ABSTRACT
A drug discovery program in search of novel 5-lipoxygenase activating protein (FLAP) inhibitors focused on driving a reduction in lipophilicity with maintained or increased ligand lipophilic efficiency (LLE) compared to previously reported compounds led to the discovery of AZD6642 (15b). Introduction of a hydrophilic tetrahydrofuran (THF) ring at the stereogenic central carbon atom led to a significant shift in physicochemical property space. The structure-activity relationship exploration and optimization of DMPK properties leading to this compound are described in addition to pharmacokinetic analysis and an investigation of the pharmacokinetic (PK)-pharmacodynamic (PD) relationship based on ex vivo leukotriene B4 (LTB4) levels in dog. AZD6642 shows high specific potency and low lipophilicity, resulting in a selective and metabolically stable profile. On the basis of initial PK/PD relation measured, a low dose to human was predicted.
Subject(s)
5-Lipoxygenase-Activating Protein Inhibitors/chemical synthesis , Anti-Inflammatory Agents/chemical synthesis , Picolinic Acids/chemical synthesis , Pyrazines/chemical synthesis , 5-Lipoxygenase-Activating Protein Inhibitors/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Dogs , Drug Discovery , Humans , Picolinic Acids/pharmacology , