|
Ability to inhibit [3H]WIN-35428 binding to cloned human dopamine (DA) transporter
|
Homo sapiens
|
240.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological activity of some known and putative duloxetine metabolites.
Year : 2004
Volume : 14
Issue : 13
First Page : 3481
Last Page : 3486
Authors : Kuo F, Gillespie TA, Kulanthaivel P, Lantz RJ, Ma TW, Nelson DL, Threlkeld PG, Wheeler WJ, Yi P, Zmijewski M.
Abstract : Several putative phase I duloxetine metabolites, 4-hydroxy-, 5-hydroxy-, 6-hydroxy-, 5-hydroxy-6-methoxy-, 6-hydroxy-5-methoxy-, 5,6-dihydroxy-, and 4,6-dihydroxyduloxetine were synthesized, and their phase II metabolite as glucuronide or sulfate conjugates were also synthesized. Their in vitro binding activities were compared to that of parent compound duloxetine.
|
Ability to inhibit the reuptake of dopamine at human dopamine transporter
|
None
|
240.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Duloxetine (Cymbalta), a dual inhibitor of serotonin and norepinephrine reuptake.
Year : 2003
Volume : 13
Issue : 24
First Page : 4477
Last Page : 4480
Authors : Bymaster FP, Beedle EE, Findlay J, Gallagher PT, Krushinski JH, Mitchell S, Robertson DW, Thompson DC, Wallace L, Wong DT.
Abstract : A series of naphthalenyloxy-arylpropylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake. One member of this series, duloxetine (Cymbalta) has proven to be effective in clinical trials for the treatment of depression.
|
Ability to inhibit the reuptake of NE at human norepinephrine transporter
|
None
|
7.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Duloxetine (Cymbalta), a dual inhibitor of serotonin and norepinephrine reuptake.
Year : 2003
Volume : 13
Issue : 24
First Page : 4477
Last Page : 4480
Authors : Bymaster FP, Beedle EE, Findlay J, Gallagher PT, Krushinski JH, Mitchell S, Robertson DW, Thompson DC, Wallace L, Wong DT.
Abstract : A series of naphthalenyloxy-arylpropylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake. One member of this series, duloxetine (Cymbalta) has proven to be effective in clinical trials for the treatment of depression.
|
Ability to inhibit [3H]nisoxetine binding to cloned human norepinephrine (NE) transporter
|
Homo sapiens
|
7.45
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological activity of some known and putative duloxetine metabolites.
Year : 2004
Volume : 14
Issue : 13
First Page : 3481
Last Page : 3486
Authors : Kuo F, Gillespie TA, Kulanthaivel P, Lantz RJ, Ma TW, Nelson DL, Threlkeld PG, Wheeler WJ, Yi P, Zmijewski M.
Abstract : Several putative phase I duloxetine metabolites, 4-hydroxy-, 5-hydroxy-, 6-hydroxy-, 5-hydroxy-6-methoxy-, 6-hydroxy-5-methoxy-, 5,6-dihydroxy-, and 4,6-dihydroxyduloxetine were synthesized, and their phase II metabolite as glucuronide or sulfate conjugates were also synthesized. Their in vitro binding activities were compared to that of parent compound duloxetine.
|
Inhibition of dopamine uptake into rat synaptosomes
|
Rattus norvegicus
|
370.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Duloxetine (Cymbalta), a dual inhibitor of serotonin and norepinephrine reuptake.
Year : 2003
Volume : 13
Issue : 24
First Page : 4477
Last Page : 4480
Authors : Bymaster FP, Beedle EE, Findlay J, Gallagher PT, Krushinski JH, Mitchell S, Robertson DW, Thompson DC, Wallace L, Wong DT.
Abstract : A series of naphthalenyloxy-arylpropylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake. One member of this series, duloxetine (Cymbalta) has proven to be effective in clinical trials for the treatment of depression.
|
Inhibition of norepinephrine uptake into rat synaptosomes
|
Rattus norvegicus
|
16.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Duloxetine (Cymbalta), a dual inhibitor of serotonin and norepinephrine reuptake.
Year : 2003
Volume : 13
Issue : 24
First Page : 4477
Last Page : 4480
Authors : Bymaster FP, Beedle EE, Findlay J, Gallagher PT, Krushinski JH, Mitchell S, Robertson DW, Thompson DC, Wallace L, Wong DT.
Abstract : A series of naphthalenyloxy-arylpropylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake. One member of this series, duloxetine (Cymbalta) has proven to be effective in clinical trials for the treatment of depression.
|
Inhibition of serotonin uptake into rat synaptosomes
|
Rattus norvegicus
|
4.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Duloxetine (Cymbalta), a dual inhibitor of serotonin and norepinephrine reuptake.
Year : 2003
Volume : 13
Issue : 24
First Page : 4477
Last Page : 4480
Authors : Bymaster FP, Beedle EE, Findlay J, Gallagher PT, Krushinski JH, Mitchell S, Robertson DW, Thompson DC, Wallace L, Wong DT.
Abstract : A series of naphthalenyloxy-arylpropylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake. One member of this series, duloxetine (Cymbalta) has proven to be effective in clinical trials for the treatment of depression.
|
Ability to inhibit [3H]paroxetine binding to cloned human serotonin (5-HT) transporter
|
Homo sapiens
|
0.79
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological activity of some known and putative duloxetine metabolites.
Year : 2004
Volume : 14
Issue : 13
First Page : 3481
Last Page : 3486
Authors : Kuo F, Gillespie TA, Kulanthaivel P, Lantz RJ, Ma TW, Nelson DL, Threlkeld PG, Wheeler WJ, Yi P, Zmijewski M.
Abstract : Several putative phase I duloxetine metabolites, 4-hydroxy-, 5-hydroxy-, 6-hydroxy-, 5-hydroxy-6-methoxy-, 6-hydroxy-5-methoxy-, 5,6-dihydroxy-, and 4,6-dihydroxyduloxetine were synthesized, and their phase II metabolite as glucuronide or sulfate conjugates were also synthesized. Their in vitro binding activities were compared to that of parent compound duloxetine.
|
Ability to inhibit the reuptake of 5-HT at human serotonin transporter
|
None
|
0.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Duloxetine (Cymbalta), a dual inhibitor of serotonin and norepinephrine reuptake.
Year : 2003
Volume : 13
Issue : 24
First Page : 4477
Last Page : 4480
Authors : Bymaster FP, Beedle EE, Findlay J, Gallagher PT, Krushinski JH, Mitchell S, Robertson DW, Thompson DC, Wallace L, Wong DT.
Abstract : A series of naphthalenyloxy-arylpropylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake. One member of this series, duloxetine (Cymbalta) has proven to be effective in clinical trials for the treatment of depression.
|
Binding affinity for Dopamine transporter
|
None
|
240.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Benzothienyloxy phenylpropanamines, novel dual inhibitors of serotonin and norepinephrine reuptake.
Year : 2004
Volume : 14
Issue : 21
First Page : 5395
Last Page : 5399
Authors : Boot JR, Brace G, Delatour CL, Dezutter N, Fairhurst J, Findlay J, Gallagher PT, Hoes I, Mahadevan S, Mitchell SN, Rathmell RE, Richards SJ, Simmonds RG, Wallace L, Whatton MA.
Abstract : A series of benzothienyloxy propylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake.
|
Binding affinity for Norepinephrine transporter
|
None
|
7.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Benzothienyloxy phenylpropanamines, novel dual inhibitors of serotonin and norepinephrine reuptake.
Year : 2004
Volume : 14
Issue : 21
First Page : 5395
Last Page : 5399
Authors : Boot JR, Brace G, Delatour CL, Dezutter N, Fairhurst J, Findlay J, Gallagher PT, Hoes I, Mahadevan S, Mitchell SN, Rathmell RE, Richards SJ, Simmonds RG, Wallace L, Whatton MA.
Abstract : A series of benzothienyloxy propylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake.
|
Binding affinity for 5-hydroxytryptamine transporter
|
None
|
0.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Benzothienyloxy phenylpropanamines, novel dual inhibitors of serotonin and norepinephrine reuptake.
Year : 2004
Volume : 14
Issue : 21
First Page : 5395
Last Page : 5399
Authors : Boot JR, Brace G, Delatour CL, Dezutter N, Fairhurst J, Findlay J, Gallagher PT, Hoes I, Mahadevan S, Mitchell SN, Rathmell RE, Richards SJ, Simmonds RG, Wallace L, Whatton MA.
Abstract : A series of benzothienyloxy propylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake.
|
Inhibition constant against dopamine transporter
|
Homo sapiens
|
370.0
nM
|
|
Journal : J. Med. Chem.
Title : Designed multiple ligands. An emerging drug discovery paradigm.
Year : 2005
Volume : 48
Issue : 21
First Page : 6523
Last Page : 6543
Authors : Morphy R, Rankovic Z.
|
Inhibition constant against serotonin transporter
|
Homo sapiens
|
4.6
nM
|
|
Journal : J. Med. Chem.
