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1.
Bioorg Med Chem ; 25(13): 3330-3349, 2017 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-28454849

RESUMEN

We previously reported that 4-(pyrrolidin-1-yl)benzonitrile derivative 1b was a selective androgen receptor modulator (SARM) that exhibited anabolic effects on organs such as muscles and the central nervous system (CNS), but neutral effects on the prostate. From further modification, we identified that 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2a showed strong AR binding affinity with improved metabolic stabilities. Based on these results, we tried to enhance the AR agonistic activities by modifying the substituents of the 5-oxopyrrolidine ring. As a consequence, we found that 4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (2f) had ideal SARM profiles in Hershberger assay and sexual behavior induction assay. Furthermore, 2f showed good pharmacokinetic profiles in rats, dogs, monkeys, excellent nuclear selectivity and acceptable toxicological profiles. We also determined its binding mode by obtaining the co-crystal structures with AR.


Asunto(s)
Andrógenos/farmacología , Descubrimiento de Drogas , Nitrilos/farmacología , Receptores Androgénicos/metabolismo , Andrógenos/síntesis química , Andrógenos/química , Animales , Células COS , Chlorocebus aethiops , Perros , Relación Dosis-Respuesta a Droga , Haplorrinos , Humanos , Masculino , Ratones , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Nitrilos/síntesis química , Nitrilos/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
2.
Bioorg Med Chem Lett ; 27(9): 1897-1901, 2017 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-28363748

RESUMEN

We recently reported a class of novel tissue-selective androgen receptor modulators (SARMs), represented by a naphthalene derivative A. However, their pharmacokinetic (PK) profiles were poor due to low metabolic stability. To improve the PK profiles, we modified the hydroxypyrrolidine and benzonitrile substituents of 4-(pyrrolidin-1-yl)benzonitrile derivative B, which had a comparable potency as that of compound A. This optimization led us to further modifications, which improved metabolic stability while maintaining potent androgen agonistic activity. Among the synthesized compounds, (2S,3S)-2,3-dimethyl-3-hydroxylpyrrolidine derivative 1c exhibited a suitable PK profile and improved metabolic stability. Compound 1c demonstrated significant efficacy in levator ani muscle without increasing the weight of the prostate in an in vivo study. In addition, compound 1c showed agonistic activity in the CNS, which was detected using sexual behavior induction assay.


Asunto(s)
Andrógenos/química , Andrógenos/farmacología , Nitrilos/química , Nitrilos/farmacología , Pirrolidinas/química , Pirrolidinas/farmacología , Receptores Androgénicos/metabolismo , Anabolizantes/química , Anabolizantes/farmacocinética , Anabolizantes/farmacología , Andrógenos/farmacocinética , Animales , Eunuquismo/tratamiento farmacológico , Eunuquismo/metabolismo , Humanos , Masculino , Modelos Moleculares , Músculos/efectos de los fármacos , Músculos/metabolismo , Nitrilos/farmacocinética , Tamaño de los Órganos/efectos de los fármacos , Próstata/efectos de los fármacos , Próstata/metabolismo , Pirrolidinas/farmacocinética , Ratas
3.
J Med Chem ; 60(2): 608-626, 2017 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-27966948

RESUMEN

On the basis of a superposition study of X-ray crystal structures of complexes of quinazoline derivative 1 and triazole derivative 2 with matrix metalloproteinase (MMP)-13 catalytic domain, a novel series of fused pyrimidine compounds which possess a 1,2,4-triazol-3-yl group as a zinc binding group (ZBG) was designed. Among the herein described and evaluated compounds, 31f exhibited excellent potency for MMP-13 (IC50 = 0.036 nM) and selectivities (greater than 1,500-fold) over other MMPs (MMP-1, -2, -3, -7, -8, -9, -10, and -14) and tumor necrosis factor-α converting enzyme (TACE). Furthermore, the inhibitor was shown to protect bovine nasal cartilage explants against degradation induced by interleukin-1 and oncostatin M. In this article, we report the discovery of extremely potent, highly selective, and orally bioavailable fused pyrimidine derivatives that possess a 1,2,4-triazol-3-yl group as a novel ZBG for selective MMP-13 inhibition.


