RESUMEN
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.
RESUMEN
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
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.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Enfermedades Metabólicas/tratamiento farmacológico , Sulfonamidas/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/antagonistas & inhibidores , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/metabolismo , Sitios de Unión , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/uso terapéutico , Humanos , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Unión Proteica , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Sulfonamidas/metabolismo , Sulfonamidas/uso terapéuticoRESUMEN
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.
RESUMEN
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
A novel series of diphenylpyridylethanamine-based inhibitors of cholesteryl ester transfer protein is described. Optimization of the urea moiety, particularly by incorporation of fluorine, is explored to balance in vitro metabolic stability with CETP potency in the whole plasma assay.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Piridinas/química , Piridinas/farmacología , Urea/análogos & derivados , Urea/farmacología , Aminas/sangre , Aminas/química , Aminas/metabolismo , Aminas/farmacología , Animales , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Halogenación , Humanos , Ratones , Piridinas/sangre , Piridinas/metabolismo , Ratas , Urea/sangre , Urea/metabolismoRESUMEN
Starting from high throughput screening hit 2-adamantyl acetic acid 3, a series of polycyclic acids have been designed and synthesized as novel, potent, and selective inhibitors of human 11ß-HSD-1. Structure-activity relationships of two different regions of the chemotype (polycyclic ring and substituents on quaternary carbon) are discussed.
Asunto(s)
Ácidos/farmacología , Adamantano/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Ácido Acético/química , Ácido Acético/farmacología , Ácidos/química , Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Unión Proteica , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Isoquinolinas/química , Isoquinolinas/farmacología , Animales , Línea Celular , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores Enzimáticos/farmacocinética , Humanos , Isoquinolinas/farmacocinética , Ratones , Ratones Endogámicos BALB C , Relación Estructura-ActividadRESUMEN
A series of pyridyl amide/sulfonamide inhibitors of 11ß-HSD-1 were modified to incorporate a novel 1,2,4-triazolopyridine scaffold. Optimization of substituents at the 3 and 8 position of the TZP core, with a special focus on enhancing metabolic stability, resulted in the identification of compound 38 as a potent and metabolically stable inhibitor of the enzyme.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Piridinas/química , Pirimidinas/química , Triazoles/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Piridinas/síntesis química , Piridinas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/farmacologíaRESUMEN
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.
Asunto(s)
Fármacos Antiobesidad/química , Inhibidores Enzimáticos/química , Piridinas/química , Acetil-CoA Carboxilasa/antagonistas & inhibidores , Acetil-CoA Carboxilasa/metabolismo , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Piridinas/síntesis química , Piridinas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Oligopéptidos/química , Oligopéptidos/farmacología , Receptores de Glucagón/agonistas , Secuencia de Aminoácidos , Animales , Células CHO , Cricetinae , Cricetulus , Perros , Relación Dosis-Respuesta a Droga , Receptor del Péptido 1 Similar al Glucagón , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Masculino , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Oligopéptidos/síntesis química , Oligopéptidos/farmacocinética , Conformación ProteicaRESUMEN
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.
Asunto(s)
Andrógenos , Músculos/efectos de los fármacos , Músculos/metabolismo , Oxazoles/química , Oxazoles/farmacología , Animales , Cristalografía por Rayos X , Humanos , Concentración de Iones de Hidrógeno , Masculino , Modelos Moleculares , Conformación Molecular , Próstata/efectos de los fármacos , Próstata/metabolismo , Ratas , Especificidad por SustratoRESUMEN
The trisubstituted pyrimidine 1 was identified through high-throughput screening as a novel calcium-sensing receptor (CaSR) antagonist. Small molecule CaSR antagonists and/or negative allosteric modulators have the potential to act as an anabolic agent for the treatment of osteoporosis. The investigation of structure-activity relationships around 1 resulted in the identification of 18c and 18d, which showed efficacy at promoting PTH release in vivo and exhibited improved potency and solubility over the original lead 1.
