagonists to the androgen receptor was investigated and several were found to have potent activity in vitro.
|
Inhibition of human androgen receptor of breast carcinoma MDA-453 cells in reporter gene assay
|
Homo sapiens
|
173.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of a novel class of androgen receptor antagonists based on the bicyclic-1H-isoindole-1,3(2H)-dione nucleus.
Year : 2005
Volume : 15
Issue : 2
First Page : 389
Last Page : 393
Authors : Salvati ME, Balog A, Wei DD, Pickering D, Attar RM, Geng J, Rizzo CA, Hunt JT, Gottardis MM, Weinmann R, Martinez R.
Abstract : A novel series of isoindoledione based compounds were identified as potent antagonists of the androgen receptor (AR). SAR around this series revealed dramatic differences in binding and function in mutant variants (MT) of the AR as compared to the wild type (WT) receptor. Optimization of the aniline portion revealed substitution patterns, which yielded potent antagonist activity against the WT AR as well as the MT AR found in the LNCaP and PCa2b human prostate tumor cell lines.
|
Inhibition of T877A androgen receptor of human prostate cancer cells in reporter gene assay
|
Homo sapiens
|
400.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of a novel class of androgen receptor antagonists based on the bicyclic-1H-isoindole-1,3(2H)-dione nucleus.
Year : 2005
Volume : 15
Issue : 2
First Page : 389
Last Page : 393
Authors : Salvati ME, Balog A, Wei DD, Pickering D, Attar RM, Geng J, Rizzo CA, Hunt JT, Gottardis MM, Weinmann R, Martinez R.
Abstract : A novel series of isoindoledione based compounds were identified as potent antagonists of the androgen receptor (AR). SAR around this series revealed dramatic differences in binding and function in mutant variants (MT) of the AR as compared to the wild type (WT) receptor. Optimization of the aniline portion revealed substitution patterns, which yielded potent antagonist activity against the WT AR as well as the MT AR found in the LNCaP and PCa2b human prostate tumor cell lines.
|
Inhibition of androgen dependent human prostate cancer cell MDA-MB-PCa2b proliferation
|
Homo sapiens
|
725.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure based approach to the design of bicyclic-1H-isoindole-1,3(2H)-dione based androgen receptor antagonists.
Year : 2005
Volume : 15
Issue : 2
First Page : 271
Last Page : 276
Authors : Salvati ME, Balog A, Shan W, Wei DD, Pickering D, Attar RM, Geng J, Rizzo CA, Gottardis MM, Weinmann R, Krystek SR, Sack J, An Y, Kish K.
Abstract : A novel series of isoindoledione based compounds were identified as potent antagonists of the androgen receptor (AR). Co-crystallization of members of this family of inhibitors was successfully accomplished with the T877A AR LBD. A working model of how this class of compounds functions to antagonize the AR was created. Based on this model, it was proposed that expanding the bicyclic portion of the molecule should result in analogs which function as effective antagonists against a variety of AR isoforms. In contrast to what was predicted by the model, SAR around this new series was dictated by the aniline portion rather than the bicyclic portion of the molecule.
|
Inhibition of L701H/T877A mutant androgen receptor of human prostate cancer MDAMB-PCa2b cell proliferation
|
Homo sapiens
|
725.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of a novel class of androgen receptor antagonists based on the bicyclic-1H-isoindole-1,3(2H)-dione nucleus.
Year : 2005
Volume : 15
Issue : 2
First Page : 389
Last Page : 393
Authors : Salvati ME, Balog A, Wei DD, Pickering D, Attar RM, Geng J, Rizzo CA, Hunt JT, Gottardis MM, Weinmann R, Martinez R.
Abstract : A novel series of isoindoledione based compounds were identified as potent antagonists of the androgen receptor (AR). SAR around this series revealed dramatic differences in binding and function in mutant variants (MT) of the AR as compared to the wild type (WT) receptor. Optimization of the aniline portion revealed substitution patterns, which yielded potent antagonist activity against the WT AR as well as the MT AR found in the LNCaP and PCa2b human prostate tumor cell lines.
|
Binding affinity for mutant T877A Androgen receptor in human LNCaP cells
|
Homo sapiens
|
35.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure based approach to the design of bicyclic-1H-isoindole-1,3(2H)-dione based androgen receptor antagonists.
Year : 2005
Volume : 15
Issue : 2
First Page : 271
Last Page : 276
Authors : Salvati ME, Balog A, Shan W, Wei DD, Pickering D, Attar RM, Geng J, Rizzo CA, Gottardis MM, Weinmann R, Krystek SR, Sack J, An Y, Kish K.
Abstract : A novel series of isoindoledione based compounds were identified as potent antagonists of the androgen receptor (AR). Co-crystallization of members of this family of inhibitors was successfully accomplished with the T877A AR LBD. A working model of how this class of compounds functions to antagonize the AR was created. Based on this model, it was proposed that expanding the bicyclic portion of the molecule should result in analogs which function as effective antagonists against a variety of AR isoforms. In contrast to what was predicted by the model, SAR around this new series was dictated by the aniline portion rather than the bicyclic portion of the molecule.
|
Inhibition of mutant T877A Androgen receptor in human LNCaP cells
|
Homo sapiens
|
400.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure based approach to the design of bicyclic-1H-isoindole-1,3(2H)-dione based androgen receptor antagonists.
Year : 2005
Volume : 15
Issue : 2
First Page : 271
Last Page : 276
Authors : Salvati ME, Balog A, Shan W, Wei DD, Pickering D, Attar RM, Geng J, Rizzo CA, Gottardis MM, Weinmann R, Krystek SR, Sack J, An Y, Kish K.
Abstract : A novel series of isoindoledione based compounds were identified as potent antagonists of the androgen receptor (AR). Co-crystallization of members of this family of inhibitors was successfully accomplished with the T877A AR LBD. A working model of how this class of compounds functions to antagonize the AR was created. Based on this model, it was proposed that expanding the bicyclic portion of the molecule should result in analogs which function as effective antagonists against a variety of AR isoforms. In contrast to what was predicted by the model, SAR around this new series was dictated by the aniline portion rather than the bicyclic portion of the molecule.
|
Inhibition of AR mediated transcriptional activation using reporter assay
|
Homo sapiens
|
890.0
nM
|
|
Journal : J. Med. Chem.
Title : (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3- yl]piperazine-1-carboxamide (YM580) as an orally potent and peripherally selective nonsteroidal androgen receptor antagonist.
Year : 2006
Volume : 49
Issue : 2
First Page : 716
Last Page : 726
Authors : Kinoyama I, Taniguchi N, Toyoshima A, Nozawa E, Kamikubo T, Imamura M, Matsuhisa A, Samizu K, Kawanimani E, Niimi T, Hamada N, Koutoku H, Furutani T, Kudoh M, Okada M, Ohta M, Tsukamoto S.
Abstract : A novel series of trans-N-aryl-2,5-dimethylpiperazine-1-carboxamide derivatives was synthesized and their androgen receptor (AR) antagonist activities and in vivo antiandrogenic effects were evaluated. Pharmacological assays indicated that compound 33 was a potent AR antagonist, and subsequent optical resolution provided (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3-yl]piperazine-1-carboxamide (33a, YM580) which exhibited the most potent antiandrogenic activity. Unlike bicalutamide, compound 33a decreased the weight of rat ventral prostate in a dose-dependent manner (ED(50) = 2.2 mg/kg/day), and induced the maximum antiandrogenic effect, comparable to that of surgical castration, without significantly affecting serum testosterone levels. Compound 33a is a promising clinical candidate for prostate cancer monotherapy.
|
Effect on ventral prostate weight with reference to control in Wistar rat at 10 mg/kg/day, po
|
Rattus norvegicus
|
45.0
%
|
|
Journal : J. Med. Chem.
Title : (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3- yl]piperazine-1-carboxamide (YM580) as an orally potent and peripherally selective nonsteroidal androgen receptor antagonist.
Year : 2006
Volume : 49
Issue : 2
First Page : 716
Last Page : 726
Authors : Kinoyama I, Taniguchi N, Toyoshima A, Nozawa E, Kamikubo T, Imamura M, Matsuhisa A, Samizu K, Kawanimani E, Niimi T, Hamada N, Koutoku H, Furutani T, Kudoh M, Okada M, Ohta M, Tsukamoto S.
Abstract : A novel series of trans-N-aryl-2,5-dimethylpiperazine-1-carboxamide derivatives was synthesized and their androgen receptor (AR) antagonist activities and in vivo antiandrogenic effects were evaluated. Pharmacological assays indicated that compound 33 was a potent AR antagonist, and subsequent optical resolution provided (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3-yl]piperazine-1-carboxamide (33a, YM580) which exhibited the most potent antiandrogenic activity. Unlike bicalutamide, compound 33a decreased the weight of rat ventral prostate in a dose-dependent manner (ED(50) = 2.2 mg/kg/day), and induced the maximum antiandrogenic effect, comparable to that of surgical castration, without significantly affecting serum testosterone levels. Compound 33a is a promising clinical candidate for prostate cancer monotherapy.
|
Inhibition of human AR
|
Homo sapiens
|
19.0
nM
|
|
Journal : J. Med. Chem.
Title : (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3- yl]piperazine-1-carboxamide (YM580) as an orally potent and peripherally selective nonsteroidal androgen receptor antagonist.
Year : 2006
Volume : 49
Issue : 2
First Page : 716
Last Page : 726
Authors : Kinoyama I, Taniguchi N, Toyoshima A, Nozawa E, Kamikubo T, Imamura M, Matsuhisa A, Samizu K, Kawanimani E, Niimi T, Hamada N, Koutoku H, Furutani T, Kudoh M, Okada M, Ohta M, Tsukamoto S.
Abstract : A novel series of trans-N-aryl-2,5-dimethylpiperazine-1-carboxamide derivatives was synthesized and their androgen receptor (AR) antagonist activities and in vivo antiandrogenic effects were evaluated. Pharmacological assays indicated that compound 33 was a potent AR antagonist, and subsequent optical resolution provided (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3-yl]piperazine-1-carboxamide (33a, YM580) which exhibited the most potent antiandrogenic activity. Unlike bicalutamide, compound 33a decreased the weight of rat ventral prostate in a dose-dependent manner (ED(50) = 2.2 mg/kg/day), and induced the maximum antiandrogenic effect, comparable to that of surgical castration, without significantly affecting serum testosterone levels. Compound 33a is a promising clinical candidate for prostate cancer monotherapy.
|
Inhibition of rat AR
|
Rattus norvegicus
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3- yl]piperazine-1-carboxamide (YM580) as an orally potent and peripherally selective nonsteroidal androgen receptor antagonist.
Year : 2006
Volume : 49
Issue : 2
First Page : 716
Last Page : 726
Authors : Kinoyama I, Taniguchi N, Toyoshima A, Nozawa E, Kamikubo T, Imamura M, Matsuhisa A, Samizu K, Kawanimani E, Niimi T, Hamada N, Koutoku H, Furutani T, Kudoh M, Okada M, Ohta M, Tsukamoto S.
