RESUMO
A novel series of spirocyclic-diamine based, isoform non-selective inhibitors of acetyl-CoA carboxylase (ACC) is described. These spirodiamine derivatives were discovered by design of a library to mimic the structural rigidity and hydrogen-bonding pattern observed in the co-crystal structure of spirochromanone inhibitor I. The lead compound 3.5.1 inhibited de novo lipogenesis in rat hepatocytes, with an IC50 of 0.30 µM.
Assuntos
Acetilcoenzima A/metabolismo , Acetil-CoA Carboxilase/antagonistas & inibidores , Descoberta de Drogas , Hepatócitos/efeitos dos fármacos , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Animais , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Hepatócitos/enzimologia , Humanos , Concentração Inibidora 50 , Modelos Biológicos , Estrutura Molecular , Ratos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
We report a systematic analysis of the relationship between salt bridge composition and 14-helix structure within a family of model beta-peptides in aqueous buffer. We find an inverse relationship between side-chain length and the extent of 14-helix structure as judged by CD. Introduction of a stabilizing salt bridge pair within a previously reported beta-peptide ligand for hDM2 led to changes in structure that were detectable by NMR.
Assuntos
Peptídeos/química , Estrutura Secundária de Proteína , Soluções Tampão , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Relação Estrutura-Atividade , Água/químicaRESUMO
A novel series of nonsteroidal mineralocorticoid receptor (MR) antagonists identified as part of our strategy to follow up on the clinical candidate PF-03882845 (2) is reported. Optimization departed from the previously described pyrazoline 3a and focused on improving the selectivity for MR versus the progesterone receptor (PR) as an approach to avoid potential sex-hormone-related adverse effects and improving biopharmaceutical properties. From this effort, (R)-14c was identified as a potent nonsteroidal MR antagonist (IC50 = 4.5 nM) with higher than 500-fold selectivity versus PR and other related nuclear hormone receptors, with improved solubility as compared to 2 and pharmacokinetic properties suitable for oral administration. (R)-14c was evaluated in vivo using the increase of urinary Na(+)/K(+) ratio in rat as a mechanism biomarker of MR antagonism. Treatment with (R)-14c by oral administration resulted in significant increases in urinary Na(+)/K(+) ratio and demonstrated this novel compound acts as an MR antagonist.
Assuntos
Antagonistas de Receptores de Mineralocorticoides/síntese química , Ácidos Nicotínicos/síntese química , Pirazóis/síntese química , Animais , Descoberta de Drogas , Masculino , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Simulação de Acoplamento Molecular , Ácidos Nicotínicos/farmacologia , Potássio/urina , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Mineralocorticoides/química , Sódio/urina , Relação Estrutura-AtividadeRESUMO
Acetyl-CoA carboxylase (ACC) catalyzes the rate-determining step in de novo lipogenesis and plays a crucial role in the regulation of fatty acid oxidation. Alterations in lipid metabolism are believed to contribute to insulin resistance; thus inhibition of ACC offers a promising option for intervention in type 2 diabetes mellitus. Herein we disclose a series of ACC inhibitors based on a spirocyclic pyrazololactam core. The lactam series has improved chemical and metabolic stability relative to our previously reported pyrazoloketone series, while retaining potent inhibition of ACC1 and ACC2. Optimization of the pyrazole and amide substituents led to quinoline amide 21, which was advanced to preclinical development.