Asunto(s)
Metaloproteinasa 13 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Pirimidinas/farmacología , Pirimidinonas/farmacología , Tiofenos/farmacología , Triazoles/farmacología , Zinc/química , Animales , Cartílago/metabolismo , Bovinos , Quelantes/síntesis química , Quelantes/farmacología , Colágeno/metabolismo , Diseño de Fármacos , Inhibidores de la Metaloproteinasa de la Matriz/síntesis química , Pirimidinas/síntesis química , Pirimidinonas/síntesis química , Quinazolinas/síntesis química , Quinazolinas/farmacología , Tiofenos/síntesis química , Triazoles/síntesis química
4.
Bioorg Med Chem ; 24(23): 6149-6165, 2016 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-27825552

RESUMEN

Matrix metalloproteinase-13 (MMP-13), a member of the collagenase family of enzymes, has been implicated to play a key role in the pathology of osteoarthritis. Recently, we have reported the discovery of a series of quinazoline-2-carboxamide based non-zinc-binding MMP-13 selective inhibitors, as exemplified by compound 1. We then continued our research of a novel class of zinc-binding inhibitors to obtain follow-up compounds with different physicochemical, pharmacokinetic, and biological activity profiles. In order to design selective MMP-13 inhibitors, we adopted a strategy of connecting a zinc-binding group with the quinazoline-2-carboxamide system, a unique S1' binder, by an appropriate linker. Among synthesized compounds, a triazolone inhibitor 35 exhibited excellent potency (IC50=0.071nM) and selectivity (greater than 170-fold) over other MMPs (MMP-1, 2, 3, 7, 8, 9, 10, 12, and 14) and tumor necrosis factor-α converting enzyme (TACE). In this article, the design, synthesis, and biological activity of novel zinc-binding MMP-13 inhibitors are described.


Asunto(s)
Amidas/farmacología , Metaloproteinasa 13 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Pirimidinas/farmacología , Quinazolinonas/farmacología , Triazoles/farmacología , Zinc/química , Proteína ADAM17/antagonistas & inhibidores , Amidas/síntesis química , Amidas/farmacocinética , Animales , Diseño de Fármacos , Humanos , Inhibidores de la Metaloproteinasa de la Matriz/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz/farmacocinética , Microsomas Hepáticos/metabolismo , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Quinazolinonas/síntesis química , Quinazolinonas/farmacocinética , Ratas , Triazoles/síntesis química , Triazoles/farmacocinética
5.
J Med Chem ; 57(21): 8886-902, 2014 Nov 13.
Artículo en Inglés | MEDLINE | ID: mdl-25264600

RESUMEN

Matrix metalloproteinase-13 (MMP-13) has been implicated to play a key role in the pathology of osteoarthritis. On the basis of X-ray crystallography, we designed a series of potent MMP-13 selective inhibitors optimized to occupy the distinct deep S1' pocket including an adjacent branch. Among them, carboxylic acid inhibitor 21k exhibited excellent potency and selectivity for MMP-13 over other MMPs. An effort to convert compound 21k to the mono sodium salt 38 was promising in all animal species studied. Moreover, no overt toxicity was observed in a preliminary repeat dose oral toxicity study of compound 21k in rats. A single oral dose of compound 38 significantly reduced degradation products (CTX-II) released from articular cartilage into the joint cavity in a rat MIA model in vivo. In this article, we report the discovery of highly potent, selective, and orally bioavailable MMP-13 inhibitors as well as their detailed structure-activity data.


Asunto(s)
Benzoatos/síntesis química , Benzoatos/farmacología , Metaloproteinasa 13 de la Matriz/efectos de los fármacos , Inhibidores de la Metaloproteinasa de la Matriz/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Quinazolinas/síntesis química , Quinazolinas/farmacología , Animales , Benzoatos/farmacocinética , Sitios de Unión , Cristalografía por Rayos X , Humanos , Concentración 50 Inhibidora , Inhibidores de la Metaloproteinasa de la Matriz/farmacocinética , Osteoartritis/tratamiento farmacológico , Quinazolinas/farmacocinética , Ratas , Relación Estructura-Actividad
6.
Bioorg Med Chem ; 22(19): 5487-505, 2014 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-25192810

RESUMEN

On the basis of X-ray co-crystal structures of matrix metalloproteinase-13 (MMP-13) in complex with its inhibitors, our structure-based drug design (SBDD) strategy was directed to achieving high affinity through optimal protein-ligand interaction with the unique S1″ hydrophobic specificity pocket. This report details the optimization of lead compound 44 to highly potent and selective MMP-13 inhibitors based on fused pyrimidine scaffolds represented by the thienopyrimidin-4-one 26c. Furthermore, we have examined the release of collagen fragments from bovine nasal cartilage in response to a combination of IL-1 and oncostatin M.


