RESUMEN
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
The synthesis and SAR of aminomethyl-substituted imidazolopyrimidine DPP4 inhibitors bearing varied pendant aryl groups is described. Compound 1, which exists as a separable mixture of non-interconvertible atropisomers was used as the starting point for investigation. The effects of substituent pattern and type as well as stereochemical effects on inhibitor potency are discussed.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Imidazoles/síntesis química , Imidazoles/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Dominio Catalítico , Dipeptidasas/antagonistas & inhibidores , Inhibidores de la Dipeptidil-Peptidasa IV/química , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/antagonistas & inhibidores , Indicadores y Reactivos , Isomerismo , Cinética , Modelos Moleculares , Solventes , Relación Estructura-ActividadRESUMEN
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
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
The synthesis and structure-activity relationships of novel dipeptidyl peptidase IV inhibitors replacing the classical cyanopyrrolidine P1 group with other small nitrogen heterocycles are described. A unique potency enhancement was achieved with beta-branched natural and unnatural amino acids, particularly adamantylglycines, linked to a (2S,3R)-2,3-methanopyrrolidine based scaffold.
Asunto(s)
Dipéptidos/química , Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores de la Dipeptidil-Peptidasa IV/química , Dipéptidos/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Evaluación Preclínica de Medicamentos , Humanos , Nitrilos/química , Nitrilos/farmacología , Relación Estructura-ActividadRESUMEN
Herein we report the first disclosure of biphenyl azoles that are nanomolar binders of adipocyte fatty acid binding protein (aFABP or aP2) with up to thousand-fold selectivity against muscle fatty acid binding protein and epidermal fatty acid binding protein. In addition a new radio-ligand to determine binding against the three fatty acid binding proteins was also synthesized.
Asunto(s)
Adipocitos/efectos de los fármacos , Azoles/antagonistas & inhibidores , Compuestos de Bifenilo/antagonistas & inhibidores , Proteínas de Unión a Ácidos Grasos/antagonistas & inhibidores , Hipoglucemiantes/farmacología , Hipolipemiantes/farmacología , Adipocitos/metabolismo , Animales , Sitios de Unión , Modelos Animales de Enfermedad , Epidermis/metabolismo , Hipoglucemiantes/síntesis química , Hipolipemiantes/síntesis química , Ratones , Modelos Químicos , Ensayo de Unión RadioliganteRESUMEN
Dipeptidyl peptidase IV (DPP4) is a multifunctional type II transmembrane serine peptidase which regulates various physiological processes, most notably plasma glucose homeostasis by cleaving peptide hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. Inhibition of DPP4 is a potentially valuable therapy for type 2 diabetes. Synthesis and structure-activity relationships of a series of substituted diprolyl nitriles are described, leading to the identification of compound 1 with a measured DPP4 K(i) of 3.6 nM.
Asunto(s)
Dipeptidil Peptidasa 4/metabolismo , Nitrilos/farmacología , Inhibidores de Proteasas/farmacología , Sitios de Unión , Ciclización , Dipeptidil Peptidasa 4/química , Modelos Moleculares , Estructura Molecular , Nitrilos/química , Inhibidores de Proteasas/química , Estructura Terciaria de ProteínaRESUMEN
Efforts to further elucidate structure-activity relationships (SAR) within our previously disclosed series of beta-quaternary amino acid linked l-cis-4,5-methanoprolinenitrile dipeptidyl peptidase IV (DPP-IV) inhibitors led to the investigation of vinyl substitution at the beta-position of alpha-cycloalkyl-substituted glycines. Despite poor systemic exposure, vinyl-substituted compounds showed extended duration of action in acute rat ex vivo plasma DPP-IV inhibition models. Oxygenated putative metabolites were prepared and were shown to exhibit the potency and extended duration of action of their precursors in efficacy models measuring glucose clearance in Zucker(fa/fa) rats. Extension of this approach to adamantylglycine-derived inhibitors led to the discovery of highly potent inhibitors, including hydroxyadamantyl compound BMS-477118 (saxagliptin), a highly efficacious, stable, and long-acting DPP-IV inhibitor, which is currently undergoing clinical trials for treatment of type 2 diabetes.
Asunto(s)
Adamantano/análogos & derivados , Adamantano/síntesis química , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipéptidos/síntesis química , Dipeptidil Peptidasa 4/metabolismo , Glicina/análogos & derivados , Glicina/síntesis química , Hipoglucemiantes/síntesis química , Inhibidores de Proteasas/síntesis química , Adamantano/farmacología , Animales , Disponibilidad Biológica , Glucemia/análisis , Diabetes Mellitus Tipo 2/fisiopatología , Dipéptidos/farmacología , Prueba de Tolerancia a la Glucosa , Glicina/farmacología , Humanos , Hipoglucemiantes/farmacología , Técnicas In Vitro , Insulina/sangre , Masculino , Ratones , Ratones Obesos , Microsomas Hepáticos/metabolismo , Nitrilos/síntesis química , Nitrilos/farmacología , Prolina/análogos & derivados , Prolina/síntesis química , Prolina/farmacología , Inhibidores de Proteasas/farmacología , Ratas , Ratas Zucker , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of methanoprolinenitrile-containing dipeptide mimetics were synthesized and assayed as inhibitors of the N-terminal sequence-specific serine protease dipeptidyl peptidase IV (DPP-IV). The catalytic action of DPP-IV is the principle means of degradation of glucagon-like peptide-1, a key mediator of glucose-stimulated insulin secretion, and DPP-IV inhibition shows clinical benefit as a novel mechanism for treatment of type 2 diabetes. However, many of the reversible inhibitors to date suffer from chemical instability stemming from an amine to nitrile intramolecular cyclization. Installation of a cyclopropyl moiety at either the 3,4- or 4,5-position of traditional 2-cyanopyrrolidide proline mimetics led to compounds with potent inhibitory activity against the enzyme. Additionally, cis-4,5-methanoprolinenitriles with beta-branching in the N-terminal amino acid provided enhanced chemical stability and high inhibitory potency. This class of inhibitors also exhibited the ability to suppress prandial glucose elevations after an oral glucose challenge in male Zucker rats.