Title : Designed multiple ligands. An emerging drug discovery paradigm.
Year : 2005
Volume : 48
Issue : 21
First Page : 6523
Last Page : 6543
Authors : Morphy R, Rankovic Z.
|
Inhibition constant against norepinephrine transporter
|
Homo sapiens
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : Designed multiple ligands. An emerging drug discovery paradigm.
Year : 2005
Volume : 48
Issue : 21
First Page : 6523
Last Page : 6543
Authors : Morphy R, Rankovic Z.
|
Inhibition of [3H]5-HT reuptake at 5HT transporter in HEK293 cells
|
Homo sapiens
|
6.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-activity relationships of N-substituted piperazine amine reuptake inhibitors.
Year : 2006
Volume : 16
Issue : 16
First Page : 4349
Last Page : 4353
Authors : Fray MJ, Bish G, Fish PV, Stobie A, Wakenhut F, Whitlock GA.
Abstract : We report the structure-activity relationships of further analogues in a series of piperazine derivatives as dual inhibitors of serotonin and noradrenaline reuptake, that is, with additional substitution of the phenyl rings, or their replacement by heterocycles. The enantiomers of compounds 1 and 2 were also profiled, and possessed drug-like physicochemical properties. In particular, compound (-)-2 lacked potent inhibitory activity against any of the important cytochromes P(450) and high selectivity over a wide range of receptors, which is unusual for a compound that inhibits human amine transporters.
|
Inhibition of [3H]NA reuptake at NA transporter in HEK293 cells
|
Homo sapiens
|
19.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-activity relationships of N-substituted piperazine amine reuptake inhibitors.
Year : 2006
Volume : 16
Issue : 16
First Page : 4349
Last Page : 4353
Authors : Fray MJ, Bish G, Fish PV, Stobie A, Wakenhut F, Whitlock GA.
Abstract : We report the structure-activity relationships of further analogues in a series of piperazine derivatives as dual inhibitors of serotonin and noradrenaline reuptake, that is, with additional substitution of the phenyl rings, or their replacement by heterocycles. The enantiomers of compounds 1 and 2 were also profiled, and possessed drug-like physicochemical properties. In particular, compound (-)-2 lacked potent inhibitory activity against any of the important cytochromes P(450) and high selectivity over a wide range of receptors, which is unusual for a compound that inhibits human amine transporters.
|
Inhibition of [3H]DA reuptake at DA transporter in HEK293 cells
|
Homo sapiens
|
870.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-activity relationships of N-substituted piperazine amine reuptake inhibitors.
Year : 2006
Volume : 16
Issue : 16
First Page : 4349
Last Page : 4353
Authors : Fray MJ, Bish G, Fish PV, Stobie A, Wakenhut F, Whitlock GA.
Abstract : We report the structure-activity relationships of further analogues in a series of piperazine derivatives as dual inhibitors of serotonin and noradrenaline reuptake, that is, with additional substitution of the phenyl rings, or their replacement by heterocycles. The enantiomers of compounds 1 and 2 were also profiled, and possessed drug-like physicochemical properties. In particular, compound (-)-2 lacked potent inhibitory activity against any of the important cytochromes P(450) and high selectivity over a wide range of receptors, which is unusual for a compound that inhibits human amine transporters.
|
Inhibition of [3H]5-HT uptake at 5HT transporter expressed in HEK293 cells
|
Homo sapiens
|
6.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N-(1,2-diphenylethyl)piperazines: a new class of dual serotonin/noradrenaline reuptake inhibitor.
Year : 2006
Volume : 16
Issue : 16
First Page : 4345
Last Page : 4348
Authors : Jonathan Fray M, Bish G, Brown AD, Fish PV, Stobie A, Wakenhut F, Whitlock GA.
Abstract : The synthesis and structure-activity relationships of a novel series of piperazine derivatives as dual inhibitors of serotonin and noradrenaline reuptake is described. Two compounds possessed comparable in vitro profiles to the dual reuptake inhibitor duloxetine.
|
Inhibition of [3H]NA uptake at NA transporter expressed in HEK293 cells
|
Homo sapiens
|
19.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N-(1,2-diphenylethyl)piperazines: a new class of dual serotonin/noradrenaline reuptake inhibitor.
Year : 2006
Volume : 16
Issue : 16
First Page : 4345
Last Page : 4348
Authors : Jonathan Fray M, Bish G, Brown AD, Fish PV, Stobie A, Wakenhut F, Whitlock GA.
Abstract : The synthesis and structure-activity relationships of a novel series of piperazine derivatives as dual inhibitors of serotonin and noradrenaline reuptake is described. Two compounds possessed comparable in vitro profiles to the dual reuptake inhibitor duloxetine.
|
Inhibition of DA transporter expressed in HEK293 cells
|
Homo sapiens
|
870.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N-(1,2-diphenylethyl)piperazines: a new class of dual serotonin/noradrenaline reuptake inhibitor.
Year : 2006
Volume : 16
Issue : 16
First Page : 4345
Last Page : 4348
Authors : Jonathan Fray M, Bish G, Brown AD, Fish PV, Stobie A, Wakenhut F, Whitlock GA.
Abstract : The synthesis and structure-activity relationships of a novel series of piperazine derivatives as dual inhibitors of serotonin and noradrenaline reuptake is described. Two compounds possessed comparable in vitro profiles to the dual reuptake inhibitor duloxetine.
|
Inhibition of [3H]5-HT from human SERT expressed in HEK293 cells
|
Homo sapiens
|
6.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N-Benzyl-N-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amines as selective dual serotonin/noradrenaline reuptake inhibitors.
Year : 2007
Volume : 17
Issue : 7
First Page : 2022
Last Page : 2025
Authors : Fish PV, Fray MJ, Stobie A, Wakenhut F, Whitlock GA.
Abstract : A series of N-benzyl-N-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine monoamine reuptake inhibitors are described. Selective dual 5-HT and NA reuptake inhibition was achieved, and analogues with weak CYP2D6 inhibition, good human in vitro metabolic stability and wide ligand selectivity, such as 12b, were identified.
|
Inhibition of [3H]NA from human NET expressed in HEK293 cells
|
Homo sapiens
|
19.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N-Benzyl-N-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amines as selective dual serotonin/noradrenaline reuptake inhibitors.
Year : 2007
Volume : 17
Issue : 7
First Page : 2022
Last Page : 2025
Authors : Fish PV, Fray MJ, Stobie A, Wakenhut F, Whitlock GA.
Abstract : A series of N-benzyl-N-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine monoamine reuptake inhibitors are described. Selective dual 5-HT and NA reuptake inhibition was achieved, and analogues with weak CYP2D6 inhibition, good human in vitro metabolic stability and wide ligand selectivity, such as 12b, were identified.
|
Inhibition of [3H]DA from human DAT expressed in HEK293 cells
|
Homo sapiens
|
870.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N-Benzyl-N-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amines as selective dual serotonin/noradrenaline reuptake inhibitors.
Year : 2007
Volume : 17
Issue : 7
First Page : 2022
Last Page : 2025
Authors : Fish PV, Fray MJ, Stobie A, Wakenhut F, Whitlock GA.
Abstract : A series of N-benzyl-N-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine monoamine reuptake inhibitors are described. Selective dual 5-HT and NA reuptake inhibition was achieved, and analogues with weak CYP2D6 inhibition, good human in vitro metabolic stability and wide ligand selectivity, such as 12b, were identified.
|
Inhibition of human NET
|
Homo sapiens
|
8.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Studies on the SAR and pharmacophore of milnacipran derivatives as monoamine transporter inhibitors.
Year : 2008
Volume : 18
Issue : 4
First Page : 1346
Last Page : 1349
Authors : Chen C, Dyck B, Fleck BA, Foster AC, Grey J, Jovic F, Mesleh M, Phan K, Tamiya J, Vickers T, Zhang M.
Abstract : Derivatives of milnacipran were synthesized and studied as monoamine transporter inhibitors. Potent analogs were discovered at NET (9k) and at both NET and SERT (9s and 9u). A pharmacophore model was established based on the conformational analysis of milnacipran in aqueous solution using NMR techniques and was consistent with the SAR results.
|
Inhibition of human SERT
|
Homo sapiens
|
6.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Studies on the SAR and pharmacophore of milnacipran derivatives as monoamine transporter inhibitors.
Year : 2008
Volume : 18
Issue : 4
First Page : 1346
Last Page : 1349
Authors : Chen C, Dyck B, Fleck BA, Foster AC, Grey J, Jovic F, Mesleh M, Phan K, Tamiya J, Vickers T, Zhang M.
Abstract : Derivatives of milnacipran were synthesized and studied as monoamine transporter inhibitors. Potent analogs were discovered at NET (9k) and at both NET and SERT (9s and 9u). A pharmacophore model was established based on the conformational analysis of milnacipran in aqueous solution using NMR techniques and was consistent with the SAR results.
|
Inhibition of human DAT
|
Homo sapiens
|
660.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Studies on the SAR and pharmacophore of milnacipran derivatives as monoamine transporter inhibitors.
Year : 2008
Volume : 18
Issue : 4
First Page : 1346
Last Page : 1349
Authors : Chen C, Dyck B, Fleck BA, Foster AC, Grey J, Jovic F, Mesleh M, Phan K, Tamiya J, Vickers T, Zhang M.
Abstract : Derivatives of milnacipran were synthesized and studied as monoamine transporter inhibitors. Potent analogs were discovered at NET (9k) and at both NET and SERT (9s and 9u). A pharmacophore model was established based on the conformational analysis of milnacipran in aqueous solution using NMR techniques and was consistent with the SAR results.
|
Inhibition of [3H]citalopram uptake at human 5HTT expressed in HEK293 cells
|
Homo sapiens
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of morpholine derivatives. SAR for dual serotonin & noradrenaline reuptake inhibition.
Year : 2008
Volume : 18
Issue : 8
First Page : 2562
Last Page : 2566
Authors : Fish PV, Deur C, Gan X, Greene K, Hoople D, Mackenny M, Para KS, Reeves K, Ryckmans T, Stiff C, Stobie A, Wakenhut F, Whitlock GA.
Abstract : Single enantiomer (SS) and (RR) 2-[(phenoxy)(phenyl)methyl]morpholine derivatives 5, 8-23 are inhibitors of monoamine reuptake. Target compounds were prepared using an enantioselective synthesis employing a highly specific enzyme-catalysed resolution of racemic n-butyl 4-benzylmorpholine-2-carboxylate (26) as the key step. Structure-activity relationships established that serotonin and noradrenaline reuptake inhibition are functions of stereochemistry and aryl/aryloxy ring substitution. Consequently, selective SRI, selective NRI and dual SNRIs were all identified. One of these compounds, a potent and selective dual SNRI, (SS)-5a was selected as a candidate for further pre-clinical evaluation.
|
Inhibition of [3H]nisoxetine reuptake at human NET expressed in HEK293 cells
|
Homo sapiens
|
45.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of morpholine derivatives. SAR for dual serotonin & noradrenaline reuptake inhibition.
Year : 2008
Volume : 18
Issue : 8
First Page : 2562
Last Page : 2566
Authors : Fish PV, Deur C, Gan X, Greene K, Hoople D, Mackenny M, Para KS, Reeves K, Ryckmans T, Stiff C, Stobie A, Wakenhut F, Whitlock GA.
Abstract : Single enantiomer (SS) and (RR) 2-[(phenoxy)(phenyl)methyl]morpholine derivatives 5, 8-23 are inhibitors of monoamine reuptake. Target compounds were prepared using an enantioselective synthesis employing a highly specific enzyme-catalysed resolution of racemic n-butyl 4-benzylmorpholine-2-carboxylate (26) as the key step. Structure-activity relationships established that serotonin and noradrenaline reuptake inhibition are functions of stereochemistry and aryl/aryloxy ring substitution. Consequently, selective SRI, selective NRI and dual SNRIs were all identified. One of these compounds, a potent and selective dual SNRI, (SS)-5a was selected as a candidate for further pre-clinical evaluation.
|
Inhibition of [3H]dopamine reuptake at human DAT expressed in HEK293 cells
|
Homo sapiens
|
435.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of morpholine derivatives. SAR for dual serotonin & noradrenaline reuptake inhibition.
Year : 2008
Volume : 18
Issue : 8
First Page : 2562
Last Page : 2566
Authors : Fish PV, Deur C, Gan X, Greene K, Hoople D, Mackenny M, Para KS, Reeves K, Ryckmans T, Stiff C, Stobie A, Wakenhut F, Whitlock GA.
Abstract : Single enantiomer (SS) and (RR) 2-[(phenoxy)(phenyl)methyl]morpholine derivatives 5, 8-23 are inhibitors of monoamine reuptake. Target compounds were prepared using an enantioselective synthesis employing a highly specific enzyme-catalysed resolution of racemic n-butyl 4-benzylmorpholine-2-carboxylate (26) as the key step. Structure-activity relationships established that serotonin and noradrenaline reuptake inhibition are functions of stereochemistry and aryl/aryloxy ring substitution. Consequently, selective SRI, selective NRI and dual SNRIs were all identified. One of these compounds, a potent and selective dual SNRI, (SS)-5a was selected as a candidate for further pre-clinical evaluation.
|
Displacement of Levo[ring-2,5,6-3H]norepinephrine from human cloned NET expressed in HEK293 cells by microplate scintillation counter
|
Homo sapiens
|
8.9
nM
|
|
Journal : J. Med. Chem.
Title : Characterization of thien-2-yl 1S,2R-milnacipran analogues as potent norepinephrine/serotonin transporter inhibitors for the treatment of neuropathic pain.
Year : 2008
Volume : 51
Issue : 22
First Page : 7265
Last Page : 7272
Authors : Dyck B, Tamiya J, Jovic F, Pick RR, Bradbury MJ, O'Brien J, Wen J, Johns M, Madan A, Fleck BA, Foster AC, Li B, Zhang M, Tran JA, Vickers T, Grey J, Saunders J, Chen C.
Abstract : Thien-2-yl 1S,2R-milnacipran analogues were synthesized and characterized as norepinephrine/serotonin transporter inhibitors. These compounds possessed higher potencies than 1S,2R-milnacipran (2R-1) while maintaining low molecular weight and moderate lipophilicity, which are the important features for the pharmacological and pharmacokinetic characteristics of milnacipran (1). Thus, compound 5c exhibited IC50 values of 2.3 and 32 nM, respectively, at NET and SERT, which were more than 10-fold better than those of 1 (NET IC50 = 77 nM, SERT IC50 = 420 nM). Moreover, 5c achieved the same efficacy as 1, but with much lower doses, in a rodent spinal nerve ligation pain model. In addition, 5c displayed desirable pharmacokinetic properties in several species, including high oral availability and significant brain penetration.
|
Displacement of [alpha,beta-3H(N)]-5-hydroxytryptamine from human cloned SERT expressed in HEK293 cells by microplate scintillation counter
|
Homo sapiens
|
6.6
nM
|
|
Journal : J. Med. Chem.
Title : Characterization of thien-2-yl 1S,2R-milnacipran analogues as potent norepinephrine/serotonin transporter inhibitors for the treatment of neuropathic pain.
Year : 2008
Volume : 51
Issue : 22
First Page : 7265
Last Page : 7272
Authors : Dyck B, Tamiya J, Jovic F, Pick RR, Bradbury MJ, O'Brien J, Wen J, Johns M, Madan A, Fleck BA, Foster AC, Li B, Zhang M, Tran JA, Vickers T, Grey J, Saunders J, Chen C.
Abstract : Thien-2-yl 1S,2R-milnacipran analogues were synthesized and characterized as norepinephrine/serotonin transporter inhibitors. These compounds possessed higher potencies than 1S,2R-milnacipran (2R-1) while maintaining low molecular weight and moderate lipophilicity, which are the important features for the pharmacological and pharmacokinetic characteristics of milnacipran (1). Thus, compound 5c exhibited IC50 values of 2.3 and 32 nM, respectively, at NET and SERT, which were more than 10-fold better than those of 1 (NET IC50 = 77 nM, SERT IC50 = 420 nM). Moreover, 5c achieved the same efficacy as 1, but with much lower doses, in a rodent spinal nerve ligation pain model. In addition, 5c displayed desirable pharmacokinetic properties in several species, including high oral availability and significant brain penetration.
|
Displacement of 3,4-[ring-2,5,6-3H]dihydroxyphenylethylamine from human cloned DAT expressed in HEK293 cells by microplate scintillation counter
|
Homo sapiens
|
660.0
nM
|
|
Journal : J. Med. Chem.
Title : Characterization of thien-2-yl 1S,2R-milnacipran analogues as potent norepinephrine/serotonin transporter inhibitors for the treatment of neuropathic pain.
Year : 2008
Volume : 51
Issue : 22
First Page : 7265
Last Page : 7272
Authors : Dyck B, Tamiya J, Jovic F, Pick RR, Bradbury MJ, O'Brien J, Wen J, Johns M, Madan A, Fleck BA, Foster AC, Li B, Zhang M, Tran JA, Vickers T, Grey J, Saunders J, Chen C.
Abstract : Thien-2-yl 1S,2R-milnacipran analogues were synthesized and characterized as norepinephrine/serotonin transporter inhibitors. These compounds possessed higher potencies than 1S,2R-milnacipran (2R-1) while maintaining low molecular weight and moderate lipophilicity, which are the important features for the pharmacological and pharmacokinetic characteristics of milnacipran (1). Thus, compound 5c exhibited IC50 values of 2.3 and 32 nM, respectively, at NET and SERT, which were more than 10-fold better than those of 1 (NET IC50 = 77 nM, SERT IC50 = 420 nM). Moreover, 5c achieved the same efficacy as 1, but with much lower doses, in a rodent spinal nerve ligation pain model. In addition, 5c displayed desirable pharmacokinetic properties in several species, including high oral availability and significant brain penetration.
|
Inhibition of norepinephrine uptake at human NET expressed in MDCK-Net6 cells
|
Homo sapiens
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3-(Arylamino)-3-phenylpropan-2-olamines as a new series of dual norepinephrine and serotonin reuptake inhibitors.