Asunto(s)
Derivados del Benceno/química , Metaloproteinasa 13 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/administración & dosificación , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Pirimidinas/farmacología , Administración Oral , Derivados del Benceno/administración & dosificación , Derivados del Benceno/farmacología , Sitios de Unión/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Inhibidores de la Metaloproteinasa de la Matriz/química , Modelos Moleculares , Estructura Molecular , Pirimidinas/administración & dosificación , Pirimidinas/química , Relación Estructura-Actividad
7.
J Med Chem ; 55(8): 3960-74, 2012 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-22490067

RESUMEN

G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) is a free fatty acid (FFA) receptor that mediates FFA-amplified glucose-stimulated insulin secretion in pancreatic ß-cells. We previously identified (2,3-dihydro-1-benzofuran-3-yl)acetic acid derivative 2 as a candidate, but it had relatively high lipophilicity. Adding a polar functional group on 2 yielded several compounds with lower lipophilicity and little effect on caspase-3/7 activity at 30 µM (a marker of toxicity in human HepG2 hepatocytes). Three optimized compounds showed promising pharmacokinetic profiles with good in vivo effects. Of these, compound 16 had the lowest lipophilicity. Metabolic analysis of 16 showed a long-acting PK profile due to high resistance to ß-oxidation. Oral administration of 16 significantly reduced plasma glucose excursion and increased insulin secretion during an OGTT in type 2 diabetic rats. Compound 16 (TAK-875) is being evaluated in human clinical trials for the treatment of type 2 diabetes.


Asunto(s)
Benzofuranos/farmacología , Glucosa/farmacología , Insulina/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Sulfonas/farmacología , Animales , Benzofuranos/síntesis química , Benzofuranos/farmacocinética , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Prueba de Tolerancia a la Glucosa , Células Hep G2 , Humanos , Secreción de Insulina , Masculino , Ratas , Receptores Acoplados a Proteínas G/efectos de los fármacos , Estereoisomerismo , Sulfonas/síntesis química , Sulfonas/farmacocinética
8.
J Med Chem ; 55(8): 3756-76, 2012 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-22428944

RESUMEN

As part of a program to identify potent GPR40 agonists with drug-like properties suitable for clinical development, the incorporation of polar substituents was explored with the intention of decreasing the lipophilicity of our recently disclosed phenylpropanoic acid derivative 1. This incorporation would allow us to mitigate the cytotoxicity issues observed with compound 1 and enable us to move away from the multifunctional free fatty acid-like structure. Substitutions on the 2',6'-dimethylbiphenyl ring were initially undertaken, which revealed the feasibility of introducing polar functionalities at the biphenyl 4'-position. Further optimization of this position and the linker led to the discovery of several 4'-alkoxybiphenyl derivatives, which showed potent GPR40 agonist activities with the best balance in terms of improved cytotoxicity profiles and favorable pharmacokinetic properties. Among them, 3-{2-fluoro-4-[({4'-[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2',6'-dimethylbiphenyl-3-yl}methyl)amino]phenyl}propanoic acid (35) exhibited a robust plasma glucose-lowering effect and insulinotropic action during an oral glucose tolerance test in rats with impaired glucose tolerance.


Asunto(s)
Óxidos S-Cíclicos/síntesis química , Hipoglucemiantes/síntesis química , Fenilpropionatos/síntesis química , Receptores Acoplados a Proteínas G/agonistas , Animales , Células CHO , Calcio/metabolismo , Caspasas/metabolismo , Supervivencia Celular , Cricetinae , Óxidos S-Cíclicos/farmacocinética , Óxidos S-Cíclicos/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Intolerancia a la Glucosa/tratamiento farmacológico , Células Hep G2 , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/uso terapéutico , Concentración 50 Inhibidora , Masculino , Fenilpropionatos/farmacocinética , Fenilpropionatos/uso terapéutico , Ratas , Receptores Acoplados a Proteínas G/metabolismo , Relación Estructura-Actividad
9.
J Med Chem ; 55(4): 1538-52, 2012 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-22242551

RESUMEN

The G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. We previously identified phenylpropanoic acid derivative 1 (3-{4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid) as a potent and orally available GPR40/FFA1 agonist; however, 1 exhibited high clearance and low oral bioavailability, which was likely due to its susceptibility to ß-oxidation at the phenylpropanoic acid moiety. To identify long-acting compounds, we attempted to block the metabolically labile sites at the phenylpropanoic acid moiety by introducing a fused-ring structure. Various fused-ring alkanoic acids with potent GPR40/FFA1 activities and good PK profiles were produced. Further optimizations of the lipophilic portion and the acidic moiety led to the discovery of dihydrobenzofuran derivative 53 ((6-{[4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}-2,3-dihydro-1-benzofuran-3-yl)acetic acid), which acted as a GPR40/FFA1 agonist with in vivo efficacy during an oral glucose tolerance test (OGTT) in rats with impaired glucose tolerance.


