RESUMO
Herein we describe the identification of 4-{[1,2,4]triazolo[1,5-a]pyridin-5-yl}benzonitrile-based inhibitors of the hypoxia-inducible factor prolylhydroxylase domain-1 (PHD-1) enzyme. These inhibitors were shown to possess a novel binding mode by X-ray crystallography, in which the triazolo N1 atom coordinates in a hitherto unreported monodentate interaction with the active site Fe2+ ion, while the benzonitrile group accepts a hydrogen-bonding interaction from the side chain residue of Asn315. Further optimization led to potent PHD-1 inhibitors with good physicochemical and pharmacokinetic properties.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Triazóis/química , Triazóis/farmacologia , Animais , Cristalografia por Raios X , Cães , Inibidores Enzimáticos/farmacocinética , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/química , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Piridinas/farmacocinética , Triazóis/farmacocinéticaRESUMO
Fatty acid binding protein 6 (FABP6) is a potential drug discovery target, which, if inhibited, may have a therapeutic benefit for the treatment of diabetes. Currently, there are no published inhibitors of FABP6, and with the target believed to be amenable to fragment-based drug discovery, a structurally enabled program was initiated. This program successfully identified fragment hits using the surface plasmon resonance (SPR) platform. Several hits were validated with SAR and were found to be displaced by the natural ligand taurocholate. We report the first crystal structure of human FABP6 in the unbound form, in complex with cholate, and with one of the key fragments.
Assuntos
Ácidos e Sais Biliares/química , Proteínas de Ligação a Ácido Graxo/química , Hormônios Gastrointestinais/química , Sítios de Ligação , Cristalografia por Raios X , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Hormônios Gastrointestinais/antagonistas & inibidores , Humanos , Modelos Moleculares , Conformação Proteica , Relação Estrutura-Atividade , Ressonância de Plasmônio de Superfície , Ácido Taurocólico/químicaRESUMO
Obesity is a leading cause of preventable mortality worldwide, with current strategies for treatment including life-style changes, pharmacological intervention and bariatric surgery. With pharmacological intervention showing at best modest patient benefits, new treatments are required. Modulation of anorectic gut hormones could offer the potential to elicit the required life-changing level of efficacy only currently seen with bariatric surgery, and without the cardiovascular risk associated with a number of the current marketed therapies. This review will discuss the gut hormones glucagon-like peptide-1 (GLP-1), Ghrelin and cholecystokinin (CCK)--for which more advanced non-peptide chemical matter has been discovered acting through these hormone pathways and/or their receptors.