Year : 2009
Volume : 19
Issue : 9
First Page : 2464
Last Page : 2467
Authors : Vu AT, Cohn ST, Terefenko EA, Moore WJ, Zhang P, Mahaney PE, Trybulski EJ, Goljer I, Dooley R, Bray JA, Johnston GH, Leiter J, Deecher DC.
Abstract : A series of 3-(arylamino)-3-phenylpropan-2-olamines was prepared and screened for their ability to inhibit monoamine reuptake. A number of analogues displayed significant dual norepinephrine and serotonin reuptake inhibition. Compounds in this class exhibited minimal affinity for the dopamine transporter.
|
Inhibition of serotonin uptake at human SERT expressed in human JAR cells
|
Homo sapiens
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3-(Arylamino)-3-phenylpropan-2-olamines as a new series of dual norepinephrine and serotonin reuptake inhibitors.
Year : 2009
Volume : 19
Issue : 9
First Page : 2464
Last Page : 2467
Authors : Vu AT, Cohn ST, Terefenko EA, Moore WJ, Zhang P, Mahaney PE, Trybulski EJ, Goljer I, Dooley R, Bray JA, Johnston GH, Leiter J, Deecher DC.
Abstract : A series of 3-(arylamino)-3-phenylpropan-2-olamines was prepared and screened for their ability to inhibit monoamine reuptake. A number of analogues displayed significant dual norepinephrine and serotonin reuptake inhibition. Compounds in this class exhibited minimal affinity for the dopamine transporter.
|
Inhibition of norepinephrine uptake at human NET expressed in MDCK cells
|
Homo sapiens
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and activity of 1-(3-amino-1-phenylpropyl)indolin-2-ones: a new class of selective norepinephrine reuptake inhibitors.
Year : 2008
Volume : 18
Issue : 18
First Page : 4929
Last Page : 4931
Authors : McComas CC, Vu AT, Mahaney PE, Cohn ST, Fensome A, Marella MA, Nogle L, Trybulski EJ, Ye F, Zhang P, Alfinito P, Bray J, Johnston G, Koury E, Deecher DC.
Abstract : Norepinephrine and serotonin play an important role in a wide variety of biological processes and are implicated in a number of neurological disorders. A novel class of 1-(3-amino-1-phenylpropyl)indolin-2-ones was designed and synthesized that displays potent norepinephrine reuptake inhibition while maintaining high selectivity (>100-fold) against the human serotonin and dopamine transporters.
|
Inhibition of serotonin uptake at human SERT expressed in JAR cells
|
Homo sapiens
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and activity of 1-(3-amino-1-phenylpropyl)indolin-2-ones: a new class of selective norepinephrine reuptake inhibitors.
Year : 2008
Volume : 18
Issue : 18
First Page : 4929
Last Page : 4931
Authors : McComas CC, Vu AT, Mahaney PE, Cohn ST, Fensome A, Marella MA, Nogle L, Trybulski EJ, Ye F, Zhang P, Alfinito P, Bray J, Johnston G, Koury E, Deecher DC.
Abstract : Norepinephrine and serotonin play an important role in a wide variety of biological processes and are implicated in a number of neurological disorders. A novel class of 1-(3-amino-1-phenylpropyl)indolin-2-ones was designed and synthesized that displays potent norepinephrine reuptake inhibition while maintaining high selectivity (>100-fold) against the human serotonin and dopamine transporters.
|
Displacement of [125I]RTI55 from DAT in Sprague-dawley rat striatum by liquid scintillation spectrophotometry
|
Rattus norvegicus
|
370.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1-Naphthyl and 4-indolyl arylalkylamines as selective monoamine reuptake inhibitors.
Year : 2009
Volume : 19
Issue : 1
First Page : 58
Last Page : 61
Authors : Manning JR, Sexton T, Childers SR, Davies HM.
Abstract : A series of enantiomerically pure 1-naphthyl and 4-indolyl arylalkylamines were prepared and evaluated for their binding affinities to the monoamine transporters. The two series of enantiomers displayed considerable differences in binding selectivity between the monoamine transporters, leading to the design of (S)-4-(3,4-dichlorophenyl)-4-(1H-indol-4-yl)-N-methylbutan-1-amine as a potent inhibitor for the dopamine and serotonin transporters.
|
Displacement of [3H]nisoxetine from Sprague-dawley rat NET by liquid scintillation spectrophotometry
|
Rattus norvegicus
|
16.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1-Naphthyl and 4-indolyl arylalkylamines as selective monoamine reuptake inhibitors.
Year : 2009
Volume : 19
Issue : 1
First Page : 58
Last Page : 61
Authors : Manning JR, Sexton T, Childers SR, Davies HM.
Abstract : A series of enantiomerically pure 1-naphthyl and 4-indolyl arylalkylamines were prepared and evaluated for their binding affinities to the monoamine transporters. The two series of enantiomers displayed considerable differences in binding selectivity between the monoamine transporters, leading to the design of (S)-4-(3,4-dichlorophenyl)-4-(1H-indol-4-yl)-N-methylbutan-1-amine as a potent inhibitor for the dopamine and serotonin transporters.
|
Displacement of [3H]citalopram from SERT in Sprague-dawley rat frontal cortex by liquid scintillation spectrophotometry
|
Rattus norvegicus
|
4.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1-Naphthyl and 4-indolyl arylalkylamines as selective monoamine reuptake inhibitors.
Year : 2009
Volume : 19
Issue : 1
First Page : 58
Last Page : 61
Authors : Manning JR, Sexton T, Childers SR, Davies HM.
Abstract : A series of enantiomerically pure 1-naphthyl and 4-indolyl arylalkylamines were prepared and evaluated for their binding affinities to the monoamine transporters. The two series of enantiomers displayed considerable differences in binding selectivity between the monoamine transporters, leading to the design of (S)-4-(3,4-dichlorophenyl)-4-(1H-indol-4-yl)-N-methylbutan-1-amine as a potent inhibitor for the dopamine and serotonin transporters.
|
Inhibition of [3H]NA uptake at human NET expressed in HEK293 cells
|
Homo sapiens
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 4-Piperidines and 3-pyrrolidines as dual serotonin and noradrenaline reuptake inhibitors: design, synthesis and structure-activity relationships.
Year : 2009
Volume : 19
Issue : 10
First Page : 2829
Last Page : 2834
Authors : Fish PV, Andrews MD, Jonathan Fray M, Stobie A, Wakenhut F, Whitlock GA.
Abstract : Single enantiomer [(aryloxy)(pyridinyl)methyl]piperidine and pyrrolidine derivatives 5-9 are inhibitors of monoamine reuptake. Structure-activity relationships established that monoamine reuptake inhibition are functions of amine, pyridine isomer, aryloxy ring substitution and stereochemistry. Consequently, selective NRIs, selective SRIs, dual SNRIs and triple SNDRIs were all identified. Dual SNRIs 5l-a and 9c were evaluated in additional pharmacology and pharmacokinetic studies as representative examples from this series.
|
Inhibition of [3H]5-HT uptake at human 5HTT expressed in HEK293 cells
|
Homo sapiens
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 4-Piperidines and 3-pyrrolidines as dual serotonin and noradrenaline reuptake inhibitors: design, synthesis and structure-activity relationships.
Year : 2009
Volume : 19
Issue : 10
First Page : 2829
Last Page : 2834
Authors : Fish PV, Andrews MD, Jonathan Fray M, Stobie A, Wakenhut F, Whitlock GA.
Abstract : Single enantiomer [(aryloxy)(pyridinyl)methyl]piperidine and pyrrolidine derivatives 5-9 are inhibitors of monoamine reuptake. Structure-activity relationships established that monoamine reuptake inhibition are functions of amine, pyridine isomer, aryloxy ring substitution and stereochemistry. Consequently, selective NRIs, selective SRIs, dual SNRIs and triple SNDRIs were all identified. Dual SNRIs 5l-a and 9c were evaluated in additional pharmacology and pharmacokinetic studies as representative examples from this series.
|
Inhibition of [3H]DA uptake at human DAT expressed in HEK293 cells
|
Homo sapiens
|
590.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 4-Piperidines and 3-pyrrolidines as dual serotonin and noradrenaline reuptake inhibitors: design, synthesis and structure-activity relationships.
Year : 2009
Volume : 19
Issue : 10
First Page : 2829
Last Page : 2834
Authors : Fish PV, Andrews MD, Jonathan Fray M, Stobie A, Wakenhut F, Whitlock GA.
