RESUMEN
A spirocyclic class of ROMK inhibitors was developed containing a structurally diverse heterocyclic sulfone moiety and spirocyclic core starting from lead 1. These compounds not only displayed exquisite ROMK potency but significantly improved selectivity over hERG. The lead compounds were found to have favorable pharmacokinetic properties and displayed robust diuretic, natriuretic and blood pressure lowering effects in spontaneously hypertensive rats.
Asunto(s)
Diuréticos/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Canales de Potasio de Rectificación Interna/antagonistas & inhibidores , Sulfonas/farmacología , Animales , Compuestos Heterocíclicos/síntesis química , Ratas , Ratas Endogámicas SHRRESUMEN
SAR in the previously described spirocyclic ROMK inhibitor series was further evolved from lead 4 by modification of the spirocyclic core and identification of novel right-side pharmacophores. In this process, it was discovered that the spiropyrrolidinone core with the carbonyl group α to the spirocenter was preferred for potent ROMK activity. Efforts aimed at decreasing hERG affinity within the series led to the discovery of multiple novel right-hand pharmacophores including 3-methoxythiadiazole, 2-methoxypyrimidine, and pyridazinone. The most promising candidate is pyridazinone analog 32 that showed an improved functional hERG/ROMK potency ratio and preclinical PK profile. In vivo evaluation of 32 demonstrated blood pressure lowering effects in the spontaneously hypertensive rat model.
Asunto(s)
Canal de Potasio ERG1/metabolismo , Bloqueadores de los Canales de Potasio/química , Canales de Potasio de Rectificación Interna/antagonistas & inhibidores , Animales , Modelos Animales de Enfermedad , Perros , Canal de Potasio ERG1/antagonistas & inhibidores , Semivida , Hipertensión/tratamiento farmacológico , Bloqueadores de los Canales de Potasio/farmacocinética , Bloqueadores de los Canales de Potasio/uso terapéutico , Canales de Potasio de Rectificación Interna/metabolismo , Pirimidinas/química , Ratas , Ratas Endogámicas SHR , Compuestos de Espiro/química , Relación Estructura-Actividad , Tiadiazoles/químicaRESUMEN
Following the discovery of small molecule acyl piperazine ROMK inhibitors and their initial preclinical validation as a novel diuretic agent, our group set out to discover new ROMK inhibitors with reduced risk for QT effects, suitable for further pharmacological experiments in additional species. Several strategies for decreasing hERG affinity while maintaining ROMK inhibition were investigated and are described herein. The most promising candidate, derived from the newly discovered 4-N-heteroaryl acetyl series, improved functional hERG/ROMK ratio by >10× over the previous lead. In vivo evaluation demonstrated comparable diuretic effects in rat with no detectable QT effects at the doses evaluated in an in vivo dog model.
Asunto(s)
Canal de Potasio ERG1/fisiología , Compuestos Heterocíclicos/farmacología , Piperazinas/farmacología , Compuestos Heterocíclicos/química , Piperazinas/química , Relación Estructura-ActividadRESUMEN
Glutamate plays a key role in cognition and mood, and it has been shown that inhibiting ionotropic glutamate receptors disrupts cognition, while enhancing ionotropic receptor activity is pro-cognitive. One approach to elevating glutamatergic tone has been to antagonize presynaptic metabotropic glutamate receptor 2 (mGluR2). A desire for selectivity over the largely homologous mGluR3 motivated a strategy to achieve selectivity through the identification of mGluR2 negative allosteric modulators (NAMs). Extensive screening and optimization efforts led to the identification of a novel series of 4-arylquinoline-2-carboxamides. This series was optimized for mGluR2 NAM potency, clean off-target activity, and desirable physical properties, which resulted in the identification of improved C4 and C7 substituents. The initial lead compound from this series was Ames-positive in a single strain with metabolic activation, indicating that a reactive metabolite was likely responsible for the genetic toxicity. Metabolic profiling and Ames assessment across multiple analogs identified key structure-activity relationships associated with Ames positivity. Further optimization led to the Ames-negative mGluR2 negative allosteric modulator MK-8768.
RESUMEN
A homology model of the nicotinic acid receptor GPR109A was constructed based on the X-ray crystal structure of bovine rhodopsin. An HTS hit was docked into the homology model. Characterization of the binding pocket by a grid-based surface calculation of the docking model suggested that a larger hydrophobic body plus a polar tail would improve interaction between the ligand and the receptor. The designed compounds were synthesized, and showed significantly improved binding affinity and activation of GPR109A.
Asunto(s)
Modelos Moleculares , Agonistas Nicotínicos/síntesis química , Agonistas Nicotínicos/farmacología , Receptores Acoplados a Proteínas G/agonistas , ortoaminobenzoatos/síntesis química , ortoaminobenzoatos/farmacología , Sitios de Unión , Técnicas Químicas Combinatorias , Humanos , Estructura Molecular , Niacina/metabolismo , Agonistas Nicotínicos/química , Receptores Nicotínicos , Relación Estructura-Actividad , ortoaminobenzoatos/químicaRESUMEN
A new subseries of ROMK inhibitors exemplified by 28 has been developed from the initial screening hit 1. The excellent selectivity for ROMK inhibition over related ion channels and pharmacokinetic properties across preclinical species support further preclinical evaluation of 28 as a new mechanism diuretic. Robust pharmacodynamic effects in both SD rats and dogs have been demonstrated.
RESUMEN
Imidazo[1,2-a]pyridyl N-arylpyridazinones were hybridized from the classic pyridinylimidazoles and the more recent dual hydrogen bond acceptors, resulting in a new structural class of selective p38 MAP kinase inhibitors.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Piridazinas/síntesis química , Animales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ratones , Proteínas Quinasas Activadas por Mitógenos/química , Modelos Moleculares , Piridazinas/química , Piridazinas/farmacología , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
A stereocontrolled synthesis of a complex pentacycle embodying the molecular architecture of the cortistatin class of natural products was achieved from the (+)-Hajos-Parrish ketone. The cornerstone of our approach is a hypervalent iodine induced tandem intramolecular oxidative dearomatization and nitrile oxide cycloaddition. The manner in which these ring formations were orchestrated has yielded a rather concise strategy for synthesis.