RESUMO
Seeking compounds preferentially potent and selective for MMP-13, we reported in the preceding Letter on a series of hydroxamic acids with a flexible benzamide tail groups.(1a) Here, we replace the amide moiety with non-hydrolyzable heterocycles in an effort to improve half-life. We identify a hydroxamate tetrazole 4e that spares MMP-1 and -14, shows >400-fold selectivity versus MMP-8 and >600-fold selectivity versus MMP-2, and has a 4.8 h half-life in rats. X-ray data (1.9 Å) for tetrazole 4c is presented.
Assuntos
Amidas/síntese química , Inibidores Enzimáticos/síntese química , Compostos Heterocíclicos/síntese química , Ácidos Hidroxâmicos/síntese química , Inibidores de Metaloproteinases de Matriz , Sulfonas/síntese química , Amidas/química , Animais , Cristalografia por Raios X , Inibidores Enzimáticos/química , Compostos Heterocíclicos/química , Ácidos Hidroxâmicos/química , Metaloproteinase 13 da Matriz/química , Modelos Moleculares , Ratos , Relação Estrutura-Atividade , Especificidade por Substrato , Sulfonas/químicaRESUMO
We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (MR) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these challenges were overcome by incorporation of a single carboxylate moiety. Structural modification of carboxylate-containing lead R-4g with a wide range of substituents at each position of the pyrazoline ring resulted in R-12o, which shows excellent activity against MR and reasonable pharmacokinetic profile. Introduction of conformational restriction led to a novel series characterized by exquisite potency and favorable steroid receptor selectivity and pharmacokinetic profile. Oral dosing of 3S,3aR-27d (PF-3882845) in the Dahl salt sensitive preclinical model of salt-induced hypertension and nephropathy showed blood pressure attenuation significantly greater than that with eplerenone, reduction in urinary albumin, and renal protection. As a result of these findings, 3S,3aR-27d was advanced to clinical studies.
Assuntos
Anti-Hipertensivos/síntese química , Hipertensão/tratamento farmacológico , Indazóis/síntese química , Nefropatias/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides , Nitrilas/síntese química , Animais , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Linhagem Celular Tumoral , Clorobenzenos , Cristalografia por Raios X , Humanos , Indazóis/farmacocinética , Indazóis/farmacologia , Indenos , Masculino , Modelos Moleculares , Conformação Molecular , Nitrilas/farmacocinética , Nitrilas/farmacologia , Ensaio Radioligante , Ratos , Ratos Endogâmicos Dahl , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of phenyl piperidine alpha-sulfone hydroxamate derivatives has been prepared utilizing a combination of solution-phase and resin-bound library technologies to afford compounds that are potent and highly selective for MMP-13, are dual-sparing of MMP-1 and MMP-14 (MT1-MMP) and exhibit oral bioavailability in rats.
Assuntos
Inibidores de Metaloproteinases de Matriz , Administração Oral , Animais , Disponibilidade Biológica , Ácidos Hidroxâmicos/administração & dosagem , Metaloproteinase 1 da Matriz/efeitos dos fármacos , Metaloproteinase 14 da Matriz/efeitos dos fármacos , Piperidinas , Ratos , Bibliotecas de Moléculas Pequenas , Solubilidade , Especificidade por Substrato , SulfonasRESUMO
A series of N-aryl isonipecotamide alpha-sulfone hydroxamate derivatives has been prepared utilizing a combination of solution-phase and resin-bound library technologies to afford compounds that are potent and highly selective for MMP-13.
