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1.
ACS Med Chem Lett ; 9(12): 1170-1174, 2018 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-30613321

RESUMO

BMS-823778 (2), a 1,2,4-triazolopyridinyl-methanol derived analog, was identified as a potent and selective inhibitor of human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD-1) enzyme (IC50 = 2.3 nM) with >10,000-fold selectivity over 11ß-HSD-2. Compound 2 exhibits robust acute pharmacodynamic effects in cynomolgus monkeys (ED50 = 0.6 mg/kg) and in diet-induced obese (DIO) mice (ED50 = 34 mg/kg). Compound 2 also showed excellent inhibition in an ex vivo adipose DIO mouse model (ED50 = 5.2 mg/kg). Oral bioavailability ranges from 44% to 100% in preclinical species. Its favorable development properties, pharmacokinetics, high adipose-to-plasma concentration ratio, and preclinical pharmacology profile have prompted the evaluation of 2 for the treatment of type 2 diabetes and metabolic syndrome in phase 2 clinical trials.

2.
J Med Chem ; 60(12): 4932-4948, 2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28537398

RESUMO

BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme (IC50 3.0 nM) with >10000-fold selectivity over human 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED50 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11ß-HSD1 enzyme for the first 12 h period after dosing followed by an "inhibition holiday" so that the potential for hypothalamic-pituitary-adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/análogos & derivados , Azetidinas/farmacologia , Inibidores Enzimáticos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Actinas/antagonistas & inibidores , Adamantano/administração & dosagem , Adamantano/química , Adamantano/farmacologia , Administração Oral , Animais , Azetidinas/administração & dosagem , Azetidinas/química , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Feminino , Meia-Vida , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Concentração Inibidora 50 , Macaca fascicularis , Masculino , Camundongos Obesos , Ratos , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 24(21): 5045-9, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25266782

RESUMO

A previous disclosure from this lab highlighted the discovery of pyridyl amides as potent 11ß-HSD1 inhibitors. In order to build additional novelty and polarity into this chemotype, replacement of the hydrogen-bonding carbonyl (CO) pharmacophore with the bioisosteric sulfonyl (SO2) group was examined. Despite initial comparisons suggesting the corresponding sulfonamides exhibited weaker activity versus their carbonyl counterparts, further optimization was performed in an effort to identify various potent and unique leads for the program. Judicious incorporation of polar moieties resulted in the identification of compounds with enhanced potency and lipophilicity profiles, resulting in leads with superior aqueous solubility and liver microsomal stability.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/química , Doenças Metabólicas/tratamento farmacológico , Sulfonamidas/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/uso terapêutico , Humanos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/uso terapêutico
4.
ACS Med Chem Lett ; 5(7): 803-8, 2014 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-25050169

RESUMO

Small alkyl groups and spirocyclic-aromatic rings directly attached to the left side and right side of the 1,2,4-triazolopyridines (TZP), respectively, were found to be potent and selective inhibitors of human 11ß-hydroxysteroid dehydrogenase-type 1 (11ß-HSD-1) enzyme. 3-(1-(4-Chlorophenyl)cyclopropyl)-8-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine (9f) was identified as a potent inhibitor of the 11ß-HSD-1 enzyme with reduced Pregnane-X receptor (PXR) transactivation activity. The binding orientation of this TZP series was revealed by X-ray crystallography structure studies.

5.
Bioorg Med Chem Lett ; 24(2): 654-60, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24360604

RESUMO

A series of 2-adamantylmethyl tetrazoles bearing a quaternary carbon at the 2-position of the adamantane ring (i.e. structure A) have been designed and synthesized as novel, potent, and selective inhibitors of human 11ß-HSD1 enzyme. Based on the SAR and the docking experiment, we report for the first time a tetrazole moiety serving as the active pharmacophore for inhibitory activity of 11ß-HSD1 enzyme. Optimization of two regions of A, R(1) and R(2) respectively, was explored with a focus on improving the inhibitory activity (IC50) and the microsomal stability in both human and mouse species. These efforts led to the identification of 26, an orally bioavailable inhibitor of human 11ß-HSD1 with a favorable development profile.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/síntese química , Tetrazóis/síntese química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Adamantano/farmacologia , Animais , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos , Camundongos Transgênicos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Estrutura Secundária de Proteína , Relação Estrutura-Atividade , Tetrazóis/farmacologia
7.
Bioorg Med Chem Lett ; 21(22): 6693-8, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21983444

RESUMO

Derived from the HTS hit 1, a series of hydroxyisoquinolines was discovered as potent and selective 11ß-HSD1 inhibitors with good cross species activity. Optimization of substituents at the 1 and 4 positions of the isoquinoline group in addition to the core modifications, with a special focus on enhancing metabolic stability and aqueous solubility, resulted in the identification of several compounds as potent advanced leads.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores Enzimáticos/farmacocinética , Humanos , Isoquinolinas/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Relação Estrutura-Atividade
8.
9.
Bioorg Med Chem Lett ; 19(20): 5872-6, 2009 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-19740659

RESUMO

We report the synthesis and enzymatic evaluation of potent inhibitors of acetyl-CoA carboxylases (ACCs) containing biphenyl or 3-phenyl pyridine cores. These compounds inhibit both ACC1 and ACC2, or are moderately selective for either enzyme, depending on side chain substitution. Typical activities of the most potent compounds in this class are in the low double-digit to single-digit nanomolar range in in vitro assays using human ACC1 and ACC2 enzymes.


