ABSTRACT
The discovery and optimization of a series of acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors based on a pyrimido[4,5-b][1,4]oxazine scaffold is described. The SAR of a moderately potent HTS hit was investigated resulting in the discovery of phenylcyclohexylacetic acid 1, which displayed good DGAT1 inhibitory activity, selectivity, and PK properties. During preclinical toxicity studies a metabolite of 1 was observed that was responsible for elevating the levels of liver enzymes ALT and AST. Subsequently, analogues were synthesized to preclude the formation of the toxic metabolite. This effort resulted in the discovery of spiroindane 42, which displayed significantly improved DGAT1 inhibition compared to 1. Spiroindane 42 was well tolerated in rodents in vivo, demonstrated efficacy in an oral triglyceride uptake study in mice, and had an acceptable safety profile in preclinical toxicity studies.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Oxazines/chemical synthesis , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , Dogs , Drug Discovery , Enzyme Inhibitors/pharmacology , High-Throughput Screening Assays , Macaca mulatta , Mice , Mice, Inbred C57BL , Oxazines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Triglycerides/metabolismABSTRACT
A new structural class of DGAT1 inhibitors was discovered and the structure-activity relationship was explored. The pyrrolotriazine core of the original lead molecule was changed to a pyrrolopyridazine core providing an increase in potency. Further exploration resulted in optimization of the propyl group at C7 and the discovery that the ester at C6 could be replaced by five-membered heterocyclic rings. The analogs prepared have DGAT1 IC(50) values ranging from >10 µM to 48 nM.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Diacylglycerol O-Acyltransferase/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Pyridazines/chemistry , Pyridazines/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Cell Line , Enzyme Inhibitors/chemical synthesis , Humans , Inhibitory Concentration 50 , Pyridazines/chemical synthesis , Pyrroles/chemical synthesis , Sterol O-Acyltransferase/antagonists & inhibitors , Sterol O-Acyltransferase/metabolism , Structure-Activity RelationshipABSTRACT
A series of 1-cycloalkyl-2-phenyl-1H-benzimidazole-5-carboxylic acid derivatives was synthesized and evaluated for inhibitory activity against HCV NS5B RNA-dependent RNA polymerase (RdRp). A SAR study was performed and led to identify the 2-[(4-diarylmethoxy)phenyl]-benzimidazoles as potent inhibitors. They inhibit subgenomic HCV RNA replication in the replicon cells at low micromolar concentrations (EC(50) as low as 1.1microM). They are selective against DNA polymerases (IC(50)>10microM) and exhibit low cytotoxicity.