RESUMEN
GPR40 AgoPAMs are highly effective antidiabetic agents that have a dual mechanism of action, stimulating both glucose-dependent insulin and GLP-1 secretion. The early lipophilic, aromatic pyrrolidine and dihydropyrazole GPR40 AgoPAMs from our laboratory were highly efficacious in lowering plasma glucose levels in rodents but possessed off-target activities and triggered rebound hyperglycemia in rats at high doses. A focus on increasing molecular complexity through saturation and chirality in combination with reducing polarity for the pyrrolidine AgoPAM chemotype resulted in the discovery of compound 46, which shows significantly reduced off-target activities as well as improved aqueous solubility, rapid absorption, and linear PK. In vivo, compound 46 significantly lowers plasma glucose levels in rats during an oral glucose challenge yet does not demonstrate the reactive hyperglycemia effect at high doses that was observed with earlier GPR40 AgoPAMs.
Asunto(s)
Glucemia , Hiperglucemia , Ratas , Animales , Receptores Acoplados a Proteínas G , Péptido 1 Similar al Glucagón , Hipoglucemiantes/farmacología , Pirrolidinas/farmacología , Pirrolidinas/química , InsulinaRESUMEN
The design, synthesis and structure-activity relationships of a novel series of 3,4-disubstituted pyrrolidine acid analogs as PPAR ligands is outlined. In both the 1,3- and 1,4-oxybenzyl pyrrolidine acid series, the preferred stereochemistry was shown to be the cis-3R,4S isomer, as exemplified by the potent dual PPARα/γ agonists 3k and 4i. The N-4-trifluoromethyl-pyrimidinyl pyrrolidine acid analog 4i was efficacious in lowering fasting glucose and triglyceride levels in diabetic db/db mice.
Asunto(s)
Hipoglucemiantes/síntesis química , PPAR alfa/agonistas , PPAR gamma/agonistas , Pirrolidinas/química , Animales , Glucemia/análisis , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diseño de Fármacos , Femenino , Hipoglucemiantes/química , Hipoglucemiantes/uso terapéutico , Ligandos , Ratones , Ratones Obesos , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Pirrolidinas/síntesis química , Pirrolidinas/uso terapéutico , Estereoisomerismo , Relación Estructura-Actividad , Triglicéridos/sangreRESUMEN
Through appropriate medicinal chemistry design tactics and computer-assisted conformational modeling, the initial lead A was evolved into a series of dihydrobenzofuran derivatives 3 as potent GPR119 agonists. This Letter describes the optimization of general structure 3, including the substituent(s) on dihydrobenzofuran, the R(1) attachment on right-hand piperidine nitrogen, and the left-hand piperidine/piperazine and its attachment R(2). The efforts led to the identification of compounds 13c and 24 as potent human GPR119 modulators with favorable metabolic stability, ion channel activity, and PXR profiles.
Asunto(s)
Benzofuranos/farmacología , Receptores Acoplados a Proteínas G/agonistas , Benzofuranos/síntesis química , Benzofuranos/química , Línea Celular , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/síntesis química , Tetrazoles/síntesis química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Adamantano/farmacología , Animales , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Ratones , Ratones Transgénicos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Estructura Secundaria de Proteína , Relación Estructura-Actividad , Tetrazoles/farmacologíaRESUMEN
MGAT2 inhibition is a potential therapeutic approach for the treatment of metabolic disorders. High-throughput screening of the BMS internal compound collection identified the aryl dihydropyridinone compound 1 (hMGAT2 IC50 = 175 nM) as a hit. Compound 1 had moderate potency against human MGAT2, was inactive vs mouse MGAT2 and had poor microsomal metabolic stability. A novel chemistry route was developed to synthesize aryl dihydropyridinone analogs to explore structure-activity relationship around this hit, leading to the discovery of potent and selective MGAT2 inhibitors 21f, 21s, and 28e that are stable to liver microsomal metabolism. After triaging out 21f due to its inferior in vivo potency, pharmacokinetics, and structure-based liabilities and tetrazole 28e due to its inferior channel liability profile, 21s (BMS-963272) was selected as the clinical candidate following demonstration of on-target weight loss efficacy in the diet-induced obese mouse model and an acceptable safety and tolerability profile in multiple preclinical species.
Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Ensayos Analíticos de Alto Rendimiento/métodos , Enfermedades Metabólicas/tratamiento farmacológico , N-Acetilglucosaminiltransferasas/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Humanos , Relación Estructura-ActividadRESUMEN
The oxycyclohexyl acid BMS-986278 (33) is a potent lysophosphatidic acid receptor 1 (LPA1) antagonist, with a human LPA1 Kb of 6.9 nM. The structure-activity relationship (SAR) studies starting from the LPA1 antagonist clinical compound BMS-986020 (1), which culminated in the discovery of 33, are discussed. The detailed in vitro and in vivo preclinical pharmacology profiles of 33, as well as its pharmacokinetics/metabolism profile, are described. On the basis of its in vivo efficacy in rodent chronic lung fibrosis models and excellent overall ADME (absorption, distribution, metabolism, excretion) properties in multiple preclinical species, 33 was advanced into clinical trials, including an ongoing Phase 2 clinical trial in patients with lung fibrosis (NCT04308681).
Asunto(s)
Descubrimiento de Drogas , Fibrosis Pulmonar/tratamiento farmacológico , Receptores del Ácido Lisofosfatídico/antagonistas & inhibidores , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Estructura Molecular , Fibrosis Pulmonar/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores del Ácido Lisofosfatídico/metabolismo , Relación Estructura-ActividadRESUMEN
Statins, because of their excellent efficacy and manageable safety profile, represent a key component in the current armamentarium for the treatment of hypercholesterolemia. Nonetheless, myopathy remains a safety concern for this important drug class. Cerivastatin was withdrawn from the market for myotoxicity safety concerns. BMS-423526 [{(3R,5S)-7-[4-(4-fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-3-yl]-3,5-dihydroxy-heptenoic acid} sodium salt], similar to cerivastatin in potency and lipophilicity, was terminated in early clinical development due to an unacceptable myotoxicity profile. In this report, we describe the guinea pig as a model of statin-induced cholesterol lowering and myotoxicity and show that this model can distinguish statins with unacceptable myotoxicity profiles from statins with acceptable safety profiles. In our guinea pig model, both cerivastatin and BMS-423526 induced myotoxicity at doses near the ED(50) for total cholesterol (TC) lowering in plasma. In contrast, wide differences between myotoxic and TC-lowering doses were established for the currently marketed, more hydrophilic statins, pravastatin, rosuvastatin, and atorvastatin. This in vivo model compared favorably to an in vitro model, which used statin inhibition of cholesterol synthesis in rat hepatocytes and L6 myoblasts as surrogates of potential efficacy and toxicity, respectively. Our conclusion is that the guinea pig is a useful preclinical in vivo model for demonstrating whether a statin is likely to have an acceptable therapeutic safety margin.
Asunto(s)
Cobayas/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Modelos Animales , Animales , Células Cultivadas , Evaluación Preclínica de Medicamentos/métodos , Cobayas/sangre , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion. Employing strategies to increase polarity and the ratio of sp3/sp2 character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitro. In vivo, compound 4 demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models.