Asunto(s)
Piridinas/química , Pirimidinas/química , Receptores Sensibles al Calcio/antagonistas & inhibidores , Regulación Alostérica , Descubrimiento de Drogas , Humanos , Concentración 50 Inhibidora , Osteoporosis/tratamiento farmacológico , Hormona Paratiroidea/metabolismo , Piridinas/farmacología , Pirimidinas/farmacología , Solubilidad , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Diacilglicerol O-Acetiltransferasa/análisis , Animales , Bovinos , Diacilglicerol O-Acetiltransferasa/metabolismo , Dimetilsulfóxido/metabolismo , Enzimas Inmovilizadas/análisis , Enzimas Inmovilizadas/metabolismo , Cinética , Microesferas , Ratas , Reproducibilidad de los Resultados , Conteo por Cintilación , Sensibilidad y Especificidad , Albúmina Sérica Bovina/metabolismo , Triglicéridos/biosíntesisRESUMEN
Acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT1) is one of the four intestinal membrane bound acyltransferases implicated in dietary fat absorption. Recently, it was found that, in addition to acylating diacylglycerol (DAG), DGAT1 also possesses robust enzymatic activity for acylating monoacylglycerol (MAG) (Yen, C. L., Monetti, M., Burri, B. J., and Farese, R. V., Jr. (2005) J. Lipid Res. 46, 1502-1511). In the current paper, we have conducted a detailed characterization of this reaction in test tube, intact cell culture, and animal models. Enzymatically, we found that triacylglycerol (TAG) synthesis from MAG by DGAT1 does not behave according to classic Michaelis-Menten kinetics. At low concentrations of 2-MAG (<50 microm), the major acylation product by DGAT1 was TAG; however, increased concentrations of 2-MAG (50-200 microm) resulted in decreased TAG formation. This unique product/substrate relationship is similar to MGAT3 but distinct from DGAT2 and MGAT2. We have also found that XP620 is an inhibitor that selectively inhibits the acylation of MAG by DGAT1 (IC(50) of human DGAT1: 16.6+/-4.0 nM (MAG as substrate) and 1499+/-318 nM (DAG as substrate); IC(50) values of human DGAT2, MGAT2, and MGAT3 are >30,000 nM). Using this pharmacological tool, we have shown that approximately 76 and approximately 89% of the in vitro TAG synthesis initiated from MAG is mediated by DGAT1 in Caco-2 cell and rat intestinal mucosal membranes, respectively. When applied to intact cultured cells, XP620 substantially decreased but did not abolish apoB secretion in differentiated Caco-2 cells. It also decreased TAG and DAG syntheses in primary enterocytes. Last, when delivered orally to rats, XP620 decreased absorption of orally administered lipids by approximately 50%. Based on these data, we conclude that the acylation of acylglycerols by DGAT1 is important for dietary fat absorption in the intestine.
Asunto(s)
Diacilglicerol O-Acetiltransferasa/biosíntesis , Grasas/metabolismo , Regulación de la Expresión Génica , Absorción Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Administración Oral , Animales , Células CACO-2 , Diacilglicerol O-Acetiltransferasa/fisiología , Grasas de la Dieta , Enterocitos/metabolismo , Compuestos Heterocíclicos con 1 Anillo , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Ratas , Ratas Sprague-DawleyRESUMEN
The first enantioselective synthesis of (D)-2-tert-butoxycarbonylamino-5,5-difluoro-5-phenyl-pentanoic acid 3 was achieved. The incorporation of the titled compound into growth hormone secretagogue (GHS) compounds resulted in new analogs 10 and 16, both of which had significantly increased in vitro potency. The compound 10 also showed improved in vivo efficacy as well as pharmacokinetic properties in rat models.
Asunto(s)
Hormona del Crecimiento/metabolismo , Ácidos Pentanoicos/síntesis química , Administración Oral , Animales , Área Bajo la Curva , Disponibilidad Biológica , Carbamatos/farmacología , Química Farmacéutica/métodos , Diseño de Fármacos , Indoles/farmacología , Modelos Químicos , Ácidos Pentanoicos/química , Ácidos Pentanoicos/farmacología , Hormonas Peptídicas/química , Ratas , Compuestos de Espiro/farmacología , Estereoisomerismo , Tetrazoles/farmacologíaRESUMEN
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.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Amidas/síntesis química , Amidas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Amidas/química , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Conformación Molecular , Estructura Molecular , Piridinas/química , Relación Estructura-ActividadRESUMEN
2-Arylbenzoxazole 5 was identified as a hit from a fluorescence-based high-throughput screen for CETP inhibitors. The synthesis and SAR investigation employing array synthesis of the A- and B-rings are described.
Asunto(s)
Benzoxazoles/síntesis química , Benzoxazoles/farmacología , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Benzoxazoles/química , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A novel series of N1 substituted tetrazole amides were prepared and showed to be potent growth hormone (GH) secretagogues. Among them, hydroxyl containing analog 31 displayed excellent in vivo activity by increasing plasma GH 10-fold in an anesthetized IV rat model.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Hormona del Crecimiento/metabolismo , Tetrazoles/química , Amidas/química , Animales , Línea Celular , Glioma/metabolismo , Hormona del Crecimiento/sangre , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
The structure-activity relationship of the O-benzyl serine side chain was investigated based on the tetrazole-based growth hormone secretagogue BMS-317180 (2). The ortho position of the benzyl moiety was found to be favorable for introduction of substituents. A series of ortho-substituted compounds were synthesized with improved in-vitro and in-vivo activity. Among them, the biphenyl compound 2p shows twofold improvement in potency compared to its parent compound BMS-317180 (2).