Abstract : Single enantiomer [(aryloxy)(pyridinyl)methyl]piperidine and pyrrolidine derivatives 5-9 are inhibitors of monoamine reuptake. Structure-activity relationships established that monoamine reuptake inhibition are functions of amine, pyridine isomer, aryloxy ring substitution and stereochemistry. Consequently, selective NRIs, selective SRIs, dual SNRIs and triple SNDRIs were all identified. Dual SNRIs 5l-a and 9c were evaluated in additional pharmacology and pharmacokinetic studies as representative examples from this series.
|
Inhibition of SERT
|
None
|
0.5012
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel, achiral aminoheterocycles as selective monoamine reuptake inhibitors.
Year : 2009
Volume : 19
Issue : 16
First Page : 4630
Last Page : 4633
Authors : Lucas MC, Carter DS, Cai HY, Lee EK, Schoenfeld RC, Steiner S, Villa M, Weikert RJ, Iyer PS.
Abstract : A variety of novel aminoheterocycle scaffolds as selective monoamine reuptake inhibitors have been prepared and one of these scaffolds is achiral. The main elements responsible for hERG channel, CYP2D6 and CYP3A4 inhibition were identified.
|
Inhibition of NET
|
None
|
7.943
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel, achiral aminoheterocycles as selective monoamine reuptake inhibitors.
Year : 2009
Volume : 19
Issue : 16
First Page : 4630
Last Page : 4633
Authors : Lucas MC, Carter DS, Cai HY, Lee EK, Schoenfeld RC, Steiner S, Villa M, Weikert RJ, Iyer PS.
Abstract : A variety of novel aminoheterocycle scaffolds as selective monoamine reuptake inhibitors have been prepared and one of these scaffolds is achiral. The main elements responsible for hERG channel, CYP2D6 and CYP3A4 inhibition were identified.
|
Inhibition of DAT
|
None
|
251.19
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel, achiral aminoheterocycles as selective monoamine reuptake inhibitors.
Year : 2009
Volume : 19
Issue : 16
First Page : 4630
Last Page : 4633
Authors : Lucas MC, Carter DS, Cai HY, Lee EK, Schoenfeld RC, Steiner S, Villa M, Weikert RJ, Iyer PS.
Abstract : A variety of novel aminoheterocycle scaffolds as selective monoamine reuptake inhibitors have been prepared and one of these scaffolds is achiral. The main elements responsible for hERG channel, CYP2D6 and CYP3A4 inhibition were identified.
|
Displacement of [3H]5HT from human 5HT transporter expressed in HEK293 cells by scintillation counting
|
Homo sapiens
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N-[(3S)-Pyrrolidin-3-yl]benzamides as novel dual serotonin and noradrenaline reuptake inhibitors: impact of small structural modifications on P-gp recognition and CNS penetration.
Year : 2009
Volume : 19
Issue : 17
First Page : 5078
Last Page : 5081
Authors : Wakenhut F, Allan GA, Fish PV, Fray MJ, Harrison AC, McCoy R, Phillips SC, Ryckmans T, Stobie A, Westbrook D, Westbrook SL, Whitlock GA.
Abstract : The structure-activity relationship and the synthesis of novel N-[(3S)-pyrrolidin-3-yl]benzamides as dual serotonin and noradrenaline monoamine reuptake inhibitors (SNRI) is described. Preferred compound 9 aka PF-184,298 is a potent SNRI with good selectivity over dopamine reuptake inhibition (DRI), good in vitro metabolic stability, weak CYP inhibition and drug-like physicochemical properties consistent with CNS target space. Evaluation in an in vivo preclinical model of stress urinary incontinence showed 9 significantly increased urethral tone at free plasma concentrations consistent with its in vitro primary pharmacology.
|
Displacement of [3H]noradrenaline from human NET receptor expressed in HEK293 cells by scintillation counting
|
Homo sapiens
|
45.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N-[(3S)-Pyrrolidin-3-yl]benzamides as novel dual serotonin and noradrenaline reuptake inhibitors: impact of small structural modifications on P-gp recognition and CNS penetration.
Year : 2009
Volume : 19
Issue : 17
First Page : 5078
Last Page : 5081
Authors : Wakenhut F, Allan GA, Fish PV, Fray MJ, Harrison AC, McCoy R, Phillips SC, Ryckmans T, Stobie A, Westbrook D, Westbrook SL, Whitlock GA.
Abstract : The structure-activity relationship and the synthesis of novel N-[(3S)-pyrrolidin-3-yl]benzamides as dual serotonin and noradrenaline monoamine reuptake inhibitors (SNRI) is described. Preferred compound 9 aka PF-184,298 is a potent SNRI with good selectivity over dopamine reuptake inhibition (DRI), good in vitro metabolic stability, weak CYP inhibition and drug-like physicochemical properties consistent with CNS target space. Evaluation in an in vivo preclinical model of stress urinary incontinence showed 9 significantly increased urethral tone at free plasma concentrations consistent with its in vitro primary pharmacology.
|
Displacement of [3H]dopamine from human DAT receptor expressed in HEK293 cells by scintillation counting
|
Homo sapiens
|
435.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N-[(3S)-Pyrrolidin-3-yl]benzamides as novel dual serotonin and noradrenaline reuptake inhibitors: impact of small structural modifications on P-gp recognition and CNS penetration.
Year : 2009
Volume : 19
Issue : 17
First Page : 5078
Last Page : 5081
Authors : Wakenhut F, Allan GA, Fish PV, Fray MJ, Harrison AC, McCoy R, Phillips SC, Ryckmans T, Stobie A, Westbrook D, Westbrook SL, Whitlock GA.
Abstract : The structure-activity relationship and the synthesis of novel N-[(3S)-pyrrolidin-3-yl]benzamides as dual serotonin and noradrenaline monoamine reuptake inhibitors (SNRI) is described. Preferred compound 9 aka PF-184,298 is a potent SNRI with good selectivity over dopamine reuptake inhibition (DRI), good in vitro metabolic stability, weak CYP inhibition and drug-like physicochemical properties consistent with CNS target space. Evaluation in an in vivo preclinical model of stress urinary incontinence showed 9 significantly increased urethral tone at free plasma concentrations consistent with its in vitro primary pharmacology.
|
Inhibition of human NET transfected in MDCK-Net6 cells
|
Homo sapiens
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Heterocyclic cycloalkanol ethylamines as norepinephrine reuptake inhibitors.
Year : 2010
Volume : 20
Issue : 9
First Page : 2809
Last Page : 2812
Authors : Sabatucci JP, Mahaney PE, Leiter J, Johnston G, Burroughs K, Cosmi S, Zhang Y, Ho D, Deecher DC, Trybulski E.
Abstract : A series of heterocyclic cycloalkanol ethylamines have been prepared to expand our norepinephrine reuptake inhibitor (NRI) program. Synthesis of a variety of heterocycles identified (+)-S-21, a potent NRI efficacious in an animal model for thermoregulatory dysfunction.
|
Inhibition of human SERT expressed in human JAR cells
|
Homo sapiens
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Heterocyclic cycloalkanol ethylamines as norepinephrine reuptake inhibitors.
Year : 2010
Volume : 20
Issue : 9
First Page : 2809
Last Page : 2812
Authors : Sabatucci JP, Mahaney PE, Leiter J, Johnston G, Burroughs K, Cosmi S, Zhang Y, Ho D, Deecher DC, Trybulski E.
Abstract : A series of heterocyclic cycloalkanol ethylamines have been prepared to expand our norepinephrine reuptake inhibitor (NRI) program. Synthesis of a variety of heterocycles identified (+)-S-21, a potent NRI efficacious in an animal model for thermoregulatory dysfunction.
|
Displacement of [3H]citalopram from human SERT expressed in HEK293 cells by scintillation proximity assay
|
Homo sapiens
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Second generation N-(1,2-diphenylethyl)piperazines as dual serotonin and noradrenaline reuptake inhibitors: improving metabolic stability and reducing ion channel activity.
Year : 2010
Volume : 20
Issue : 12
First Page : 3788
Last Page : 3792
Authors : Fray MJ, Fish PV, Allan GA, Bish G, Clarke N, Eccles R, Harrison AC, Le Net JL, Phillips SC, Regan N, Sobry C, Stobie A, Wakenhut F, Westbrook D, Westbrook SL, Whitlock GA.
Abstract : New N-(1,2-diphenylethyl)piperazines 6 are disclosed as dual serotonin and noradrenaline reuptake inhibitors (SNRI) which may have potential in treating stress urinary incontinence (SUI). In this Letter, we present new data for SNRI PF-526014 (4) including performance in a canine in vivo model of SUI, cardiovascular assessment, pharmacokinetics in dog and determination of the primary routes of metabolism in vitro. Starting from 4, detailed structure activity relationships established that potent dual SNRIs could be achieved by appropriate substitution of the phenyl rings (6: R; R(1)) combined with a preferred stereochemistry. From this set of compounds, piperazine (-)-6a was identified as a potent and selective dual SNRI with improved metabolic stability and reduced ion channel activity when compared to 4. Based on this profile, (-)-6a was selected for further evaluation in a preclinical model of SUI.
|
Displacement of [3H]nisoxetine from human NET expressed in HEK293 cells by scintillation proximity assay
|
Homo sapiens
|
45.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Second generation N-(1,2-diphenylethyl)piperazines as dual serotonin and noradrenaline reuptake inhibitors: improving metabolic stability and reducing ion channel activity.