Abstract : A novel series of trans-N-aryl-2,5-dimethylpiperazine-1-carboxamide derivatives was synthesized and their androgen receptor (AR) antagonist activities and in vivo antiandrogenic effects were evaluated. Pharmacological assays indicated that compound 33 was a potent AR antagonist, and subsequent optical resolution provided (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3-yl]piperazine-1-carboxamide (33a, YM580) which exhibited the most potent antiandrogenic activity. Unlike bicalutamide, compound 33a decreased the weight of rat ventral prostate in a dose-dependent manner (ED(50) = 2.2 mg/kg/day), and induced the maximum antiandrogenic effect, comparable to that of surgical castration, without significantly affecting serum testosterone levels. Compound 33a is a promising clinical candidate for prostate cancer monotherapy.
|
Inhibition of rat AR-mediated reporter gene expression in COS7 cells
|
Rattus norvegicus
|
850.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of indole-containing tetracycles as a new scaffold for androgen receptor ligands.
Year : 2006
Volume : 16
Issue : 12
First Page : 3233
Last Page : 3237
Authors : Zhang X, Li X, Allan GF, Musto A, Lundeen SG, Sui Z.
Abstract : A novel series of tetracyclic indoles have been designed, synthesized and evaluated as androgen receptor (AR) ligands. Studies of structure-activity relationships (SARs) were investigated, which led to some compounds in this series as strong binders to androgen receptors.
|
Inhibition of prostate weight in Sprague-Dawley rat at 2 mg/day, po relative to control
|
Rattus norvegicus
|
70.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and SAR of novel hydantoin derivatives as selective androgen receptor modulators.
Year : 2006
Volume : 16
Issue : 22
First Page : 5763
Last Page : 5766
Authors : Zhang X, Allan GF, Sbriscia T, Linton O, Lundeen SG, Sui Z.
Abstract : A novel series of hydantoin derivatives were identified by in vivo studies as tissue selective androgen receptor modulators. SAR around this series revealed that the function of the ligand could be altered by minor structural modification.
|
Inhibition of seminal vesicle weight in Sprague-Dawley rat at 2 mg/day, po relative to control
|
Rattus norvegicus
|
80.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and SAR of novel hydantoin derivatives as selective androgen receptor modulators.
Year : 2006
Volume : 16
Issue : 22
First Page : 5763
Last Page : 5766
Authors : Zhang X, Allan GF, Sbriscia T, Linton O, Lundeen SG, Sui Z.
Abstract : A novel series of hydantoin derivatives were identified by in vivo studies as tissue selective androgen receptor modulators. SAR around this series revealed that the function of the ligand could be altered by minor structural modification.
|
Displacement of [3H]mibolerone from androgen receptor expressed in CHOK1 cells
|
Homo sapiens
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of 7alpha-substituted dihydrotestosterones as androgen receptor pure antagonists and their structure-activity relationships.
Year : 2007
Volume : 15
Issue : 1
First Page : 174
Last Page : 185
Authors : Tachibana K, Imaoka I, Yoshino H, Emura T, Kodama H, Furuta Y, Kato N, Nakamura M, Ohta M, Taniguchi K, Ishikura N, Nagamuta M, Onuma E, Sato H.
Abstract : A series of 7alpha-substituted dihydrotestosterone derivatives were synthesized and evaluated for androgen receptor (AR) pure antagonistic activity. From reporter gene assay (RGA), the compound with a side chain containing N-n-butyl-N-methyl amide (19a) showed pure antagonistic activity (IC(50)=340nM, FI(5)>10,000nM), whereas known AR antagonists showed partial agonistic activities. The optimization of 19a led to compound 23 (CH4892280), which showed more potent pure antagonistic activity (IC(50)=190nM, FI(5)>10,000nM). The SARs of tested compounds suggested that the length of the side chain and the substituents on the amide nitrogen are important for pure antagonistic activities.
|
Antagonist activity at androgen receptor expressed in HeLa cells assessed as inhibition of dihydrotestosterone-induced transcriptional activity by reporter gene assay
|
Homo sapiens
|
140.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of 7alpha-substituted dihydrotestosterones as androgen receptor pure antagonists and their structure-activity relationships.
Year : 2007
Volume : 15
Issue : 1
First Page : 174
Last Page : 185
Authors : Tachibana K, Imaoka I, Yoshino H, Emura T, Kodama H, Furuta Y, Kato N, Nakamura M, Ohta M, Taniguchi K, Ishikura N, Nagamuta M, Onuma E, Sato H.
Abstract : A series of 7alpha-substituted dihydrotestosterone derivatives were synthesized and evaluated for androgen receptor (AR) pure antagonistic activity. From reporter gene assay (RGA), the compound with a side chain containing N-n-butyl-N-methyl amide (19a) showed pure antagonistic activity (IC(50)=340nM, FI(5)>10,000nM), whereas known AR antagonists showed partial agonistic activities. The optimization of 19a led to compound 23 (CH4892280), which showed more potent pure antagonistic activity (IC(50)=190nM, FI(5)>10,000nM). The SARs of tested compounds suggested that the length of the side chain and the substituents on the amide nitrogen are important for pure antagonistic activities.
|
Antagonist activity at human androgen receptor expressed in CV1 cells
|
Homo sapiens
|
162.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of an androgen receptor modulator pharmacophore based on 2-quinolinones.
Year : 2007
Volume : 17
Issue : 6
First Page : 1523
Last Page : 1526
Authors : van Oeveren A, Pio BA, Tegley CM, Higuchi RI, Wu M, Jones TK, Marschke KB, Negro-Vilar A, Zhi L.
Abstract : A series of alkylamino-2-quinolinone compounds (3) was discovered as androgen receptor modulators based on an early linear tricyclic quinoline pharmacophore (1). The series demonstrated selective high binding affinity to androgen receptor and potent receptor modulating activities in the cotransfection assays.
|
Binding affinity to human androgen receptor expressed in CV1 cells
|
Homo sapiens
|
151.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of an androgen receptor modulator pharmacophore based on 2-quinolinones.
Year : 2007
Volume : 17
Issue : 6
First Page : 1523
Last Page : 1526
Authors : van Oeveren A, Pio BA, Tegley CM, Higuchi RI, Wu M, Jones TK, Marschke KB, Negro-Vilar A, Zhi L.
Abstract : A series of alkylamino-2-quinolinone compounds (3) was discovered as androgen receptor modulators based on an early linear tricyclic quinoline pharmacophore (1). The series demonstrated selective high binding affinity to androgen receptor and potent receptor modulating activities in the cotransfection assays.
|
Inhibition of testoterone-induced prostate weight in castrated immature Sprague-Dawley rat at 2 mg/day relative to control
|
Rattus norvegicus
|
70.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-(2,2,2-Trifluoroethyl)-5,6-dichlorobenzimidazole derivatives as potent androgen receptor antagonists.
Year : 2007
Volume : 17
Issue : 4
First Page : 955
Last Page : 958
Authors : Ng RA, Guan J, Alford VC, Lanter JC, Allan GF, Sbriscia T, Lundeen SG, Sui Z.
Abstract : The synthesis and in vivo SAR of N-benzyl, N-aceto, and N-ethylene ether derivatives of 2-(2,2,2-trifluoroethyl)-5,6-dichloro-benzimidazole as novel androgen receptor antagonists are described. SAR studies led to the discovery of 4-bromo-benzyl benzimidazole 17 as a more potent androgen receptor antagonist in the rat prostate (ID(50)=0.13mg/day), compared with bicalutamide (ID(50)=0.23mg/day).
|
Displacement of [3H]mibolerone from human androgen receptor expressed in CHOK1 cells
|
Homo sapiens
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery and structure-activity relationships of new steroidal compounds bearing a carboxy-terminal side chain as androgen receptor pure antagonists.
Year : 2007
Volume : 17
Issue : 20
First Page : 5573
Last Page : 5576
Authors : Tachibana K, Imaoka I, Yoshino H, Kato N, Nakamura M, Ohta M, Kawata H, Taniguchi K, Ishikura N, Nagamuta M, Onuma E, Sato H.
Abstract : Lead optimization of CH4892280 (4), an androgen receptor (AR) pure antagonist, was investigated. Compounds 6 and 7, which have a carboxylic acid at the end of the side chain at the position 7alpha of dihydrotestosterone (DHT), showed partial agonistic activities in reporter gene assay (RGA). Conversion of the steroidal core structure to 17alpha-methyltestosterone gave compound 14, which showed weak pure antagonistic activity. Optimization of the side chain by the insertion of a phenyl ring led to compounds 22 and 28-30, which showed pure antagonistic activities at submicromolar concentrations. The structure-activity relationships were clarified.
|
Antagonist activity at human androgen receptor expressed in HeLa cells assessed as inhibition of dihydrotestosterone induced transcriptional activity by reporter gene assay
|
Homo sapiens
|
140.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery and structure-activity relationships of new steroidal compounds bearing a carboxy-terminal side chain as androgen receptor pure antagonists.
Year : 2007
Volume : 17
Issue : 20
First Page : 5573
Last Page : 5576
Authors : Tachibana K, Imaoka I, Yoshino H, Kato N, Nakamura M, Ohta M, Kawata H, Taniguchi K, Ishikura N, Nagamuta M, Onuma E, Sato H.
Abstract : Lead optimization of CH4892280 (4), an androgen receptor (AR) pure antagonist, was investigated. Compounds 6 and 7, which have a carboxylic acid at the end of the side chain at the position 7alpha of dihydrotestosterone (DHT), showed partial agonistic activities in reporter gene assay (RGA). Conversion of the steroidal core structure to 17alpha-methyltestosterone gave compound 14, which showed weak pure antagonistic activity. Optimization of the side chain by the insertion of a phenyl ring led to compounds 22 and 28-30, which showed pure antagonistic activities at submicromolar concentrations. The structure-activity relationships were clarified.
|
Inhibition of prostate weight in testosterone treated castrated immature Sprague-Dawley rat at 2 mg/day
|
Rattus norvegicus
|
70.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and SAR of potent and selective androgen receptor antagonists: 5,6-Dichloro-benzimidazole derivatives.
Year : 2007
Volume : 17
Issue : 3
First Page : 784
Last Page : 788
Authors : Ng RA, Guan J, Alford VC, Lanter JC, Allan GF, Sbriscia T, Linton O, Lundeen SG, Sui Z.
Abstract : The synthesis and in vivo SAR of 5,6-dichloro-benzimidazole derivatives as novel selective androgen receptor antagonists are described. During screening of 2-alkyl benzimidazoles, it was found that a trifluoromethyl group greatly enhances antagonist activity in the prostate. Benzimidazole 1 is a potent AR antagonist in the rat prostate (ID50 = 0.15 mg/day).
|
Displacement of [3H]DHT from human androgen receptor in MDA453 cells
|
Homo sapiens
|
64.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification and optimization of a novel series of [2.2.1]-oxabicyclo imide-based androgen receptor antagonists.