Assuntos
Fármacos Antiobesidade/química , Inibidores Enzimáticos/química , Piridinas/química , Acetil-CoA Carboxilase/antagonistas & inibidores , Acetil-CoA Carboxilase/metabolismo , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Piridinas/síntese química , Piridinas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
10.
J Med Chem ; 52(23): 7788-99, 2009 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-19702274

RESUMO

Glucagon-like peptide 1 (GLP-1) is a 30 or 31 amino acid peptide hormone that contributes to the physiological regulation of glucose homeostasis and food intake. Herein, we report the discovery of a novel class of 11 amino acid GLP-1 receptor agonists. These peptides consist of a structurally optimized 9-mer, which is closely related to the N-terminal 9 amino acids of GLP-1, linked to a substituted C-terminal biphenylalanine (BIP) dipeptide. SAR studies resulted in 11-mer GLP-1R agonists with similar in vitro potency to the native 30-mer. Peptides 21 and 22 acutely reduced plasma glucose excursions and increased plasma insulin concentrations in a mouse model of diabetes. These peptides also showed sustained exposures over several hours in mouse and dog models. The described 11-mer GLP-1 receptor agonists represent a new tool in further understanding GLP-1 receptor pharmacology that may lead to novel antidiabetic agents.


Assuntos
Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Receptores de Glucagon/agonistas , Sequência de Aminoácidos , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Relação Dose-Resposta a Droga , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Masculino , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/farmacocinética , Conformação Proteica
11.
J Med Chem ; 52(9): 2794-8, 2009 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-19351168

RESUMO

A novel selective androgen receptor modulator (SARM) scaffold was discovered as a byproduct obtained during synthesis of our earlier series of imidazolidin-2-ones. The resulting oxazolidin-2-imines are among the most potent SARMs known, with many analogues exhibiting sub-nM in vitro potency in binding and functional assays. Despite the potential for hydrolytic instability at gut pH, compounds of the present class showed good oral bioavailability and were highly active in a standard rodent pharmacological model.


Assuntos
Androgênios , Músculos/efeitos dos fármacos , Músculos/metabolismo , Oxazóis/química , Oxazóis/farmacologia , Animais , Cristalografia por Raios X , Humanos , Concentração de Íons de Hidrogênio , Masculino , Modelos Moleculares , Conformação Molecular , Próstata/efeitos dos fármacos , Próstata/metabolismo , Ratos , Especificidade por Substrato
12.
Anal Biochem ; 383(2): 144-50, 2008 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-18834848

RESUMO

Acyl-coenzyme A:diacylglycerol acyltransferase (DGAT) is a key enzyme in triacylglycerol synthesis, and inhibiting this enzyme is a promising approach for treating obesity, type II diabetes, and dyslipidemia. There are two distinct DGAT enzymes: DGAT1 and DGAT2. The conventional assay for measuring DGAT activity is a thin layer chromatography (TLC) method, which is not amenable to screening a large number of compounds. To increase the throughput, we have developed a novel, homogeneous scintillation proximity assay (SPA) for DGAT. In this assay, when (3)H-labeled acyl-CoA is used as the acyl donor and diacylglycerol is used as the acyl acceptor, the (3)H-labeled triacylglycerol product formed in the reaction binds to polylysine SPA beads, producing a signal that is measured in a TopCount or LEADseeker. The apparent Michaelis-Menten kinetic parameters determined by this DGAT SPA method agreed well with the values determined with the conventional TLC assay. The statistical values also indicate that the DGAT SPA is a robust assay, with a Z' of more than 0.60 and a signal/background ratio of approximately 9. These results suggest that the current assay provides high-throughput capacity for the identification of DGAT inhibitors.