Year : 2010
Volume : 20
Issue : 12
First Page : 3788
Last Page : 3792
Authors : Fray MJ, Fish PV, Allan GA, Bish G, Clarke N, Eccles R, Harrison AC, Le Net JL, Phillips SC, Regan N, Sobry C, Stobie A, Wakenhut F, Westbrook D, Westbrook SL, Whitlock GA.
Abstract : New N-(1,2-diphenylethyl)piperazines 6 are disclosed as dual serotonin and noradrenaline reuptake inhibitors (SNRI) which may have potential in treating stress urinary incontinence (SUI). In this Letter, we present new data for SNRI PF-526014 (4) including performance in a canine in vivo model of SUI, cardiovascular assessment, pharmacokinetics in dog and determination of the primary routes of metabolism in vitro. Starting from 4, detailed structure activity relationships established that potent dual SNRIs could be achieved by appropriate substitution of the phenyl rings (6: R; R(1)) combined with a preferred stereochemistry. From this set of compounds, piperazine (-)-6a was identified as a potent and selective dual SNRI with improved metabolic stability and reduced ion channel activity when compared to 4. Based on this profile, (-)-6a was selected for further evaluation in a preclinical model of SUI.
|
Displacement of [3H]dopamine from human DAT expressed in HEK293 cells by scintillation proximity assay
|
Homo sapiens
|
435.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Second generation N-(1,2-diphenylethyl)piperazines as dual serotonin and noradrenaline reuptake inhibitors: improving metabolic stability and reducing ion channel activity.
Year : 2010
Volume : 20
Issue : 12
First Page : 3788
Last Page : 3792
Authors : Fray MJ, Fish PV, Allan GA, Bish G, Clarke N, Eccles R, Harrison AC, Le Net JL, Phillips SC, Regan N, Sobry C, Stobie A, Wakenhut F, Westbrook D, Westbrook SL, Whitlock GA.
Abstract : New N-(1,2-diphenylethyl)piperazines 6 are disclosed as dual serotonin and noradrenaline reuptake inhibitors (SNRI) which may have potential in treating stress urinary incontinence (SUI). In this Letter, we present new data for SNRI PF-526014 (4) including performance in a canine in vivo model of SUI, cardiovascular assessment, pharmacokinetics in dog and determination of the primary routes of metabolism in vitro. Starting from 4, detailed structure activity relationships established that potent dual SNRIs could be achieved by appropriate substitution of the phenyl rings (6: R; R(1)) combined with a preferred stereochemistry. From this set of compounds, piperazine (-)-6a was identified as a potent and selective dual SNRI with improved metabolic stability and reduced ion channel activity when compared to 4. Based on this profile, (-)-6a was selected for further evaluation in a preclinical model of SUI.
|
Displacement of [3H]nisoxetine from rat NET in rat cerebral cortex
|
Rattus norvegicus
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Diaryldiamines with dual inhibition of the histamine H(3) receptor and the norepinephrine transporter and the efficacy of 4-(3-(methylamino)-1-phenylpropyl)-6-(2-(pyrrolidin-1-yl)ethoxy)naphthalen-1-ol in pain.
Year : 2010
Volume : 53
Issue : 21
First Page : 7869
Last Page : 7873
Authors : Altenbach RJ, Black LA, Strakhova MI, Manelli AM, Carr TL, Marsh KC, Wetter JM, Wensink EJ, Hsieh GC, Honore P, Garrison TR, Brioni JD, Cowart MD.
Abstract : A series of compounds was designed as dual inhibitors of the H(3) receptor and the norepinephrine transporter. Compound 5 (rNET K(i) = 14 nM; rH(3)R K(i) = 37 nM) was found to be efficacious in a rat model of osteoarthritic pain.
|
Inhibition of rat NET
|
Rattus norvegicus
|
3.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 4-Phenyl tetrahydroisoquinolines as dual norepinephrine and dopamine reuptake inhibitors.
Year : 2012
Volume : 22
Issue : 23
First Page : 7219
Last Page : 7222
Authors : Pechulis AD, Beck JP, Curry MA, Wolf MA, Harms AE, Xi N, Opalka C, Sweet MP, Yang Z, Vellekoop AS, Klos AM, Crocker PJ, Hassler C, Laws M, Kitchen DB, Smith MA, Olson RE, Liu S, Molino BF.
Abstract : Novel 4-phenyl tetrahydroisoquinolines that inhibit both dopamine and norepinephrine transporters were designed and prepared. In this Letter, we describe the synthesis, in vitro activity and associated structure-activity relationships of this series. We also report the ex vivo NET occupancy of a representative compound, 41.
|
Inhibition of human NET
|
Homo sapiens
|
5.97
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 4-Phenyl tetrahydroisoquinolines as dual norepinephrine and dopamine reuptake inhibitors.
Year : 2012
Volume : 22
Issue : 23
First Page : 7219
Last Page : 7222
Authors : Pechulis AD, Beck JP, Curry MA, Wolf MA, Harms AE, Xi N, Opalka C, Sweet MP, Yang Z, Vellekoop AS, Klos AM, Crocker PJ, Hassler C, Laws M, Kitchen DB, Smith MA, Olson RE, Liu S, Molino BF.
Abstract : Novel 4-phenyl tetrahydroisoquinolines that inhibit both dopamine and norepinephrine transporters were designed and prepared. In this Letter, we describe the synthesis, in vitro activity and associated structure-activity relationships of this series. We also report the ex vivo NET occupancy of a representative compound, 41.
|
Antinociceptive activity in rat assessed reduction formalin-induced hind paw acute pain at 10 mg/kg, ip
|
Rattus norvegicus
|
49.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A novel class of 3-(phenoxy-phenyl-methyl)-pyrrolidines as potent and balanced norepinephrine and serotonin reuptake inhibitors: synthesis and structure-activity relationships.
Year : 2013
Volume : 23
Issue : 5
First Page : 1456
Last Page : 1461
Authors : Van Orden LJ, Van Dyke PM, Saito DR, Church TJ, Chang R, Smith JA, Martin WJ, Jaw-Tsai S, Stangeland EL.
Abstract : A series of 3-(phenoxy-phenyl-methyl)-pyrrolidine analogues were discovered to be potent and balanced norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors. Several of these compounds were identified to have suitable in vitro pharmacokinetic properties for an orally dosed and CNS-targeted drug. Compound 39b, in particular, was identified as a potent NET and SERT reuptake inhibitor (NSRI) with minimal off-target activity and demonstrated robust efficacy in the spinal nerve ligation model of pain behavior.
|
Displacement of [3H]WIN35428 from human recombinant DAT transfected in HEK293 cell membrane
|
Homo sapiens
|
316.23
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A novel class of 3-(phenoxy-phenyl-methyl)-pyrrolidines as potent and balanced norepinephrine and serotonin reuptake inhibitors: synthesis and structure-activity relationships.
Year : 2013
Volume : 23
Issue : 5
First Page : 1456
Last Page : 1461
Authors : Van Orden LJ, Van Dyke PM, Saito DR, Church TJ, Chang R, Smith JA, Martin WJ, Jaw-Tsai S, Stangeland EL.
Abstract : A series of 3-(phenoxy-phenyl-methyl)-pyrrolidine analogues were discovered to be potent and balanced norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors. Several of these compounds were identified to have suitable in vitro pharmacokinetic properties for an orally dosed and CNS-targeted drug. Compound 39b, in particular, was identified as a potent NET and SERT reuptake inhibitor (NSRI) with minimal off-target activity and demonstrated robust efficacy in the spinal nerve ligation model of pain behavior.
|
Inhibition of human recombinant SERT expressed in HEK293 cells assessed as inhibition of [3H]5HT reuptake
|
Homo sapiens
|
0.3162
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A novel class of 3-(phenoxy-phenyl-methyl)-pyrrolidines as potent and balanced norepinephrine and serotonin reuptake inhibitors: synthesis and structure-activity relationships.
Year : 2013
Volume : 23
Issue : 5
First Page : 1456
Last Page : 1461
Authors : Van Orden LJ, Van Dyke PM, Saito DR, Church TJ, Chang R, Smith JA, Martin WJ, Jaw-Tsai S, Stangeland EL.
Abstract : A series of 3-(phenoxy-phenyl-methyl)-pyrrolidine analogues were discovered to be potent and balanced norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors. Several of these compounds were identified to have suitable in vitro pharmacokinetic properties for an orally dosed and CNS-targeted drug. Compound 39b, in particular, was identified as a potent NET and SERT reuptake inhibitor (NSRI) with minimal off-target activity and demonstrated robust efficacy in the spinal nerve ligation model of pain behavior.
|
Inhibition of human recombinant NET expressed in HEK293 cells assessed as inhibition of [3H]NE reuptake
|
Homo sapiens
|
1.585
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A novel class of 3-(phenoxy-phenyl-methyl)-pyrrolidines as potent and balanced norepinephrine and serotonin reuptake inhibitors: synthesis and structure-activity relationships.