Year : 2008
Volume : 18
Issue : 6
First Page : 1910
Last Page : 1915
Authors : Salvati ME, Balog A, Shan W, Rampulla R, Giese S, Mitt T, Furch JA, Vite GD, Attar RM, Jure-Kunkel M, Geng J, Rizzo CA, Gottardis MM, Krystek SR, Gougoutas J, Galella MA, Obermeier M, Fura A, Chandrasena G.
Abstract : A novel series of [2.2.1]-oxabicyclo imide-based compounds were identified as potent antagonists of the androgen receptor. Molecular modeling and iterative drug design were applied to optimize this series. The lead compound [3aS-(3aalpha,4beta,5beta,7beta,7aalpha)]-4-(octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile was shown to have potent in vivo efficacy after oral dosing in the CWR22 human prostate tumor xenograph model.
|
Antagonist activity at human androgen receptor in MDA453 cells by alkaline phosphatase reporter gene assay
|
Homo sapiens
|
173.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification and optimization of a novel series of [2.2.1]-oxabicyclo imide-based androgen receptor antagonists.
Year : 2008
Volume : 18
Issue : 6
First Page : 1910
Last Page : 1915
Authors : Salvati ME, Balog A, Shan W, Rampulla R, Giese S, Mitt T, Furch JA, Vite GD, Attar RM, Jure-Kunkel M, Geng J, Rizzo CA, Gottardis MM, Krystek SR, Gougoutas J, Galella MA, Obermeier M, Fura A, Chandrasena G.
Abstract : A novel series of [2.2.1]-oxabicyclo imide-based compounds were identified as potent antagonists of the androgen receptor. Molecular modeling and iterative drug design were applied to optimize this series. The lead compound [3aS-(3aalpha,4beta,5beta,7beta,7aalpha)]-4-(octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile was shown to have potent in vivo efficacy after oral dosing in the CWR22 human prostate tumor xenograph model.
|
Antagonist activity at human androgen receptor african green monkey CV1 cells by cotransfection assay
|
Homo sapiens
|
162.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a novel series of nonsteroidal androgen receptor modulators: 5- or 6-oxachrysen-2-ones.
Year : 2008
Volume : 18
Issue : 11
First Page : 3431
Last Page : 3435
Authors : Zhao S, Shen Y, van Oeveren A, Marschke KB, Zhi L.
Abstract : A novel oxachrysenone series (2) of nonsteroidal selective androgen receptor modulators (SARM) was developed based on the 6-aryl-2-quinolinones (1). Synthesis and preliminary SAR results based on in vitro assays are discussed. In the cotransfection assay, lead compound 5d showed AR agonist activity more potent than dihydrotestosterone (DHT), whereas compound 17b was a potent antagonist similar to bicalutamide.
|
Binding affinity to human androgen receptor expressed in monkey COS7 cells by whole cell binding assay
|
Homo sapiens
|
151.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a novel series of nonsteroidal androgen receptor modulators: 5- or 6-oxachrysen-2-ones.
Year : 2008
Volume : 18
Issue : 11
First Page : 3431
Last Page : 3435
Authors : Zhao S, Shen Y, van Oeveren A, Marschke KB, Zhi L.
Abstract : A novel oxachrysenone series (2) of nonsteroidal selective androgen receptor modulators (SARM) was developed based on the 6-aryl-2-quinolinones (1). Synthesis and preliminary SAR results based on in vitro assays are discussed. In the cotransfection assay, lead compound 5d showed AR agonist activity more potent than dihydrotestosterone (DHT), whereas compound 17b was a potent antagonist similar to bicalutamide.
|
Activity at androgen receptor in human Saos2 cells assessed as IL6 repression
|
Homo sapiens
|
232.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a novel series of nonsteroidal androgen receptor modulators: 5- or 6-oxachrysen-2-ones.
Year : 2008
Volume : 18
Issue : 11
First Page : 3431
Last Page : 3435
Authors : Zhao S, Shen Y, van Oeveren A, Marschke KB, Zhi L.
Abstract : A novel oxachrysenone series (2) of nonsteroidal selective androgen receptor modulators (SARM) was developed based on the 6-aryl-2-quinolinones (1). Synthesis and preliminary SAR results based on in vitro assays are discussed. In the cotransfection assay, lead compound 5d showed AR agonist activity more potent than dihydrotestosterone (DHT), whereas compound 17b was a potent antagonist similar to bicalutamide.
|
Antagonist activity at human androgen receptor in CV1 cells by transcriptional activation assay
|
Homo sapiens
|
162.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Selective androgen receptor modulators based on a series of 7H-[1,4]oxazino[3,2-g]quinolin-7-ones with improved in vivo activity.
Year : 2008
Volume : 18
Issue : 9
First Page : 2967
Last Page : 2971
Authors : Long YO, Higuchi RI, Caferro TR, Lau TL, Wu M, Cummings ML, Martinborough EA, Marschke KB, Chang WY, López FJ, Karanewsky DS, Zhi L.
Abstract : Modification on a lead series of [1,4]oxazino[3,2-g]quinolin-7-ones at the 2-position led to selective androgen receptor modulators with improved in vivo activity. The most potent analog (-)-33a exhibited full maintenance of levator ani muscle at 3mg/kg and reduced activity on ventral prostate weight in a 2-week orally-dosed and orchidectomized rat maintenance assay.
|
Displacement of [3H]DHT from human Androgen receptor in human MDA-MB-453 cells
|
Homo sapiens
|
151.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Selective androgen receptor modulators based on a series of 7H-[1,4]oxazino[3,2-g]quinolin-7-ones with improved in vivo activity.
Year : 2008
Volume : 18
Issue : 9
First Page : 2967
Last Page : 2971
Authors : Long YO, Higuchi RI, Caferro TR, Lau TL, Wu M, Cummings ML, Martinborough EA, Marschke KB, Chang WY, López FJ, Karanewsky DS, Zhi L.
Abstract : Modification on a lead series of [1,4]oxazino[3,2-g]quinolin-7-ones at the 2-position led to selective androgen receptor modulators with improved in vivo activity. The most potent analog (-)-33a exhibited full maintenance of levator ani muscle at 3mg/kg and reduced activity on ventral prostate weight in a 2-week orally-dosed and orchidectomized rat maintenance assay.
|
Displacement of [3H]mibolerone from human AR expressed in CHO-K1 cells after 2 hrs by scintillation counting
|
Homo sapiens
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity relationships of bioisosteric replacement of the carboxylic acid in novel androgen receptor pure antagonists.
Year : 2010
Volume : 18
Issue : 9
First Page : 3159
Last Page : 3168
Authors : Yoshino H, Sato H, Tachibana K, Shiraishi T, Nakamura M, Ohta M, Ishikura N, Nagamuta M, Onuma E, Nakagawa T, Arai S, Ahn KH, Jung KY, Kawata H.
Abstract : A series of 5,5-dimethylthiohydantoin derivatives were synthesized and evaluated for androgen receptor pure antagonistic activities for the treatment of hormone refractory prostate cancer. CH4933468 (32d) with a sulfonamide side chain not only exhibited antagonistic activity with no agonistic activity in the reporter gene assay but also inhibited the growth of bicalutamide-resistant cell lines. This compound also inhibited tumor growth of the LNCaP xenograft in mice dose-dependently.
|
Antagonist activity at AR in bicalutamide-resistant human LNCAP cells assessed as effect on cell proliferation after 6 days
|
Homo sapiens
|
550.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity relationships of bioisosteric replacement of the carboxylic acid in novel androgen receptor pure antagonists.
Year : 2010
Volume : 18
Issue : 9
First Page : 3159
Last Page : 3168
Authors : Yoshino H, Sato H, Tachibana K, Shiraishi T, Nakamura M, Ohta M, Ishikura N, Nagamuta M, Onuma E, Nakagawa T, Arai S, Ahn KH, Jung KY, Kawata H.
Abstract : A series of 5,5-dimethylthiohydantoin derivatives were synthesized and evaluated for androgen receptor pure antagonistic activities for the treatment of hormone refractory prostate cancer. CH4933468 (32d) with a sulfonamide side chain not only exhibited antagonistic activity with no agonistic activity in the reporter gene assay but also inhibited the growth of bicalutamide-resistant cell lines. This compound also inhibited tumor growth of the LNCaP xenograft in mice dose-dependently.
|
Displacement of [3H]DHT from AR in human MDA-MB-453 cells
|
Homo sapiens
|
64.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of 4-[3,5-dioxo-11-oxa-4,9-diazatricyclo[5.3.1.0(2,6)]undec-4-yl]-2-trifluoromethyl-benzonitriles as androgen receptor antagonists.
Year : 2010
Volume : 20
Issue : 15
First Page : 4491
Last Page : 4495
Authors : Xiao HY, Balog A, Attar RM, Fairfax D, Fleming LB, Holst CL, Martin GS, Rossiter LM, Chen J, Cvjic ME, Dell-John J, Geng J, Gottardis MM, Han WC, Nation A, Obermeier M, Rizzo CA, Schweizer L, Spires T, Shan W, Gavai A, Salvati ME, Vite G.
Abstract : A novel series of 4-[3,5-dioxo-11-oxa-4,9-diazatricyclo[5.3.1.0(2,6)]undec-4-yl]-2-trifluoromethyl-benzonitriles has been synthesized. The ability of these compounds to act as antagonists of the androgen receptor was investigated and several were found to have potent activity in vitro and in vivo.
|
Antagonist activity at human wild type AR expressed in human MDA-MB-435 cells by transactivation assay
|
Homo sapiens
|
173.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of 4-[3,5-dioxo-11-oxa-4,9-diazatricyclo[5.3.1.0(2,6)]undec-4-yl]-2-trifluoromethyl-benzonitriles as androgen receptor antagonists.
Year : 2010
Volume : 20
Issue : 15
First Page : 4491
Last Page : 4495
Authors : Xiao HY, Balog A, Attar RM, Fairfax D, Fleming LB, Holst CL, Martin GS, Rossiter LM, Chen J, Cvjic ME, Dell-John J, Geng J, Gottardis MM, Han WC, Nation A, Obermeier M, Rizzo CA, Schweizer L, Spires T, Shan W, Gavai A, Salvati ME, Vite G.
Abstract : A novel series of 4-[3,5-dioxo-11-oxa-4,9-diazatricyclo[5.3.1.0(2,6)]undec-4-yl]-2-trifluoromethyl-benzonitriles has been synthesized. The ability of these compounds to act as antagonists of the androgen receptor was investigated and several were found to have potent activity in vitro and in vivo.
|
Antagonist activity at wild type human AR expressed in human LNCAP cells by transactivation assay
|
Homo sapiens
|
400.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of 4-[3,5-dioxo-11-oxa-4,9-diazatricyclo[5.3.1.0(2,6)]undec-4-yl]-2-trifluoromethyl-benzonitriles as androgen receptor antagonists.