Assuntos
Diacilglicerol O-Aciltransferase/análise , Animais , Bovinos , Diacilglicerol O-Aciltransferase/metabolismo , Dimetil Sulfóxido/metabolismo , Enzimas Imobilizadas/análise , Enzimas Imobilizadas/metabolismo , Cinética , Microesferas , Ratos , Reprodutibilidade dos Testes , Contagem de Cintilação , Sensibilidade e Especificidade , Soroalbumina Bovina/metabolismo , Triglicerídeos/biossíntese
13.
Bioorg Med Chem Lett ; 18(11): 3168-72, 2008 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-18485702

RESUMO

Several series of pyridine amides were identified as selective and potent 11beta-HSD1 inhibitors. The most potent inhibitors feature 2,6- or 3,5-disubstitution on the pyridine core. Various linkers (CH(2)SO(2), CH(2)S, CH(2)O, S, O, N, bond) between the distal aryl and central pyridyl groups are tolerated, and lipophilic amide groups are generally favored. On the distal aryl group, a number of substitutions are well tolerated. A crystal structure was obtained for a complex between 11beta-HSD1 and the most potent inhibitor in this series.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Amidas/química , Técnicas de Química Combinatória , Cristalografia por Raios X , Desenho de Drogas , Humanos , Concentração Inibidora 50 , Conformação Molecular , Estrutura Molecular , Piridinas/química , Relação Estrutura-Atividade
14.
Biochim Biophys Acta ; 1774(9): 1184-91, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17707701

RESUMO

11beta-hydroxysteroid dehydrogenase 1 regulates the tissue availability of cortisol by interconverting cortisone and cortisol. It is capable of functioning as both a reductase and a dehydrogenase depending upon the surrounding milieu. In this work, we have studied the reaction mechanism of a soluble form of human 11beta-hydroxysteroid dehydrogenase 1 and its mode of inhibition by potent and selective inhibitors belonging to three different structural classes. We found that catalysis follows an ordered addition with NADP(H) binding preceding the binding of the steroid. While all three inhibitors tested bound to the steroid binding pocket, they differed in their interactions with the cofactor NADP(H). Compound A, a pyridyl amide bound more efficiently to the NADPH-bound form of 11beta-hydroxysteroid dehydrogenase 1. Compound B, an adamantyl triazole, was unaffected by NADP(H) binding and the sulfonamide, Compound C, showed preferential binding to the NADP+ -bound form of 11beta-hydroxysteroid dehydrogenase 1. These differences were found to augment significant selectivity towards inhibition of the reductase reaction versus the dehydrogenase reaction. This selectivity may translate to differences in the in vivo effects of 11beta-hydroxysteroid dehydrogenase 1 inhibitors.


Assuntos
11-beta-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenases/metabolismo , Piridinas/farmacologia , Sulfonamidas/farmacologia , Triazóis/farmacologia , Humanos , Cinética , NADP/metabolismo
16.
J Med Chem ; 50(13): 3015-25, 2007 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-17552509

RESUMO

A novel series of imidazolin-2-ones were designed and synthesized as highly potent, orally active and muscle selective androgen receptor modulators (SARMs), with most of the compounds exhibiting low nM in vitro potency in androgen receptor (AR) binding and functional assays. Once daily oral treatment with the lead compound 11a (AR Ki = 0.9 nM, EC50 = 1.8 nM) for 14 days induced muscle growth with an ED50 of 0.09 mg/kg, providing approximately 50-fold selectivity over prostate growth in an orchidectomized rat model. Pharmacokinetic studies in rats demonstrated that the lead compound 11a had oral bioavailability of 65% and a plasma half-life of 5.5 h. On the basis of their preclinical profiles, the SARMs in this series are expected to provide beneficial anabolic effects on muscle with minimal androgenic effects on prostate tissue.


Assuntos
Anabolizantes/síntese química , Imidazóis/síntese química , Músculo Esquelético/efeitos dos fármacos , Pirróis/síntese química , Receptores Androgênicos/metabolismo , Administração Oral , Anabolizantes/farmacocinética , Anabolizantes/farmacologia , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Meia-Vida , Imidazóis/farmacocinética , Imidazóis/farmacologia , Masculino , Modelos Moleculares , Músculo Esquelético/anatomia & histologia , Orquiectomia , Próstata/anatomia & histologia , Próstata/efeitos dos fármacos , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
17.
Anal Biochem ; 363(2): 263-74, 2007 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-17335769