Year : 2013
Volume : 23
Issue : 5
First Page : 1456
Last Page : 1461
Authors : Van Orden LJ, Van Dyke PM, Saito DR, Church TJ, Chang R, Smith JA, Martin WJ, Jaw-Tsai S, Stangeland EL.
Abstract : A series of 3-(phenoxy-phenyl-methyl)-pyrrolidine analogues were discovered to be potent and balanced norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors. Several of these compounds were identified to have suitable in vitro pharmacokinetic properties for an orally dosed and CNS-targeted drug. Compound 39b, in particular, was identified as a potent NET and SERT reuptake inhibitor (NSRI) with minimal off-target activity and demonstrated robust efficacy in the spinal nerve ligation model of pain behavior.
|
Inhibition of [3H]5-HT reuptake at SERT in rat brain synaptosomes at 10 uM
|
Rattus norvegicus
|
89.5
%
|
|
Journal : J. Nat. Prod.
Title : Antidepressant abietane diterpenoids from Chinese eaglewood.
Year : 2013
Volume : 76
Issue : 2
First Page : 216
Last Page : 222
Authors : Yang L, Qiao L, Ji C, Xie D, Gong NB, Lu Y, Zhang J, Dai J, Guo S.
Abstract : Ten new abietane diterpenoids, aquilarabietic acids A-J (1-10), and a new podocarpane diterpenoid, aquilarabietic acid K (11), were isolated from the petroleum ether and ethanol extracts of Chinese eaglewood. Among them, 3, 9, and 10 are artifacts. Their structures were established on the basis of data from extensive spectroscopic and X-ray diffraction analyses. Bioassay results indicated that 1 at 10 μM demonstrated remarkable antidepressant activity in vitro by inhibiting norepinephrine reuptake in rat brain synaptosomes by 81.4% and with an IC(50) value of 9.1 × 10(-7) M.
|
Inhibition of [3H]NE reuptake at NET in rat brain synaptosomes at 10 uM
|
Rattus norvegicus
|
81.4
%
|
|
Journal : J. Nat. Prod.
Title : Antidepressant abietane diterpenoids from Chinese eaglewood.
Year : 2013
Volume : 76
Issue : 2
First Page : 216
Last Page : 222
Authors : Yang L, Qiao L, Ji C, Xie D, Gong NB, Lu Y, Zhang J, Dai J, Guo S.
Abstract : Ten new abietane diterpenoids, aquilarabietic acids A-J (1-10), and a new podocarpane diterpenoid, aquilarabietic acid K (11), were isolated from the petroleum ether and ethanol extracts of Chinese eaglewood. Among them, 3, 9, and 10 are artifacts. Their structures were established on the basis of data from extensive spectroscopic and X-ray diffraction analyses. Bioassay results indicated that 1 at 10 μM demonstrated remarkable antidepressant activity in vitro by inhibiting norepinephrine reuptake in rat brain synaptosomes by 81.4% and with an IC(50) value of 9.1 × 10(-7) M.
|
Displacement of [3H]-nisoxetine from Sprague-Dawley rat brain NET after 1 hr
|
Rattus norvegicus
|
1.24
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of a potent, dual serotonin and norepinephrine reuptake inhibitor.
Year : 2013
Volume : 4
Issue : 6
First Page : 560
Last Page : 564
Authors : Dreyfus N, Myers JK, Badescu VO, de Frutos O, de la Puente ML, Ding C, Filla SA, Fynboe K, Gernert DL, Heinz BA, Hemrick-Luecke SK, Johnson KW, Johnson MP, López P, Love PL, Martin LJ, Masquelin T, McCoy MJ, Mendiola J, Morrow D, Muhlhauser M, Pascual G, Perun TJ, Pfeifer LA, Phebus LA, Richards SJ, Rincón JA, Seest EP, Shah J, Shaojuan J, Simmons RM, Stephenson GA, Tromiczak EG, Thompson LK, Walter MW, Weber WW, Zarrinmayeh H, Thomas CE, Joshi E, Iyengar S, Johansson AM.
Abstract : The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.
|
Displacement of [3H]-citalopram from Sprague-Dawley rat brain SERT after 1 hr
|
Rattus norvegicus
|
0.082
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of a potent, dual serotonin and norepinephrine reuptake inhibitor.
Year : 2013
Volume : 4
Issue : 6
First Page : 560
Last Page : 564
Authors : Dreyfus N, Myers JK, Badescu VO, de Frutos O, de la Puente ML, Ding C, Filla SA, Fynboe K, Gernert DL, Heinz BA, Hemrick-Luecke SK, Johnson KW, Johnson MP, López P, Love PL, Martin LJ, Masquelin T, McCoy MJ, Mendiola J, Morrow D, Muhlhauser M, Pascual G, Perun TJ, Pfeifer LA, Phebus LA, Richards SJ, Rincón JA, Seest EP, Shah J, Shaojuan J, Simmons RM, Stephenson GA, Tromiczak EG, Thompson LK, Walter MW, Weber WW, Zarrinmayeh H, Thomas CE, Joshi E, Iyengar S, Johansson AM.
Abstract : The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.
|
Displacement of [3H]WIN35428 from human DAT transfected in HEK293 cells after 3 hrs by Wallac counting analysis
|
Homo sapiens
|
484.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of a potent, dual serotonin and norepinephrine reuptake inhibitor.
Year : 2013
Volume : 4
Issue : 6
First Page : 560
Last Page : 564
Authors : Dreyfus N, Myers JK, Badescu VO, de Frutos O, de la Puente ML, Ding C, Filla SA, Fynboe K, Gernert DL, Heinz BA, Hemrick-Luecke SK, Johnson KW, Johnson MP, López P, Love PL, Martin LJ, Masquelin T, McCoy MJ, Mendiola J, Morrow D, Muhlhauser M, Pascual G, Perun TJ, Pfeifer LA, Phebus LA, Richards SJ, Rincón JA, Seest EP, Shah J, Shaojuan J, Simmons RM, Stephenson GA, Tromiczak EG, Thompson LK, Walter MW, Weber WW, Zarrinmayeh H, Thomas CE, Joshi E, Iyengar S, Johansson AM.
Abstract : The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.
|
Displacement of [3H]Nisoxetine from human NET transfected in HEK293 cells after 3 hrs by Wallac counting analysis
|
Homo sapiens
|
29.0
nM
|
|
Displacement of [3H]Nisoxetine from human NET transfected in HEK293 cells after 3 hrs by Wallac counting analysis
|
Homo sapiens
|
6.7
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of a potent, dual serotonin and norepinephrine reuptake inhibitor.
Year : 2013
Volume : 4
Issue : 6
First Page : 560
Last Page : 564
Authors : Dreyfus N, Myers JK, Badescu VO, de Frutos O, de la Puente ML, Ding C, Filla SA, Fynboe K, Gernert DL, Heinz BA, Hemrick-Luecke SK, Johnson KW, Johnson MP, López P, Love PL, Martin LJ, Masquelin T, McCoy MJ, Mendiola J, Morrow D, Muhlhauser M, Pascual G, Perun TJ, Pfeifer LA, Phebus LA, Richards SJ, Rincón JA, Seest EP, Shah J, Shaojuan J, Simmons RM, Stephenson GA, Tromiczak EG, Thompson LK, Walter MW, Weber WW, Zarrinmayeh H, Thomas CE, Joshi E, Iyengar S, Johansson AM.
Abstract : The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.
|
Displacement of [3H]citalopram from human SERT transfected in HEK293 cells after 3 hrs by Wallac counting analysis
|
Homo sapiens
|
2.3
nM
|
|
Displacement of [3H]citalopram from human SERT transfected in HEK293 cells after 3 hrs by Wallac counting analysis
|
Homo sapiens
|
0.24
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of a potent, dual serotonin and norepinephrine reuptake inhibitor.
Year : 2013
Volume : 4
Issue : 6
First Page : 560
Last Page : 564
Authors : Dreyfus N, Myers JK, Badescu VO, de Frutos O, de la Puente ML, Ding C, Filla SA, Fynboe K, Gernert DL, Heinz BA, Hemrick-Luecke SK, Johnson KW, Johnson MP, López P, Love PL, Martin LJ, Masquelin T, McCoy MJ, Mendiola J, Morrow D, Muhlhauser M, Pascual G, Perun TJ, Pfeifer LA, Phebus LA, Richards SJ, Rincón JA, Seest EP, Shah J, Shaojuan J, Simmons RM, Stephenson GA, Tromiczak EG, Thompson LK, Walter MW, Weber WW, Zarrinmayeh H, Thomas CE, Joshi E, Iyengar S, Johansson AM.