Year : 2010
Volume : 20
Issue : 15
First Page : 4491
Last Page : 4495
Authors : Xiao HY, Balog A, Attar RM, Fairfax D, Fleming LB, Holst CL, Martin GS, Rossiter LM, Chen J, Cvjic ME, Dell-John J, Geng J, Gottardis MM, Han WC, Nation A, Obermeier M, Rizzo CA, Schweizer L, Spires T, Shan W, Gavai A, Salvati ME, Vite G.
Abstract : A novel series of 4-[3,5-dioxo-11-oxa-4,9-diazatricyclo[5.3.1.0(2,6)]undec-4-yl]-2-trifluoromethyl-benzonitriles has been synthesized. The ability of these compounds to act as antagonists of the androgen receptor was investigated and several were found to have potent activity in vitro and in vivo.
|
Antagonist activity at human androgen receptor expressed in human CV1 cells assessed as inhibition of receptor-mediated transactivation by MMTV-luciferase reporter gene assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 20-Aminosteroids as a novel class of selective and complete androgen receptor antagonists and inhibitors of prostate cancer cell growth.
Year : 2010
Volume : 18
Issue : 19
First Page : 6960
Last Page : 6969
Authors : Fousteris MA, Schubert U, Roell D, Roediger J, Bailis N, Nikolaropoulos SS, Baniahmad A, Giannis A.
Abstract : Here, the synthesis and the evaluation of novel 20-aminosteroids on androgen receptor (AR) activity is reported. Compounds 11 and 18 of the series inhibit both the wild type and the T877A mutant AR-mediated transactivation indicating AR antagonistic function. Interestingly, minor structural changes such as stereoisomers of the amino lactame moiety exhibit preferences for antagonism among wild type and mutant AR. Other tested nuclear receptors are only weakly or not affected. In line with this, the prostate cancer cell growth of androgen-dependent but not of cancer cells lacking expression of the AR is inhibited. Further, the expression of the prostate specific antigen used as a diagnostic marker is also repressed. Finally steroid 18 enhances cellular senescence that might explain in part the growth inhibition mediated by this derivative. Steroids 11 and 18 are the first steroids that act as complete AR antagonists and exhibit AR specificity.
|
Antiandrogen activity against androgen receptor in androgen-dependent mouse SC3 cells assessed as inhibition of testosterone-induced cell proliferation by WST1 assay
|
Mus musculus
|
670.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel selective anti-androgens with a diphenylpentane skeleton.
Year : 2010
Volume : 20
Issue : 22
First Page : 6661
Last Page : 6666
Authors : Maruyama K, Noguchi-Yachide T, Sugita K, Hashimoto Y, Ishikawa M.
Abstract : We have proposed a multi-template approach for drug development, focusing on similar fold structures of proteins, and have effectively generated lead compounds for several drug targets. Modification of these polypharmacological lead compounds is then needed to generate target-selective compounds. In the work presented here, we aimed at separation of the anti-androgen activity and vitamin D activity of previously identified diphenylpentane lead compounds. Based on the determined X-ray crystal structures of androgen receptor and vitamin D receptor, bulky substituents were introduced at the t-butyl group in the lead compounds 2 and 3. As a result of this structural development, we obtained 16c, which exhibits more potent anti-androgen activity (IC(50): 0.13 μM) than clinically used anti-androgen bicalutamide (IC(50): 0.67 μM) with 30-fold selectivity over vitamin D activity. This result indicates that lead compounds obtained via the multi-template approach can indeed be structurally modified to generate target-selective compounds.
|
Antagonist activity at human AR expressed in human HeLa cells co-transfected with MMTV-Luc-Hyg after 48 hrs by transient-luciferase reporter gene assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design and synthesis of an androgen receptor pure antagonist (CH5137291) for the treatment of castration-resistant prostate cancer.
Year : 2010
Volume : 18
Issue : 23
First Page : 8150
Last Page : 8157
Authors : Yoshino H, Sato H, Shiraishi T, Tachibana K, Emura T, Honma A, Ishikura N, Tsunenari T, Watanabe M, Nishimoto A, Nakamura R, Nakagawa T, Ohta M, Takata N, Furumoto K, Kimura K, Kawata H.
Abstract : A series of 5,5-dimethylthiohydantoin derivatives were synthesized and evaluated for androgen receptor pure antagonistic activities for the treatment of castration-resistant prostate cancer. Since CH4933468, which we reported previously, had a problem with agonist metabolites, novel thiohydantoin derivatives were identified by applying two strategies. One was the replacement of the alkylsulfonamide moiety by a phenylsulfonamide to avoid the production of agonist metabolites. The other was the replacement of the phenyl ring with a pyridine ring to improve in vivo potency and reduce hERG affinity. Pharmacological assays indicated that CH5137291 (17b) was a potent AR pure antagonist which did not produce the agonist metabolite. Moreover, CH5137291 completely inhibited in vivo tumor growth of LNCaP-BC2, a castration-resistant prostate cancer model.
|
Antagonist activity at AR in human bicalutamide-resistant LNCAP cells assessed as inhibition of cell proliferation after 6 days
|
Homo sapiens
|
600.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design and synthesis of an androgen receptor pure antagonist (CH5137291) for the treatment of castration-resistant prostate cancer.
Year : 2010
Volume : 18
Issue : 23
First Page : 8150
Last Page : 8157
Authors : Yoshino H, Sato H, Shiraishi T, Tachibana K, Emura T, Honma A, Ishikura N, Tsunenari T, Watanabe M, Nishimoto A, Nakamura R, Nakagawa T, Ohta M, Takata N, Furumoto K, Kimura K, Kawata H.
Abstract : A series of 5,5-dimethylthiohydantoin derivatives were synthesized and evaluated for androgen receptor pure antagonistic activities for the treatment of castration-resistant prostate cancer. Since CH4933468, which we reported previously, had a problem with agonist metabolites, novel thiohydantoin derivatives were identified by applying two strategies. One was the replacement of the alkylsulfonamide moiety by a phenylsulfonamide to avoid the production of agonist metabolites. The other was the replacement of the phenyl ring with a pyridine ring to improve in vivo potency and reduce hERG affinity. Pharmacological assays indicated that CH5137291 (17b) was a potent AR pure antagonist which did not produce the agonist metabolite. Moreover, CH5137291 completely inhibited in vivo tumor growth of LNCaP-BC2, a castration-resistant prostate cancer model.
|
Inhibition of human ERG at 10 uM by whole cell patch-clamp technique
|
Homo sapiens
|
7.4
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design and synthesis of an androgen receptor pure antagonist (CH5137291) for the treatment of castration-resistant prostate cancer.
Year : 2010
Volume : 18
Issue : 23
First Page : 8150
Last Page : 8157
Authors : Yoshino H, Sato H, Shiraishi T, Tachibana K, Emura T, Honma A, Ishikura N, Tsunenari T, Watanabe M, Nishimoto A, Nakamura R, Nakagawa T, Ohta M, Takata N, Furumoto K, Kimura K, Kawata H.
Abstract : A series of 5,5-dimethylthiohydantoin derivatives were synthesized and evaluated for androgen receptor pure antagonistic activities for the treatment of castration-resistant prostate cancer. Since CH4933468, which we reported previously, had a problem with agonist metabolites, novel thiohydantoin derivatives were identified by applying two strategies. One was the replacement of the alkylsulfonamide moiety by a phenylsulfonamide to avoid the production of agonist metabolites. The other was the replacement of the phenyl ring with a pyridine ring to improve in vivo potency and reduce hERG affinity. Pharmacological assays indicated that CH5137291 (17b) was a potent AR pure antagonist which did not produce the agonist metabolite. Moreover, CH5137291 completely inhibited in vivo tumor growth of LNCaP-BC2, a castration-resistant prostate cancer model.
|
Displacement of [3H]testosterone from Sprague-Dawley rat AR by liquid scintillation counting
|
Rattus norvegicus
|
54.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of tricyclic tetrahydroquinolines as a new series of nonsteroidal selective androgen receptor modulators (SARMs).
Year : 2011
Volume : 21
Issue : 6
First Page : 1744
Last Page : 1747
Authors : Nagata N, Miyakawa M, Amano S, Furuya K, Yamamoto N, Inoguchi K.
Abstract : Some tricyclic tetrahydroquinolines (THQs) were found to have the potential of a new series of nonsteroidal selective androgen receptor modulators (SARMs). Compound 5b was first designed and synthesized under our hypothesis based on a four-point pharmacophoric requirement of the 3-carbonyl, 18-methyl, 17-hydroxyl, and 13-quaternary carbon groups of dihydrotestosterone (DHT). It was revealed that this compound exhibits not only a strong androgen receptor (AR) agonistic activity (EC(50)=9.2 nM) but also the highest selectivity in binding affinity to AR among the steroid hormone receptors. Furthermore, this compound showed a weak virilizing effect with retention of the desired anabolic effect as compared with DHT in vivo.
|
Antagonist activity at androgen receptor T877A mutant expressed in african green monkey CV1 cells assessed as inhibition of dihydrotestosterone-induced transcriptional activity at 1 to 1000 nM by luciferase reporter gene assay
|
None
|
84.0
%
|
|
Journal : J. Med. Chem.
Title : Unexpected binding orientation of bulky-B-ring anti-androgens and implications for future drug targets.
Year : 2011
Volume : 54
Issue : 11
First Page : 3973
Last Page : 3976
Authors : Duke CB, Jones A, Bohl CE, Dalton JT, Miller DD.
Abstract : Several new androgen receptor antagonists were synthesized and found to have varying activities across typically anti-androgen resistant mutants (Thr877 → Ala and Trp741 → Leu) and markedly improved potency over previously reported pan-antagonists. X-ray crystallography of a new anti-androgen in an androgen receptor mutant (Thr877 → Ala) shows that the receptor can accommodate the added bulk presented by phenyl to naphthyl substitution, casting doubt on previous reports of predicted binding orientation and the causes of antagonism in bulky-B-ring antagonists.
|
Displacement of [3H]testosterone from androgen receptor in Sprague-Dawley rat prostate gland after 2 hrs by liquid scintillation counting
|
Rattus norvegicus
|
25.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Tetrahydroquinolines as a novel series of nonsteroidal selective androgen receptor modulators: structural requirements for better physicochemical and biological properties.
Year : 2011
Volume : 21
Issue : 21
First Page : 6310
Last Page : 6313
Authors : Nagata N, Miyakawa M, Amano S, Furuya K, Yamamoto N, Nejishima H, Inoguchi K.
Abstract : A rationally designed tetrahydroquinoline (1) for nonsteroidal selective androgen receptor modulators was modified for the exploration of promising compounds by Grieco three-component condensation using various dienophiles. Based on the in vitro effects and physicochemical properties of the synthesized compounds, compound 4c was selected for further study. Compound 4c increased the femoral bone mineral density as much as DHT, but it reduced the uterus effect compared with DHT in ovariectomized rats. Thus, compound 4c has desirable osteoanabolic effects with weak undesirable effects on the uterus in a female osteoporosis model.
|
Antagonist activity at human AR overexpressed in human LNCAP cells at 1 uM by luciferase reporter gene assay in the presence of agonist R1881
|
Homo sapiens
|
72.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of aryloxy tetramethylcyclobutanes as novel androgen receptor antagonists.