RESUMO

Peroxisome proliferator-activated receptors (PPARs) and other members of the nuclear hormone receptor family are important drug targets for the treatment of metabolic diseases. PPARalpha and PPARgamma play crucial roles in lipid and glucose metabolism, respectively. Therefore, screening methods that help to rapidly identify activators of these receptors should be of considerable value. A homogeneous fluorescence polarization (FP) ligand binding assay capable of rapidly identifying ligands that bind to both PPARalpha and PPARgamma has been developed using purified PPARalpha or PPARgamma ligand binding domains and a fluorescein-labeled analog (FLA) of a potent dual PPARalpha/gamma activator. FLA activator showed good binding affinity toward both PPARalpha (K(i)=0.7microM) and PPARgamma (K(i)=0.4microM). The binding of FLA activator was rapid and reached a plateau within 10 min. The resulting FP signal was stable for at least 18h. The FP binding assay performed robustly in a 384-well format, and the average Z' value was 0.77. There was a good correlation between the binding potency (IC(50) values) and rank order of binding potency for a panel of standard PPAR ligands obtained in FP binding assay and scintillation proximity assay or gel filtration binding assays using (3)H-labeled PPARalpha (r(2)=0.99) and PPARgamma (r(2)=0.99) ligands. There was also a good correlation of IC(50) values obtained by FP binding assay and scintillation proximity assay for the clinically used PPAR activators. Thus, the FP binding assay with a single fluorescein-labeled PPARalpha/gamma dual activator offers a homogeneous nonradioactive, sensitive, robust, and less expensive high-throughput assay for detecting compounds that bind to both PPARgamma and PPARalpha. Using this FP binding assay, we have identified a large number of PPARalpha/gamma dual activators. A similar assay platform may be easily adapted to other members of the nuclear hormone receptor family.


Assuntos
Polarização de Fluorescência/métodos , Ligantes , PPAR alfa/metabolismo , PPAR gama/metabolismo , Cromatografia em Gel , Dimetil Sulfóxido/química , Humanos , Cinética , Modelos Biológicos , Estrutura Molecular , PPAR alfa/agonistas , PPAR alfa/genética , PPAR gama/agonistas , PPAR gama/genética , Ligação Proteica , Reprodutibilidade dos Testes
19.
Bioorg Med Chem Lett ; 17(7): 1860-4, 2007 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-17292608

RESUMO

Pharmacokinetic studies in cynomolgus monkeys with a novel prototype selective androgen receptor modulator revealed trace amounts of an aniline fragment released through hydrolytic metabolism. This aniline fragment was determined to be mutagenic in an Ames assay. Subsequent concurrent optimization for target activity and avoidance of mutagenicity led to the identification of a pharmacologically superior clinical candidate without mutagenic potential.


Assuntos
Antagonistas de Androgênios/química , Antagonistas de Androgênios/síntese química , Química Farmacêutica/métodos , Hidantoínas/química , Hidantoínas/síntese química , Receptores Androgênicos/metabolismo , Antagonistas de Androgênios/farmacologia , Animais , Desenho de Drogas , Escherichia coli/metabolismo , Genes Reporter , Cinética , Macaca fascicularis , Modelos Químicos , Conformação Molecular , Mutagênese , Mutagênicos , Relação Estrutura-Atividade
20.
Endocrinology ; 148(1): 4-12, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17008401

RESUMO

A novel, highly potent, orally active, nonsteroidal tissue selective androgen receptor (AR) modulator (BMS-564929) has been identified, and this compound has been advanced to clinical trials for the treatment of age-related functional decline. BMS-564929 is a subnanomolar AR agonist in vitro, is highly selective for the AR vs. other steroid hormone receptors, and exhibits no significant interactions with SHBG or aromatase. Dose response studies in castrated male rats show that BMS-564929 is substantially more potent than testosterone (T) in stimulating the growth of the levator ani muscle, and unlike T, highly selective for muscle vs. prostate. Key differences in the binding interactions of BMS-564929 with the AR relative to the native hormones were revealed through x-ray crystallography, including several unique contacts located in specific helices of the ligand binding domain important for coregulatory protein recruitment. Results from additional pharmacological studies effectively exclude alternative mechanistic contributions to the observed tissue selectivity of this unique, orally active androgen. Because concerns regarding the potential hyperstimulatory effects on prostate and an inconvenient route of administration are major drawbacks that limit the clinical use of T, the potent oral activity and tissue selectivity exhibited by BMS-564929 are expected to yield a clinical profile that provides the demonstrated beneficial effects of T in muscle and other tissues with a more favorable safety window.


Assuntos
Imidazóis/síntese química , Imidazóis/farmacologia , Músculo Esquelético/efeitos dos fármacos , Próstata/efeitos dos fármacos , Pirróis/síntese química , Pirróis/farmacologia , Receptores Androgênicos/metabolismo , Testosterona/análogos & derivados , Envelhecimento/metabolismo , Animais , Aromatase/metabolismo , Ligação Competitiva , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cristalografia por Raios X , Di-Hidrotestosterona/química , Di-Hidrotestosterona/metabolismo , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Humanos , Imidazóis/metabolismo , Ligantes , Hormônio Luteinizante/sangue , Masculino , Músculo Esquelético/fisiologia , Orquiectomia , Próstata/fisiologia , Estrutura Terciária de Proteína , Pirróis/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Androgênicos/química , Receptores Androgênicos/genética , Testosterona/química , Testosterona/metabolismo , Transcrição Genética/fisiologia
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