Asunto(s)
Acetatos/síntesis química , Ácidos Acíclicos/síntesis química , Benzofuranos/síntesis química , Insulina/sangre , Receptores Acoplados a Proteínas G/agonistas , Acetatos/farmacocinética , Acetatos/farmacología , Ácidos Acíclicos/farmacocinética , Ácidos Acíclicos/farmacología , Animales , Benzofuranos/farmacocinética , Benzofuranos/farmacología , Células CHO , Cricetinae , Cricetulus , Femenino , Intolerancia a la Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/metabolismo , Secreción de Insulina , Modelos Moleculares , Unión Proteica , Ratas , Ratas Wistar , Especificidad de la Especie
10.
Bioorg Med Chem ; 20(1): 422-34, 2012 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-22094279

RESUMEN

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.


Asunto(s)
Antagonistas de Receptores Androgénicos/síntesis química , Antineoplásicos/síntesis química , Diseño de Fármacos , Pirroles/química , Receptores Androgénicos/química , Sustitución de Aminoácidos , Antagonistas de Receptores Androgénicos/farmacología , Antagonistas de Receptores Androgénicos/uso terapéutico , Antagonistas de Receptores Androgénicos/toxicidad , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Resistencia a Antineoplásicos , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , Ratones Desnudos , Mutación , Neoplasias de la Próstata/tratamiento farmacológico , Pirroles/farmacología , Pirroles/uso terapéutico , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Trasplante Heterólogo
11.
J Med Chem ; 54(5): 1365-78, 2011 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-21319751

RESUMEN

G protein-coupled receptor 40 (GPR40) is being recently considered to be a new potential drug target for the treatment of type 2 diabetes because of its role in the enhancement of free fatty acid-regulated glucose-stimulated insulin secretion in pancreatic ß-cells. We initially identified benzyloxyphenylpropanoic acid (1b) (EC(50) = 510 nM), which was designed based on the structure of free fatty acids, as a promising lead compound with GPR40 agonist activity. Chemical modification of compound 1b led to the discovery of 3-{4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid (4p) as a potent GPR40 agonist (EC(50) = 5.7 nM). Compound 4p exhibited acceptable pharmacokinetic profiles and significant glucose-lowering effects during an oral glucose tolerance test in diabetic rats. Moreover, no hypoglycemic event was observed even after administration of a high dose of compound 4p to normal fasted rats. These pharmacological results suggest that GPR40 agonists might be novel glucose-dependent insulin secretagogues with little or no risk of hypoglycemia.


Asunto(s)
Compuestos de Bifenilo/síntesis química , Hipoglucemiantes/síntesis química , Fenilpropionatos/síntesis química , Receptores Acoplados a Proteínas G/agonistas , Administración Oral , Animales , Compuestos de Bifenilo/farmacocinética , Compuestos de Bifenilo/farmacología , Glucemia/análisis , Células CHO , Cricetinae , Cricetulus , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/tratamiento farmacológico , Diseño de Fármacos , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Masculino , Fenilpropionatos/farmacocinética , Fenilpropionatos/farmacología , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad
12.
ACS Med Chem Lett ; 1(6): 290-4, 2010 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-24900210

RESUMEN

GPR40, one of the G protein-coupled receptors predominantly expressed in pancreatic ß-cells, mediates enhancement of glucose-stimulated insulin secretion by free fatty acids. A potent and selective GPR40 agonist is theorized to be a safe and effective antidiabetic drug with little or no risk of hypoglycemia. Cyclization of the phenylpropanoic acid moiety of lead compound 1 produced fused phenylalkanoic acids with favorable in vitro agonist activities and pharmacokinetic profiles. Further optimization led to the discovery of dihydrobenzofuran derivative 9a ([(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate, TAK-875) as a potent, selective, and orally bioavailable GPR40 agonist, with a pharmacokinetic profile enabling long-acting drug efficacy. Compound 9a showed potent plasma glucose-lowering action and insulinotropic action during an oral glucose tolerance test in female Wistar fatty rats with impaired glucose tolerance. Compound 9a is currently in clinical trials for the treatment of type 2 diabetes mellitus.

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