Year : 2011
Volume : 54
Issue : 21
First Page : 7693
Last Page : 7704
Authors : Guo C, Linton A, Kephart S, Ornelas M, Pairish M, Gonzalez J, Greasley S, Nagata A, Burke BJ, Edwards M, Hosea N, Kang P, Hu W, Engebretsen J, Briere D, Shi M, Gukasyan H, Richardson P, Dack K, Underwood T, Johnson P, Morell A, Felstead R, Kuruma H, Matsimoto H, Zoubeidi A, Gleave M, Los G, Fanjul AN.
Abstract : An aryloxy tetramethylcyclobutane was identified as a novel template for androgen receptor (AR) antagonists via cell-based high-throughput screening. Follow-up to the initial "hit" established 5 as a viable lead. Further optimization to achieve full AR antagonism led to the discovery of 26 and 30, both of which demonstrated excellent in vivo tumor growth inhibition upon oral administration in a castration-resistant prostate cancer (CRPC) animal model.
|
Antitumor activity against human LNCAP cells xenografted in athymic nude Harlan Sprague-Dawley mouse assessed as tumor volume inhibition at 10 mg/kg, po administered once daily for 5 weeks measured after 5 weeks relative to vehicle treated control
|
Homo sapiens
|
41.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of aryloxy tetramethylcyclobutanes as novel androgen receptor antagonists.
Year : 2011
Volume : 54
Issue : 21
First Page : 7693
Last Page : 7704
Authors : Guo C, Linton A, Kephart S, Ornelas M, Pairish M, Gonzalez J, Greasley S, Nagata A, Burke BJ, Edwards M, Hosea N, Kang P, Hu W, Engebretsen J, Briere D, Shi M, Gukasyan H, Richardson P, Dack K, Underwood T, Johnson P, Morell A, Felstead R, Kuruma H, Matsimoto H, Zoubeidi A, Gleave M, Los G, Fanjul AN.
Abstract : An aryloxy tetramethylcyclobutane was identified as a novel template for androgen receptor (AR) antagonists via cell-based high-throughput screening. Follow-up to the initial "hit" established 5 as a viable lead. Further optimization to achieve full AR antagonism led to the discovery of 26 and 30, both of which demonstrated excellent in vivo tumor growth inhibition upon oral administration in a castration-resistant prostate cancer (CRPC) animal model.
|
Displacement of [17-alpha-methyl-3H]-mibolerone from human androgen receptor expressed in HEK293 derived FreeStyle293F cells after 3 hrs
|
Homo sapiens
|
54.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of 4-phenylpyrrole derivatives as novel androgen receptor antagonists.
Year : 2012
Volume : 20
Issue : 1
First Page : 422
Last Page : 434
Authors : Yamamoto S, Matsunaga N, Hitaka T, Yamada M, Hara T, Miyazaki J, Santou T, Kusaka M, Yamaoka M, Kanzaki N, Furuya S, Tasaka A, Hamamura K, Ito M.
Abstract : A series of 4-phenylpyrrole derivatives D were designed, synthesized, and evaluated for their potential as novel orally available androgen receptor antagonists therapeutically effective against castration-resistant prostate cancers. 4-Phenylpyrrole compound 1 exhibited androgen receptor (AR) antagonistic activity against T877A and W741C mutant-type ARs as well as wild-type AR. An arylmethyl group incorporated into compound 1 contributed to enhancement of antagonistic activity. Compound 4n, 1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile exhibited inhibitory effects on tumor cell growth against the bicalutamide-resistant LNCaP-cxD2 cell line as well as the androgen receptor-dependent JDCaP cell line in a mouse xenograft model. These results demonstrate that this series of pyrrole compounds are novel androgen receptor antagonists with efficacy against prostate cancer cells, including castration-resistant prostate cancers such as bicalutamide-resistant prostate cancer.
|
Displacement of [17-alpha-methyl-3H]-mibolerone from human androgen receptor T877A mutant expressed in HEK293 derived FreeStyle293F cells after 3 hrs
|
Homo sapiens
|
120.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of 4-phenylpyrrole derivatives as novel androgen receptor antagonists.
Year : 2012
Volume : 20
Issue : 1
First Page : 422
Last Page : 434
Authors : Yamamoto S, Matsunaga N, Hitaka T, Yamada M, Hara T, Miyazaki J, Santou T, Kusaka M, Yamaoka M, Kanzaki N, Furuya S, Tasaka A, Hamamura K, Ito M.
Abstract : A series of 4-phenylpyrrole derivatives D were designed, synthesized, and evaluated for their potential as novel orally available androgen receptor antagonists therapeutically effective against castration-resistant prostate cancers. 4-Phenylpyrrole compound 1 exhibited androgen receptor (AR) antagonistic activity against T877A and W741C mutant-type ARs as well as wild-type AR. An arylmethyl group incorporated into compound 1 contributed to enhancement of antagonistic activity. Compound 4n, 1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile exhibited inhibitory effects on tumor cell growth against the bicalutamide-resistant LNCaP-cxD2 cell line as well as the androgen receptor-dependent JDCaP cell line in a mouse xenograft model. These results demonstrate that this series of pyrrole compounds are novel androgen receptor antagonists with efficacy against prostate cancer cells, including castration-resistant prostate cancers such as bicalutamide-resistant prostate cancer.
|
Antagonist activity at human androgen receptor expressed in COS7 cells assessed as inhibition of DHT-induced luciferase activity after 24 hrs by reporter gene assay
|
Homo sapiens
|
330.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of 4-phenylpyrrole derivatives as novel androgen receptor antagonists.
Year : 2012
Volume : 20
Issue : 1
First Page : 422
Last Page : 434
Authors : Yamamoto S, Matsunaga N, Hitaka T, Yamada M, Hara T, Miyazaki J, Santou T, Kusaka M, Yamaoka M, Kanzaki N, Furuya S, Tasaka A, Hamamura K, Ito M.
Abstract : A series of 4-phenylpyrrole derivatives D were designed, synthesized, and evaluated for their potential as novel orally available androgen receptor antagonists therapeutically effective against castration-resistant prostate cancers. 4-Phenylpyrrole compound 1 exhibited androgen receptor (AR) antagonistic activity against T877A and W741C mutant-type ARs as well as wild-type AR. An arylmethyl group incorporated into compound 1 contributed to enhancement of antagonistic activity. Compound 4n, 1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile exhibited inhibitory effects on tumor cell growth against the bicalutamide-resistant LNCaP-cxD2 cell line as well as the androgen receptor-dependent JDCaP cell line in a mouse xenograft model. These results demonstrate that this series of pyrrole compounds are novel androgen receptor antagonists with efficacy against prostate cancer cells, including castration-resistant prostate cancers such as bicalutamide-resistant prostate cancer.
|
Antagonist activity at human androgen receptor T877A mutant expressed in COS7 cells assessed as inhibition of DHT-induced luciferase activity after 24 hrs by reporter gene assay
|
Homo sapiens
|
470.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of 4-phenylpyrrole derivatives as novel androgen receptor antagonists.
Year : 2012
Volume : 20
Issue : 1
First Page : 422
Last Page : 434
Authors : Yamamoto S, Matsunaga N, Hitaka T, Yamada M, Hara T, Miyazaki J, Santou T, Kusaka M, Yamaoka M, Kanzaki N, Furuya S, Tasaka A, Hamamura K, Ito M.
Abstract : A series of 4-phenylpyrrole derivatives D were designed, synthesized, and evaluated for their potential as novel orally available androgen receptor antagonists therapeutically effective against castration-resistant prostate cancers. 4-Phenylpyrrole compound 1 exhibited androgen receptor (AR) antagonistic activity against T877A and W741C mutant-type ARs as well as wild-type AR. An arylmethyl group incorporated into compound 1 contributed to enhancement of antagonistic activity. Compound 4n, 1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile exhibited inhibitory effects on tumor cell growth against the bicalutamide-resistant LNCaP-cxD2 cell line as well as the androgen receptor-dependent JDCaP cell line in a mouse xenograft model. These results demonstrate that this series of pyrrole compounds are novel androgen receptor antagonists with efficacy against prostate cancer cells, including castration-resistant prostate cancers such as bicalutamide-resistant prostate cancer.
|
Agonist activity at human androgen receptor W741C mutant expressed in COS7 cells assessed as luciferase activity after 24 hrs by reporter gene assay
|
Homo sapiens
|
180.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of 4-phenylpyrrole derivatives as novel androgen receptor antagonists.
Year : 2012
Volume : 20
Issue : 1
First Page : 422
Last Page : 434
Authors : Yamamoto S, Matsunaga N, Hitaka T, Yamada M, Hara T, Miyazaki J, Santou T, Kusaka M, Yamaoka M, Kanzaki N, Furuya S, Tasaka A, Hamamura K, Ito M.
Abstract : A series of 4-phenylpyrrole derivatives D were designed, synthesized, and evaluated for their potential as novel orally available androgen receptor antagonists therapeutically effective against castration-resistant prostate cancers. 4-Phenylpyrrole compound 1 exhibited androgen receptor (AR) antagonistic activity against T877A and W741C mutant-type ARs as well as wild-type AR. An arylmethyl group incorporated into compound 1 contributed to enhancement of antagonistic activity. Compound 4n, 1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile exhibited inhibitory effects on tumor cell growth against the bicalutamide-resistant LNCaP-cxD2 cell line as well as the androgen receptor-dependent JDCaP cell line in a mouse xenograft model. These results demonstrate that this series of pyrrole compounds are novel androgen receptor antagonists with efficacy against prostate cancer cells, including castration-resistant prostate cancers such as bicalutamide-resistant prostate cancer.
|
Displacement of [17-alpha-methyl-3H]mibolerone from androgen receptor expressed in HEK293 cells after 3 hrs
|
None
|
54.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of 4-arylmethyl-1-phenylpyrazole and 4-aryloxy-1-phenylpyrazole derivatives as novel androgen receptor antagonists.
Year : 2012
Volume : 20
Issue : 7
First Page : 2338
Last Page : 2352
Authors : Yamamoto S, Tomita N, Suzuki Y, Suzaki T, Kaku T, Hara T, Yamaoka M, Kanzaki N, Hasuoka A, Baba A, Ito M.
Abstract : A series of 4-arylmethyl-1-phenylpyrazole and 4-aryloxy-1-phenylpyrazole compounds B were designed, synthesized, and evaluated for their potential as new-generation androgen receptor (AR) antagonists therapeutically effective against castration-resistant prostate cancer (CRPC). Introduction of a bulky amide substituent (R(2)) to the terminal aryl ring of the 4-arylmethyl group favored the reduction of agonistic activity and improved the pharmacokinetic (PK) properties. Similarly, introduction of a bulky substituent in the 4-aryloxy derivatives also resulted in improved PK properties. Compounds 28 h and 44b exhibited potent antitumor effects against a CRPC model of LNCaP-hr cell line in a mouse xenograft model. On the contrary, bicalutamide showed only partial suppression of tumor growth. These results suggest that the novel pyrazole derivatives are new-generation AR antagonists, different from the 'first-generation' antagonists such as bicalutamide in a CRPC treatment model.
|
Displacement of [17-alpha-methyl-3H]mibolerone from androgen receptor T877A mutant expressed in HEK293 cells after 3 hrs
|
None
|
120.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of 4-arylmethyl-1-phenylpyrazole and 4-aryloxy-1-phenylpyrazole derivatives as novel androgen receptor antagonists.