Asunto(s)
Descubrimiento de Drogas , Pirazoles/farmacología , Pirazoles/farmacocinética , Receptores Acoplados a Proteínas G/agonistas , Administración Oral , Animales , Disponibilidad Biológica , Humanos , Masculino , Ratones , Modelos Moleculares , Conformación Molecular , Pirazoles/administración & dosificación , Pirazoles/química , Pirrolidinas/químicaRESUMEN
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.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/análogos & derivados , Azetidinas/farmacología , Inhibidores Enzimáticos/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Actinas/antagonistas & inhibidores , Adamantano/administración & dosificación , Adamantano/química , Adamantano/farmacología , Administración Oral , Animales , Azetidinas/administración & dosificación , Azetidinas/química , Disponibilidad Biológica , Cristalografía por Rayos X , Perros , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Femenino , Semivida , Humanos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Concentración 50 Inhibidora , Macaca fascicularis , Masculino , Ratones Obesos , Ratas , Relación Estructura-ActividadRESUMEN
Factor XIa (FXIa) is a blood coagulation enzyme that is involved in the amplification of thrombin generation. Mounting evidence suggests that direct inhibition of FXIa can block pathologic thrombus formation while preserving normal hemostasis. Preclinical studies using a variety of approaches to reduce FXIa activity, including direct inhibitors of FXIa, have demonstrated good antithrombotic efficacy without increasing bleeding. On the basis of this potential, we targeted our efforts at identifying potent inhibitors of FXIa with a focus on discovering an acute antithrombotic agent for use in a hospital setting. Herein we describe the discovery of a potent FXIa clinical candidate, 55 (FXIa Ki = 0.7 nM), with excellent preclinical efficacy in thrombosis models and aqueous solubility suitable for intravenous administration. BMS-962212 is a reversible, direct, and highly selective small molecule inhibitor of FXIa.
Asunto(s)
Anticoagulantes/química , Anticoagulantes/uso terapéutico , Factor XIa/antagonistas & inhibidores , Isoquinolinas/química , Isoquinolinas/uso terapéutico , Trombosis/tratamiento farmacológico , para-Aminobenzoatos/química , para-Aminobenzoatos/uso terapéutico , Animales , Anticoagulantes/farmacocinética , Anticoagulantes/farmacología , Coagulación Sanguínea/efectos de los fármacos , Cristalografía por Rayos X , Perros , Descubrimiento de Drogas , Factor XIa/química , Factor XIa/metabolismo , Humanos , Isoquinolinas/farmacocinética , Isoquinolinas/farmacología , Masculino , Simulación del Acoplamiento Molecular , Conejos , Ratas , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacocinética , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Trombosis/sangre , para-Aminobenzoatos/farmacocinética , para-Aminobenzoatos/farmacologíaRESUMEN
A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding Ki and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both Gq-coupled intracellular Ca2+ flux and Gs-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.
Asunto(s)
Hipoglucemiantes/farmacología , Pirrolidinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Glucemia/análisis , Glucemia/metabolismo , Línea Celular , Células Cultivadas , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/uso terapéutico , Insulina/metabolismo , Masculino , Ratones Endogámicos C57BL , Modelos Moleculares , Pirrolidinas/química , Pirrolidinas/farmacocinética , Pirrolidinas/uso terapéutico , Ratas , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Identification of MCHR1 antagonists with a preclinical safety profile to support clinical evaluation as antiobesity agents has been a challenge. Our finding that a basic moiety is not required for MCHR1 antagonists to achieve high affinity allowed us to explore structures less prone to off-target activities such as hERG inhibition. We report the SAR evolution of hydroxylated thienopyrimidinone ethers culminating in the identification of 27 (BMS-819881), which entered obesity clinical trials as the phosphate ester prodrug 35 (BMS-830216).