Abstract : The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.
|
Inhibition of human SERT expressed in HEK293 cells at incubated for 15 mins by neurotransmitter reuptake assay
|
Homo sapiens
|
10.4
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Exploration of 3-Aminoazetidines as Triple Reuptake Inhibitors by Bioisosteric Modification of 3-α-Oxyazetidine.
Year : 2014
Volume : 5
Issue : 9
First Page : 999
Last Page : 1004
Authors : Han M, Song C, Jeong N, Hahn HG.
Abstract : For a development of broad spectrum antidepressant 3-aminoazetidine derivatives, two series of compounds were explored by bioisosteric modification of 3-α-oxyazetidine. We synthesized 166 novel 3-aminoazetidine derivatives in series A and B, starting from Boc-protected 3-azetidinone (3) and Boc-protected 3-azetidinal (9) respectively, through parallel syntheses. The inhibitory reuptake activities against serotonin (5-HT), norepinephrine (NE), and dopamine (DA) neurotransmitters were measured by the Neurotransmitter Transporter Uptake Assay Kit using the human embryonic kidney 293 (HEK293) cells stably transfected with the respective three kinds of human transporters (hSERT, hNET, and hDAT). Our study aimed to identify compounds having relative inhibitory activities against hSERT > hNET > hDAT. Lead optimization including microsomal stability, CYP, hERG assay, Ames test, BBB, and PK study resulted in the identification of compound 10dl as a candidate for further studies.
|
Inhibition of human NET expressed in HEK293 cells at incubated for 15 mins by neurotransmitter reuptake assay
|
Homo sapiens
|
515.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Exploration of 3-Aminoazetidines as Triple Reuptake Inhibitors by Bioisosteric Modification of 3-α-Oxyazetidine.
Year : 2014
Volume : 5
Issue : 9
First Page : 999
Last Page : 1004
Authors : Han M, Song C, Jeong N, Hahn HG.
Abstract : For a development of broad spectrum antidepressant 3-aminoazetidine derivatives, two series of compounds were explored by bioisosteric modification of 3-α-oxyazetidine. We synthesized 166 novel 3-aminoazetidine derivatives in series A and B, starting from Boc-protected 3-azetidinone (3) and Boc-protected 3-azetidinal (9) respectively, through parallel syntheses. The inhibitory reuptake activities against serotonin (5-HT), norepinephrine (NE), and dopamine (DA) neurotransmitters were measured by the Neurotransmitter Transporter Uptake Assay Kit using the human embryonic kidney 293 (HEK293) cells stably transfected with the respective three kinds of human transporters (hSERT, hNET, and hDAT). Our study aimed to identify compounds having relative inhibitory activities against hSERT > hNET > hDAT. Lead optimization including microsomal stability, CYP, hERG assay, Ames test, BBB, and PK study resulted in the identification of compound 10dl as a candidate for further studies.
|
Inhibition of human DAT expressed in HEK293 cells at incubated for 15 mins by neurotransmitter reuptake assay
|
Homo sapiens
|
977.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Exploration of 3-Aminoazetidines as Triple Reuptake Inhibitors by Bioisosteric Modification of 3-α-Oxyazetidine.
Year : 2014
Volume : 5
Issue : 9
First Page : 999
Last Page : 1004
Authors : Han M, Song C, Jeong N, Hahn HG.
Abstract : For a development of broad spectrum antidepressant 3-aminoazetidine derivatives, two series of compounds were explored by bioisosteric modification of 3-α-oxyazetidine. We synthesized 166 novel 3-aminoazetidine derivatives in series A and B, starting from Boc-protected 3-azetidinone (3) and Boc-protected 3-azetidinal (9) respectively, through parallel syntheses. The inhibitory reuptake activities against serotonin (5-HT), norepinephrine (NE), and dopamine (DA) neurotransmitters were measured by the Neurotransmitter Transporter Uptake Assay Kit using the human embryonic kidney 293 (HEK293) cells stably transfected with the respective three kinds of human transporters (hSERT, hNET, and hDAT). Our study aimed to identify compounds having relative inhibitory activities against hSERT > hNET > hDAT. Lead optimization including microsomal stability, CYP, hERG assay, Ames test, BBB, and PK study resulted in the identification of compound 10dl as a candidate for further studies.
|
Inhibition of human recombinant CYP3A4 incubated for 5 mins by fluorescence assay
|
Homo sapiens
|
440.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Exploration of 3-Aminoazetidines as Triple Reuptake Inhibitors by Bioisosteric Modification of 3-α-Oxyazetidine.
Year : 2014
Volume : 5
Issue : 9
First Page : 999
Last Page : 1004
Authors : Han M, Song C, Jeong N, Hahn HG.
Abstract : For a development of broad spectrum antidepressant 3-aminoazetidine derivatives, two series of compounds were explored by bioisosteric modification of 3-α-oxyazetidine. We synthesized 166 novel 3-aminoazetidine derivatives in series A and B, starting from Boc-protected 3-azetidinone (3) and Boc-protected 3-azetidinal (9) respectively, through parallel syntheses. The inhibitory reuptake activities against serotonin (5-HT), norepinephrine (NE), and dopamine (DA) neurotransmitters were measured by the Neurotransmitter Transporter Uptake Assay Kit using the human embryonic kidney 293 (HEK293) cells stably transfected with the respective three kinds of human transporters (hSERT, hNET, and hDAT). Our study aimed to identify compounds having relative inhibitory activities against hSERT > hNET > hDAT. Lead optimization including microsomal stability, CYP, hERG assay, Ames test, BBB, and PK study resulted in the identification of compound 10dl as a candidate for further studies.
|
Inhibition of serotonin reuptake at human SERT expressed in HEK293 cells after 15 mins by fluorescence neurotransmitter transporter assay
|
Homo sapiens
|
10.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of 3-phenethylazetidine derivatives as triple reuptake inhibitors.
Year : 2014
Volume : 24
Issue : 15
First Page : 3234
Last Page : 3237
Authors : Yun J, Han M, Song C, Cheon SH, Choi K, Hahn HG.
Abstract : We report the synthesis of 3-phenethylazetidine derivatives 2 and their biological activities against 5-HT, NE and DA transporters as well as microsomal stability, CYP inhibition, and hERG inhibition profiles. Compound 2at showed most potent triple reuptake inhibitor with good selectivity as a candidate for depression.
|
Inhibition of norepinephrine reuptake at human NET expressed in HEK293 cells after 15 mins by fluorescence neurotransmitter transporter assay
|
Homo sapiens
|
515.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of 3-phenethylazetidine derivatives as triple reuptake inhibitors.
Year : 2014
Volume : 24
Issue : 15
First Page : 3234
Last Page : 3237
Authors : Yun J, Han M, Song C, Cheon SH, Choi K, Hahn HG.
Abstract : We report the synthesis of 3-phenethylazetidine derivatives 2 and their biological activities against 5-HT, NE and DA transporters as well as microsomal stability, CYP inhibition, and hERG inhibition profiles. Compound 2at showed most potent triple reuptake inhibitor with good selectivity as a candidate for depression.
|
Inhibition of DA reuptake at human DAT expressed in HEK293 cells after 15 mins by fluorescence neurotransmitter transporter assay
|
Homo sapiens
|
977.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of 3-phenethylazetidine derivatives as triple reuptake inhibitors.
Year : 2014
Volume : 24
Issue : 15
First Page : 3234
Last Page : 3237
Authors : Yun J, Han M, Song C, Cheon SH, Choi K, Hahn HG.
Abstract : We report the synthesis of 3-phenethylazetidine derivatives 2 and their biological activities against 5-HT, NE and DA transporters as well as microsomal stability, CYP inhibition, and hERG inhibition profiles. Compound 2at showed most potent triple reuptake inhibitor with good selectivity as a candidate for depression.
|
Inhibition of recombinant human CYP3A4 preincubated for 5 mins before fluorescent substrate addition by fluorescence assay
|
Homo sapiens
|
440.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of 3-phenethylazetidine derivatives as triple reuptake inhibitors.
Year : 2014
Volume : 24
Issue : 15
First Page : 3234
Last Page : 3237
Authors : Yun J, Han M, Song C, Cheon SH, Choi K, Hahn HG.
Abstract : We report the synthesis of 3-phenethylazetidine derivatives 2 and their biological activities against 5-HT, NE and DA transporters as well as microsomal stability, CYP inhibition, and hERG inhibition profiles. Compound 2at showed most potent triple reuptake inhibitor with good selectivity as a candidate for depression.
|
Inhibition of His-tagged human recombinant SHMT2 expressed in Escherichia coli BLR(DE3) assessed as reduction in NADPH level using L-serine, THF and NADP+ at 6.5 or 26.5 uM incubated for 5 mins by SHMT2-MTHFD coupled reaction based fluorescence assay relative to control
|
Homo sapiens
|
83.8
%
|
|
Title : Compositions and methods relating to inhibiting serine hyrdoxymethyltransferase 2 activity
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
11.22
%
|
|
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.
|
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
|
Chlorocebus sabaeus
|
6.99
%
|
|
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
|
Chlorocebus sabaeus
|
6.99
%
|
|
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.