Year : 2012
Volume : 20
Issue : 7
First Page : 2338
Last Page : 2352
Authors : Yamamoto S, Tomita N, Suzuki Y, Suzaki T, Kaku T, Hara T, Yamaoka M, Kanzaki N, Hasuoka A, Baba A, Ito M.
Abstract : A series of 4-arylmethyl-1-phenylpyrazole and 4-aryloxy-1-phenylpyrazole compounds B were designed, synthesized, and evaluated for their potential as new-generation androgen receptor (AR) antagonists therapeutically effective against castration-resistant prostate cancer (CRPC). Introduction of a bulky amide substituent (R(2)) to the terminal aryl ring of the 4-arylmethyl group favored the reduction of agonistic activity and improved the pharmacokinetic (PK) properties. Similarly, introduction of a bulky substituent in the 4-aryloxy derivatives also resulted in improved PK properties. Compounds 28 h and 44b exhibited potent antitumor effects against a CRPC model of LNCaP-hr cell line in a mouse xenograft model. On the contrary, bicalutamide showed only partial suppression of tumor growth. These results suggest that the novel pyrazole derivatives are new-generation AR antagonists, different from the 'first-generation' antagonists such as bicalutamide in a CRPC treatment model.
|
Antagonist activity at androgen receptor expressed in Cos7 cells assessed as inhibition of dihydrotestosterone-induced luciferase activity after 24 hrs by reporter gene assay
|
None
|
330.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of 4-arylmethyl-1-phenylpyrazole and 4-aryloxy-1-phenylpyrazole derivatives as novel androgen receptor antagonists.
Year : 2012
Volume : 20
Issue : 7
First Page : 2338
Last Page : 2352
Authors : Yamamoto S, Tomita N, Suzuki Y, Suzaki T, Kaku T, Hara T, Yamaoka M, Kanzaki N, Hasuoka A, Baba A, Ito M.
Abstract : A series of 4-arylmethyl-1-phenylpyrazole and 4-aryloxy-1-phenylpyrazole compounds B were designed, synthesized, and evaluated for their potential as new-generation androgen receptor (AR) antagonists therapeutically effective against castration-resistant prostate cancer (CRPC). Introduction of a bulky amide substituent (R(2)) to the terminal aryl ring of the 4-arylmethyl group favored the reduction of agonistic activity and improved the pharmacokinetic (PK) properties. Similarly, introduction of a bulky substituent in the 4-aryloxy derivatives also resulted in improved PK properties. Compounds 28 h and 44b exhibited potent antitumor effects against a CRPC model of LNCaP-hr cell line in a mouse xenograft model. On the contrary, bicalutamide showed only partial suppression of tumor growth. These results suggest that the novel pyrazole derivatives are new-generation AR antagonists, different from the 'first-generation' antagonists such as bicalutamide in a CRPC treatment model.
|
Antagonist activity at androgen receptor T877A mutant expressed in Cos7 cells assessed as inhibition of dihydrotestosterone-induced luciferase activity after 24 hrs by reporter gene assay
|
None
|
470.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of 4-arylmethyl-1-phenylpyrazole and 4-aryloxy-1-phenylpyrazole derivatives as novel androgen receptor antagonists.
Year : 2012
Volume : 20
Issue : 7
First Page : 2338
Last Page : 2352
Authors : Yamamoto S, Tomita N, Suzuki Y, Suzaki T, Kaku T, Hara T, Yamaoka M, Kanzaki N, Hasuoka A, Baba A, Ito M.
Abstract : A series of 4-arylmethyl-1-phenylpyrazole and 4-aryloxy-1-phenylpyrazole compounds B were designed, synthesized, and evaluated for their potential as new-generation androgen receptor (AR) antagonists therapeutically effective against castration-resistant prostate cancer (CRPC). Introduction of a bulky amide substituent (R(2)) to the terminal aryl ring of the 4-arylmethyl group favored the reduction of agonistic activity and improved the pharmacokinetic (PK) properties. Similarly, introduction of a bulky substituent in the 4-aryloxy derivatives also resulted in improved PK properties. Compounds 28 h and 44b exhibited potent antitumor effects against a CRPC model of LNCaP-hr cell line in a mouse xenograft model. On the contrary, bicalutamide showed only partial suppression of tumor growth. These results suggest that the novel pyrazole derivatives are new-generation AR antagonists, different from the 'first-generation' antagonists such as bicalutamide in a CRPC treatment model.
|
Antagonist activity at Androgen receptor T877A mutant (unknown origin) expressed in human Cos-7 cells co-expressing pGL3-MMTV-luc vector assessed as luciferase activity by reporter gene assay
|
Homo sapiens
|
470.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives as novel androgen receptor antagonists.
Year : 2013
Volume : 21
Issue : 1
First Page : 70
Last Page : 83
Authors : Yamamoto S, Kobayashi H, Kaku T, Aikawa K, Hara T, Yamaoka M, Kanzaki N, Hasuoka A, Baba A, Ito M.
Abstract : We designed and synthesized a series of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives D and evaluated their potential as novel androgen receptor (AR) antagonists therapeutically effective against castration-resistant prostate cancer (CRPC). Introduction of a methyl group at the 2-position (R(2)) of the pyrrolidine ring increased the AR binding affinity. The (2S,3R) configuration of the pyrrolidine ring was favorable for the AR antagonistic activity. It was found that introduction of an amide substituent (R(1)) and a pyridin-3-yl group (Q) was effective for reducing the AR agonistic activity which appeared during the optimization of lead compound 6. Compound 54 showed potent antitumor effects against a CRPC model of LNCaP-hr cell line in a mouse xenograft, in which bicalutamide exhibited only partial suppression of tumor growth. Thus, the pyrrolidine derivatives such as 54 are novel AR antagonists, and their properties having efficacy against CRPC are distinct from those of a representative first-generation antagonist, bicalutamide.
|
Antagonist activity at wild type Androgen receptor (unknown origin) expressed in human Cos-7 cells co-expressing pGL3-MMTV-luc vector assessed as luciferase activity by reporter gene assay
|
Homo sapiens
|
330.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives as novel androgen receptor antagonists.
Year : 2013
Volume : 21
Issue : 1
First Page : 70
Last Page : 83
Authors : Yamamoto S, Kobayashi H, Kaku T, Aikawa K, Hara T, Yamaoka M, Kanzaki N, Hasuoka A, Baba A, Ito M.
Abstract : We designed and synthesized a series of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives D and evaluated their potential as novel androgen receptor (AR) antagonists therapeutically effective against castration-resistant prostate cancer (CRPC). Introduction of a methyl group at the 2-position (R(2)) of the pyrrolidine ring increased the AR binding affinity. The (2S,3R) configuration of the pyrrolidine ring was favorable for the AR antagonistic activity. It was found that introduction of an amide substituent (R(1)) and a pyridin-3-yl group (Q) was effective for reducing the AR agonistic activity which appeared during the optimization of lead compound 6. Compound 54 showed potent antitumor effects against a CRPC model of LNCaP-hr cell line in a mouse xenograft, in which bicalutamide exhibited only partial suppression of tumor growth. Thus, the pyrrolidine derivatives such as 54 are novel AR antagonists, and their properties having efficacy against CRPC are distinct from those of a representative first-generation antagonist, bicalutamide.
|
Inhibition of Androgen receptor T877A mutant (unknown origin) expressed in Freestyle293F cells
|
Homo sapiens
|
120.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives as novel androgen receptor antagonists.
Year : 2013
Volume : 21
Issue : 1
First Page : 70
Last Page : 83
Authors : Yamamoto S, Kobayashi H, Kaku T, Aikawa K, Hara T, Yamaoka M, Kanzaki N, Hasuoka A, Baba A, Ito M.
Abstract : We designed and synthesized a series of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives D and evaluated their potential as novel androgen receptor (AR) antagonists therapeutically effective against castration-resistant prostate cancer (CRPC). Introduction of a methyl group at the 2-position (R(2)) of the pyrrolidine ring increased the AR binding affinity. The (2S,3R) configuration of the pyrrolidine ring was favorable for the AR antagonistic activity. It was found that introduction of an amide substituent (R(1)) and a pyridin-3-yl group (Q) was effective for reducing the AR agonistic activity which appeared during the optimization of lead compound 6. Compound 54 showed potent antitumor effects against a CRPC model of LNCaP-hr cell line in a mouse xenograft, in which bicalutamide exhibited only partial suppression of tumor growth. Thus, the pyrrolidine derivatives such as 54 are novel AR antagonists, and their properties having efficacy against CRPC are distinct from those of a representative first-generation antagonist, bicalutamide.
|
Inhibition of wild type Androgen receptor (unknown origin) expressed in Freestyle293F cells
|
Homo sapiens
|
54.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives as novel androgen receptor antagonists.
Year : 2013
Volume : 21
Issue : 1
First Page : 70
Last Page : 83
Authors : Yamamoto S, Kobayashi H, Kaku T, Aikawa K, Hara T, Yamaoka M, Kanzaki N, Hasuoka A, Baba A, Ito M.
Abstract : We designed and synthesized a series of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives D and evaluated their potential as novel androgen receptor (AR) antagonists therapeutically effective against castration-resistant prostate cancer (CRPC). Introduction of a methyl group at the 2-position (R(2)) of the pyrrolidine ring increased the AR binding affinity. The (2S,3R) configuration of the pyrrolidine ring was favorable for the AR antagonistic activity. It was found that introduction of an amide substituent (R(1)) and a pyridin-3-yl group (Q) was effective for reducing the AR agonistic activity which appeared during the optimization of lead compound 6. Compound 54 showed potent antitumor effects against a CRPC model of LNCaP-hr cell line in a mouse xenograft, in which bicalutamide exhibited only partial suppression of tumor growth. Thus, the pyrrolidine derivatives such as 54 are novel AR antagonists, and their properties having efficacy against CRPC are distinct from those of a representative first-generation antagonist, bicalutamide.
|
SANGER: Inhibition of human HT-3 cell growth in a cell viability assay.
|
Homo sapiens
|
731.34
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
Displacement of [3H]R1881 from AR in human MDA-MB-453 cells
|
Homo sapiens
|
31.0
nM
|
|
Journal : J. Med. Chem.
Title : Systematic structure modifications of multitarget prostate cancer drug candidate galeterone to produce novel androgen receptor down-regulating agents as an approach to treatment of advanced prostate cancer.
Year : 2013
Volume : 56
Issue : 12
First Page : 4880
Last Page : 4898
Authors : Purushottamachar P, Godbole AM, Gediya LK, Martin MS, Vasaitis TS, Kwegyir-Afful AK, Ramalingam S, Ates-Alagoz Z, Njar VC.