Asunto(s)
Fármacos Antiobesidad/farmacología , Descubrimiento de Drogas , Obesidad/tratamiento farmacológico , Receptores de Somatostatina/antagonistas & inhibidores , Animales , Fármacos Antiobesidad/farmacocinética , Fármacos Antiobesidad/uso terapéutico , Perros , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Masculino , RatasRESUMEN
An indole-based P1 moiety was incorporated into a previously established factor Xa inhibitor series. The indole group was designed to hydrogen-bond with the carbonyl of Gly218, while its 3-methyl or 3-chloro substituent was intended to interact with Tyr228. These interactions were subsequently observed in the X-ray crystal structure of compound 18. SAR studies led to the identification of compound 20 as the most potent FXa inhibitor in this series (IC(50) = 2.4 nM, EC(2xPT) = 1.2 microM). An in-depth energetic analysis suggests that the increased binding energy of 3-chloroindole-versus 3-methylindole-containing compounds in this series is due primarily to (a) the more hydrophobic nature of chloro- versus methyl-containing compounds and (b) an increased interaction of 3-chloroindole versus 3-methylindole with Gly218 backbone. The stronger hydrophobicity of chloro- versus methyl-substituted aromatics may partly explain the general preference for chloro- versus methyl-substituted P1 groups in FXa, which extends beyond the current series.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos , Inhibidores del Factor Xa , Indoles , Teoría Cuántica , Animales , Sitios de Unión/efectos de los fármacos , Simulación por Computador , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Factor Xa/efectos de los fármacos , Humanos , Enlace de Hidrógeno , Indoles/síntesis química , Indoles/química , Indoles/farmacología , Ratones , Modelos Químicos , Modelos Moleculares , Relación Estructura-Actividad , Análisis de Supervivencia , Ponzoñas/farmacología , Trombosis de la Vena/tratamiento farmacológico , Trombosis de la Vena/enzimologíaRESUMEN
Analysis of nucleosides and nucleotides is desirable in many biological studies, but the task is analytically challenging due to the high polarity of the analytes. In this study, resolution of mixtures containing nucleosides and their mono-, di- and triphosphates was achieved using a porous graphitic carbon (PGC) stationary phase, Hypercarb, under conditions suitable for liquid chromatography/mass spectrometry (LC/MS). Different organic mobile phases and modifiers were evaluated and the separation of 16 nucleosides and nucleotides was optimized using gradient elution with a water/acetonitrile mobile phase containing ammonium acetate and diethylamine as modifiers. The ammonium acetate concentration proved to be critical for retention and diethylamine was found to improve the peak shapes of di- and triphosphates for mass spectrometric detection. A variety of silica-based columns designed for polar compound separation were also tested using optimized LC conditions and compared with results obtained with the Hypercarb column. Only the Hypercarb column provided separations suitable for accurate quantitation of mixed nucleosides and their phosphates.
Asunto(s)
Cromatografía Liquida/métodos , Fosfatos de Dinucleósidos/análisis , Grafito/química , Nucleósidos/análisis , Espectrometría de Masa por Ionización de Electrospray/métodosRESUMEN
An automated chiral chromatography/tandem mass spectrometry bioanalytical method for the determination of albuterol in dog plasma was developed. The method employed on-line sample extraction using turbulent flow chromatography coupled to a Chirobiotic T column for chiral separation using a polar organic mobile phase consisting of methanol, 0.02% formic acid, and 0.1% ammonium formate. The analytes were detected by a tandem mass spectrometer operated in positive ion mode. The (S)- and (R)-isomers were resolved chromatographically with retention times of 5.1 and 5.6 min, respectively. The analytical run time was 8 min. The enantiomers did not interconvert either in mobile phase or in dog plasma at room temperature over the course of at least 2 h. The assay has a linear dynamic range from 2.5-2500 nM for both enantiomers. The lower limit of quantitation (LLOQ) was 2.5 nM for both enantiomers using 50 microL of plasma. The accuracy and precision of intraday validation were determined at five concentration levels of six replicates. The accuracy of the method for the (R)-isomer ranged from 94-103% of nominal concentrations, and the precision (%CV) ranged from 3.6-12%. The accuracy of the method for the (S)-isomer ranged from 94.5-108% of nominal concentrations, and the precision ranged from 3.2-9.3%. Interday accuracy and precision were evaluated for three days at five concentrations for one replicate. The accuracy of the method for the (R)-isomer ranged from 98-110% of nominal concentrations, and the precision ranged from 1.5-10.6%. The accuracy of the method for the (S)-isomer ranged from 96-104% of nominal concentrations, and the precision ranged from 1.5-8.7%. The combination of turbulent flow on-line sample extraction with polar organic mode chiral chromatography provided a specific, rugged, and high-throughput method for the chiral analysis of albuterol in biological fluids.