RESUMO
Vorapaxar is an approved drug for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. Subsequent to the discovery of Vorapaxar, medicinal chemistry efforts were continued to identify structurally differentiated leads. Toward this goal, extensive structure-activity relationship studies using a C-ring-truncated version of Vorapaxar culminated in the discovery of three leads, represented as 13, 14, and 23. Among these leads, compound 14 possessed favorable pharmacokinetic properties and an off-target profile, which supported additional profiling in an exploratory rat toxicology study.
Assuntos
Infarto do Miocárdio , Trombose , Animais , Humanos , Lactonas , Infarto do Miocárdio/tratamento farmacológico , Inibidores da Agregação Plaquetária , Ratos , Receptor PAR-1 , Receptores Ativados por Proteinase , Trombose/induzido quimicamente , Trombose/tratamento farmacológicoRESUMO
Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles, including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction. This relationship is consistent with a clinical outcomes trial of a CETP inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction compared to standard of care alone. We discuss here the discovery of MK-8262, a CETP inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk.
Assuntos
Anticolesterolemiantes/uso terapêutico , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Doença das Coronárias/tratamento farmacológico , Oxazolidinonas/uso terapêutico , Animais , Anticolesterolemiantes/síntese química , Anticolesterolemiantes/farmacocinética , Anticolesterolemiantes/toxicidade , Cães , Humanos , Macaca mulatta , Camundongos Endogâmicos C57BL , Estrutura Molecular , Oxazolidinonas/síntese química , Oxazolidinonas/farmacocinética , Oxazolidinonas/toxicidade , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
A search for a suitable replacement for the central norbornyl scaffold presented in the recently disclosed novel FLAP inhibitors is herein described, as well as the SAR study performed on the endo and exo-aryl groups.