Abstract : As part of our program to explore the influence of small structural modifications of our drug candidate 3β-(hydroxy)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (galeterone, 5) on the modulation of the androgen receptor (AR), we have prepared and evaluated a series of novel C-3, C-16, and C-17 analogues. Using structure activity analysis, we established that the benzimidazole moiety at C-17 is essential and optimal and also that hydrophilic and heteroaromatic groups at C-3 enhance both antiproliferative (AP) and AR degrading (ARD) activities. The most potent antiproliferative compounds were 3β-(1H-imidazole-1-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (47), 3-((EZ)-hydroximino)-17-(1H-benzimidazol-1-yl)androsta-4,16-diene (36), and 3β-(pyridine-4-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (43), with GI50 values of 0.87, 1.91, and 2.57 μM, respectively. Compared to 5, compound 47 was 4- and 8-fold more potent with respect to AP and ARD activities, respectively. Importantly, we also discovered that our compounds, including 5, 36, 43, and 47, could degrade both full-length and truncated ARs in CWR22rv1 human prostate cancer cells. With these activities, they have potential for development as new drugs for the treatment of all forms of prostate cancer.
|
Inhibition of androgen receptor in human LNCAP cells after 1 day by luciferase reporter gene assay
|
Homo sapiens
|
270.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of non-LBD inhibitor for androgen receptor by structure-guide design.
Year : 2013
Volume : 23
Issue : 13
First Page : 3887
Last Page : 3890
Authors : Ryu BJ, Kim N, Kim JT, Koo TS, Yoo SE, Jeong SH, Kim SH, Kang NS.
Abstract : In this study, we synthesized the BF-3 binding small molecules, a series of pyridazinone-based compounds, as a novel class of non-LBP antiandrogens for treating prostate cancer by inhibiting androgen receptor. The new class compound was discovered to inhibitor the viability of AR-dependent human prostate LNCap cells and AR activity combining with the computational method. It showed a good physicochemical and PK property.
|
Antagonist activity at androgen receptor T877A mutant (unknown origin) expressed in human LNCAP cells assessed as inhibition of DHT-induced cell growth after 6 days by WST-8 assay
|
Homo sapiens
|
940.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Design and Synthesis of 4-(4-Benzoylaminophenoxy)phenol Derivatives As Androgen Receptor Antagonists.
Year : 2013
Volume : 4
Issue : 10
First Page : 937
Last Page : 941
Authors : Yamada A, Fujii S, Mori S, Kagechika H.
Abstract : We report the design and synthesis of novel 4-(4-benzoylaminophenoxy)phenol derivatives that bind to the androgen receptor (AR) ligand-binding domain and exhibit potent androgen-antagonistic activity. Compound 22 is one of the most potent of these derivatives, inhibiting the dihydrotestosterone-promoted growth of SC-3 cell line bearing wild-type AR (IC50 0.75 μM), LNCaP cell line bearing T877A-mutated AR (IC50 0.043 μM), and 22Rv1 cell line bearing H874Y-mutated AR (IC50 0.22 μM). Structure-activity relationship studies confirmed that the pharmacophore of these novel AR antagonists is distinct from the nitro- or cyano-substituted anilide substructure of other nonsteroidal AR antagonists. This novel pharmacophore is expected to provide a basis for designing new antiprostate cancer agents.
|
Antagonist activity at androgen receptor in human LNCAP cells assessed as inhibition of androgen-stimulated cell growth at 20 uM measured every 3 days relative to dihydrotestosterone
|
Homo sapiens
|
28.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Preliminary investigations into triazole derived androgen receptor antagonists.
Year : 2014
Volume : 22
Issue : 9
First Page : 2692
Last Page : 2706
Authors : Altimari JM, Niranjan B, Risbridger GP, Schweiker SS, Lohning AE, Henderson LC.
Abstract : A range of 1,4-substituted-1,2,3-N-phenyltriazoles were synthesized and evaluated as non-steroidal androgen receptor (AR) antagonists. The motivation for this study was to replace the N-phenyl amide portion of small molecule antiandrogens with a 1,2,3-triazole and determine effects, if any, on biological activity. The synthetic methodology presented herein is robust, high yielding and extremely rapid. Using this methodology a series of 17 N-aryl triazoles were synthesized from commercially available starting materials in less than 3h. After preliminary biological screening at 20 and 40 μM, the most promising three compounds were found to display IC50 values of 40-50 μM against androgen dependent (LNCaP) cells and serve as a starting point for further structure-activity investigations. All compounds in this work were the focus of an in silico study to dock the compounds into the human androgen receptor ligand binding domain (hARLBD) and compare their predicted binding affinity with known antiandrogens. A comparison of receptor-ligand interactions for the wild type and T877A mutant AR revealed two novel polar interactions. One with Q738 of the wild type site and the second with the mutated A877 residue.
|
Antagonist activity at androgen receptor in human LNCAP cells assessed as inhibition of androgen-stimulated cell growth at 40 uM measured every 3 days relative to dihydrotestosterone
|
Homo sapiens
|
33.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Preliminary investigations into triazole derived androgen receptor antagonists.
Year : 2014
Volume : 22
Issue : 9
First Page : 2692
Last Page : 2706
Authors : Altimari JM, Niranjan B, Risbridger GP, Schweiker SS, Lohning AE, Henderson LC.
Abstract : A range of 1,4-substituted-1,2,3-N-phenyltriazoles were synthesized and evaluated as non-steroidal androgen receptor (AR) antagonists. The motivation for this study was to replace the N-phenyl amide portion of small molecule antiandrogens with a 1,2,3-triazole and determine effects, if any, on biological activity. The synthetic methodology presented herein is robust, high yielding and extremely rapid. Using this methodology a series of 17 N-aryl triazoles were synthesized from commercially available starting materials in less than 3h. After preliminary biological screening at 20 and 40 μM, the most promising three compounds were found to display IC50 values of 40-50 μM against androgen dependent (LNCaP) cells and serve as a starting point for further structure-activity investigations. All compounds in this work were the focus of an in silico study to dock the compounds into the human androgen receptor ligand binding domain (hARLBD) and compare their predicted binding affinity with known antiandrogens. A comparison of receptor-ligand interactions for the wild type and T877A mutant AR revealed two novel polar interactions. One with Q738 of the wild type site and the second with the mutated A877 residue.
|
Antagonist activity against pSG5-tagged human androgen receptor expressed in COS1 cells assessed as reduction in receptor-mediated transcriptional activity by AR-regulated rat probasin promoter fragment driven firefly luciferase reporter assay
|
Homo sapiens
|
86.9
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of second-generation tropanol-based androgen receptor modulators.
Year : 2015
Volume : 58
Issue : 3
First Page : 1569
Last Page : 1574
Authors : Sundén H, Holland MC, Poutiainen PK, Jääskeläinen T, Pulkkinen JT, Palvimo JJ, Olsson R.
Abstract : To circumvent antiandrogen resistance in prostate cancer, antiandrogens effective for both the androgen receptor (AR) and AR mutants are required. The AR antagonists in this study originate from previous findings, which showed that subtle differences in substitution pattern lead to a conformational change that alters the ligand activity, rendering an agonist to an antagonist. We have identified small yet potent tropanol-based ligands possessing significant antiandrogenic activity with both wild-type AR and the two most common AR ligand binding domain (LBD) mutants.
|
Displacement of [3H]R1881 from pSG5-tagged human androgen receptor expressed in COS1 cells assessed as relative binding inhibition
|
Homo sapiens
|
86.9
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of second-generation tropanol-based androgen receptor modulators.
Year : 2015
Volume : 58
Issue : 3
First Page : 1569
Last Page : 1574
Authors : Sundén H, Holland MC, Poutiainen PK, Jääskeläinen T, Pulkkinen JT, Palvimo JJ, Olsson R.
Abstract : To circumvent antiandrogen resistance in prostate cancer, antiandrogens effective for both the androgen receptor (AR) and AR mutants are required. The AR antagonists in this study originate from previous findings, which showed that subtle differences in substitution pattern lead to a conformational change that alters the ligand activity, rendering an agonist to an antagonist. We have identified small yet potent tropanol-based ligands possessing significant antiandrogenic activity with both wild-type AR and the two most common AR ligand binding domain (LBD) mutants.
|
Antagonist activity against pSG5-tagged human androgen receptor expressed in COS1 cells assessed as receptor-mediated testosterone-induced transcriptional activity at 10 uM by AR-regulated rat probasin promoter fragment driven firefly luciferase reporter assay (Rvb = 100 +/- 5.7%)
|
Homo sapiens
|
15.5
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of second-generation tropanol-based androgen receptor modulators.
Year : 2015
Volume : 58
Issue : 3
First Page : 1569
Last Page : 1574
Authors : Sundén H, Holland MC, Poutiainen PK, Jääskeläinen T, Pulkkinen JT, Palvimo JJ, Olsson R.
Abstract : To circumvent antiandrogen resistance in prostate cancer, antiandrogens effective for both the androgen receptor (AR) and AR mutants are required. The AR antagonists in this study originate from previous findings, which showed that subtle differences in substitution pattern lead to a conformational change that alters the ligand activity, rendering an agonist to an antagonist. We have identified small yet potent tropanol-based ligands possessing significant antiandrogenic activity with both wild-type AR and the two most common AR ligand binding domain (LBD) mutants.
|
Displacement of [3H]R1881 from androgen receptor in human LNCAP cells
|
Homo sapiens
|
971.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and development of Galeterone (TOK-001 or VN/124-1) for the treatment of all stages of prostate cancer.
Year : 2015
Volume : 58
Issue : 5
First Page : 2077
Last Page : 2087
Authors : Njar VC, Brodie AM.
Abstract : In our effort to discover potent and specific inhibitors of 17α-hydroxylase/17,20-lyase (CYP17), the key enzyme which catalyzes the biosynthesis of androgens from progestins, 3β-(hydroxy)-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (Galeterone or TOK-001, formerly called VN/124-1) was identified as a selective development candidate which modulates multiple targets in the androgen receptor (AR) signaling pathway. This drug annotation summarizes the mechanisms of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for galeterone, which has successfully completed phase II clinical development in men with castration resistant (advanced) prostate cancer (CRPC). Phase III clinical studies in CRPC patients are scheduled to begin in early 2015.
|
Antiproliferative activity against human LNCAP cells after 3 days
|
Homo sapiens
|
732.7
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and biological evaluation of novel 5-oxo-2-thioxoimidazolidine derivatives as potent androgen receptor antagonists.
Year : 2015
Volume : 99
First Page : 51
Last Page : 66
Authors : Ivachtchenko AV, Ivanenkov YA, Mitkin OD, Vorobiev AA, Kuznetsova IV, Shevkun NA, Koryakova AG, Karapetian RN, Trifelenkov AS, Kravchenko DV, Veselov MS, Chufarova NV.
Abstract : A series of novel highly active androgen receptor (AR) antagonists containing spiro-4-(5-oxo-3-phenyl-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile core was designed based on the SAR studies available from the reported AR antagonists and in silico modeling. Within the series, compound (R)-6 (ONC1-13B) and its related analogues, including its active N-dealkylated metabolite, were found to be the most potent molecules with the target activity (IC50, androgen-sensitive human PCa LNCaP cells) in the range of 59-80 nM (inhibition of PSA production). The disclosed hits were at least two times more active than bicalutamide, nilutamide and enzalutamide within the performed assay. Several compounds were classified as partial agonists. Hit-compounds demonstrated benefit pharmacokinetic profiles in rats. Comparative SAR and 3D molecular docking studies were performed for the hit compounds elucidating the observed differences in the binding potency.
|
Antagonist activity at androgen receptor (unknown origin)
|
Homo sapiens
|
160.2
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and biological evaluation of novel 5-oxo-2-thioxoimidazolidine derivatives as potent androgen receptor antagonists.
Year : 2015
Volume : 99
First Page : 51
Last Page : 66
Authors : Ivachtchenko AV, Ivanenkov YA, Mitkin OD, Vorobiev AA, Kuznetsova IV, Shevkun NA, Koryakova AG, Karapetian RN, Trifelenkov AS, Kravchenko DV, Veselov MS, Chufarova NV.
Abstract : A series of novel highly active androgen receptor (AR) antagonists containing spiro-4-(5-oxo-3-phenyl-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile core was designed based on the SAR studies available from the reported AR antagonists and in silico modeling. Within the series, compound (R)-6 (ONC1-13B) and its related analogues, including its active N-dealkylated metabolite, were found to be the most potent molecules with the target activity (IC50, androgen-sensitive human PCa LNCaP cells) in the range of 59-80 nM (inhibition of PSA production). The disclosed hits were at least two times more active than bicalutamide, nilutamide and enzalutamide within the performed assay. Several compounds were classified as partial agonists. Hit-compounds demonstrated benefit pharmacokinetic profiles in rats. Comparative SAR and 3D molecular docking studies were performed for the hit compounds elucidating the observed differences in the binding potency.
|
Displacement of [3H]-DHT from androgen receptor in human MDA-MB-453 cells after 90 mins by TopCount analysis
|
Homo sapiens
|
64.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of BMS-641988, a Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer.
Year : 2015
Volume : 6
Issue : 8
First Page : 908
Last Page : 912
Authors : Balog A, Rampulla R, Martin GS, Krystek SR, Attar R, Dell-John J, DiMarco JD, Fairfax D, Gougoutas J, Holst CL, Nation A, Rizzo C, Rossiter LM, Schweizer L, Shan W, Spergel S, Spires T, Cornelius G, Gottardis M, Trainor G, Vite GD, Salvati ME.
Abstract : BMS-641988 (23) is a novel, nonsteroidal androgen receptor antagonist designed for the treatment of prostate cancer. The compound has high binding affinity for the AR and acts as a functional antagonist in vitro. BMS-641988 is efficacious in multiple human prostate cancer xenograft models, including CWR22-BMSLD1 where it displays superior efficacy relative to bicalutamide. Based on its promising preclinical profile, BMS-641988 was selected for clinical development.
|
Antagonist activity at androgen receptor in human MDA-MB-453 cells assessed as inhibition of DHT-induced PSA expression by alkaline phosphatase reporter gene assay
|
Homo sapiens
|
173.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of BMS-641988, a Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer.
Year : 2015
Volume : 6
Issue : 8
First Page : 908
Last Page : 912
Authors : Balog A, Rampulla R, Martin GS, Krystek SR, Attar R, Dell-John J, DiMarco JD, Fairfax D, Gougoutas J, Holst CL, Nation A, Rizzo C, Rossiter LM, Schweizer L, Shan W, Spergel S, Spires T, Cornelius G, Gottardis M, Trainor G, Vite GD, Salvati ME.
Abstract : BMS-641988 (23) is a novel, nonsteroidal androgen receptor antagonist designed for the treatment of prostate cancer. The compound has high binding affinity for the AR and acts as a functional antagonist in vitro. BMS-641988 is efficacious in multiple human prostate cancer xenograft models, including CWR22-BMSLD1 where it displays superior efficacy relative to bicalutamide. Based on its promising preclinical profile, BMS-641988 was selected for clinical development.
|
Reporter Assay: The compounds were subjected to tests using an artificial AR response reporter system in a hormone refractory prostate cancer cell line. In this system, the prostate cancer LNCaP cells were engineered to stably express about 5-fold higher level of AR than endogenous level. The exogenous AR has similar properties to endogenous AR in that both are stabilized by a synthetic androgen R1881. The AR-over expressed cells were also engineered to stably incorporate an AR response reporter and the reporter activity of these cells shows features of hormone refractory prostate cancer.
|
Homo sapiens
|
889.0
nM
|
|
Title : Treatment of hyperproliferative disorders with diarylhydantoin compounds
Year : 2015
|
Induction of mitochondrial dysfunction in Sprague-Dawley rat liver mitochondria assessed as inhibition of mitochondrial respiration per mg mitochondrial protein measured for 20 mins by A65N-1 oxygen probe based fluorescence assay
|
Rattus norvegicus
|
48.9
nM
|
|
Journal : Hepatology
Title : Human drug-induced liver injury severity is highly associated with dual inhibition of liver mitochondrial function and bile salt export pump.
Year : 2014
Volume : 60
Issue : 3
First Page : 1015
Last Page : 1022
Authors : Aleo MD, Luo Y, Swiss R, Bonin PD, Potter DM, Will Y.
Abstract : Drug-induced liver injury (DILI) accounts for 20-40% of all instances of clinical hepatic failure and is a common reason for withdrawal of an approved drug or discontinuation of a potentially new drug from clinical/nonclinical development. Numerous individual risk factors contribute to the susceptibility to human DILI and its severity that are either compound- and/or patient-specific. Compound-specific primary mechanisms linked to DILI include: cytotoxicity, reactive metabolite formation, inhibition of bile salt export pump (BSEP), and mitochondrial dysfunction. Since BSEP is an energy-dependent protein responsible for the efflux of bile acids from hepatocytes, it was hypothesized that humans exposed to drugs that impair both mitochondrial energetics and BSEP functional activity are more sensitive to more severe manifestations of DILI than drugs that only have a single liability factor. As annotated in the United States National Center for Toxicological Research Liver Toxicity Knowledge Base (NCTR-LTKB), the inhibitory properties of 24 Most-DILI-, 28 Less-DILI-, and 20 No-DILI-concern drugs were investigated. Drug potency for inhibiting BSEP or mitochondrial activity was generally correlated across human DILI concern categories. However, drugs with dual potency as mitochondrial and BSEP inhibitors were highly associated with more severe human DILI, more restrictive product safety labeling related to liver injury, and appear more sensitive to the drug exposure (Cmax) where more restrictive labeling occurs.These data affirm that severe manifestations of human DILI are multifactorial, highly associated with combinations of drug potency specifically related to known mechanisms of DILI (like mitochondrial and BSEP inhibition), and, along with patient-specific factors, lead to differences in the severity and exposure thresholds associated with clinical DILI.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
-1.51
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
6.59
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
7.16
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
4.08
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
15.75
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
-0.48
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
-5.03
%
|
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
-1.9
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Antagonist activity at GAL4-DBD fused rat androgen receptor expressed in UAS-bla 293 cells assessed as reduction in R1881-induced activation at 10 uM incubated for 16 hrs followed by fluorescence substrate addition and measured after 2 hrs by beta lactamase reporter gene assay relative to control
|
Rattus norvegicus
|
83.0
%
|
|
Journal : Eur J Med Chem
Title : A new series of bicalutamide, enzalutamide and enobosarm derivatives carrying pentafluorosulfanyl (SF<sub>5</sub>) and pentafluoroethyl (C<sub>2</sub>F<sub>5</sub>) substituents: Improved antiproliferative agents against prostate cancer.
Year : 2019
Volume : 180
First Page : 1
Last Page : 14
Authors : Pertusati F, Ferla S, Bassetto M, Brancale A, Khandil S, Westwell AD, McGuigan C.
Abstract : SAR studies on bicalutamide, enobosarm and enzalutamide analogues, functionalised with polyfluorinated groups, is presented. Among the novel bicalutamide and enobosarm derivatives synthesised, several displayed significantly improved in vitro anticancer activity, with IC<sub>50</sub> values in the low micromolar range against four different prostate cancer cell lines (LNCaP, VCaP, DU-145 and 22Rv1), showing up to 48-fold increase in comparison with the parent structures. In particular, SF<sub>5</sub> enobosarm analogues were found to be most potent compounds, full AR antagonists and with favourable ADME properties. The most promising compound (48a) was evaluated for its in vivo efficacy in PC xenograft mouse model (22Rv1) with results comparable to the standard-of-care docetaxel.
|
Antagonist activity at GAL4-DBD fused rat androgen receptor expressed in UAS-bla 293 cells assessed as reduction in R1881-induced activation incubated for 16 hrs followed by fluorescence substrate addition and measured after 2 hrs by beta lactamase reporter gene assay
|
Rattus norvegicus
|
490.0
nM
|
|
Journal : Eur J Med Chem
Title : A new series of bicalutamide, enzalutamide and enobosarm derivatives carrying pentafluorosulfanyl (SF<sub>5</sub>) and pentafluoroethyl (C<sub>2</sub>F<sub>5</sub>) substituents: Improved antiproliferative agents against prostate cancer.
Year : 2019
Volume : 180
First Page : 1
Last Page : 14
Authors : Pertusati F, Ferla S, Bassetto M, Brancale A, Khandil S, Westwell AD, McGuigan C.
Abstract : SAR studies on bicalutamide, enobosarm and enzalutamide analogues, functionalised with polyfluorinated groups, is presented. Among the novel bicalutamide and enobosarm derivatives synthesised, several displayed significantly improved in vitro anticancer activity, with IC<sub>50</sub> values in the low micromolar range against four different prostate cancer cell lines (LNCaP, VCaP, DU-145 and 22Rv1), showing up to 48-fold increase in comparison with the parent structures. In particular, SF<sub>5</sub> enobosarm analogues were found to be most potent compounds, full AR antagonists and with favourable ADME properties. The most promising compound (48a) was evaluated for its in vivo efficacy in PC xenograft mouse model (22Rv1) with results comparable to the standard-of-care docetaxel.
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SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
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Severe acute respiratory syndrome coronavirus 2
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5.174
%
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Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
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Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
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Chlorocebus sabaeus
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-0.13
%
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Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
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Chlorocebus sabaeus
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-0.13
%
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Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
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Inhibition of [3H] MIB binding to rat prostate androgen receptor LBD by competitive binding assay
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Rattus norvegicus
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509.0
nM
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Antagonist activity at human androgen receptor expressed in HEK-293 cells harboring GRE-LUC and CMV-renilla luciferase assessed as inhibition of transactivation incubated for 24 hrs in presence of R1881 by dual luciferase assay
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Homo sapiens
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248.0
nM
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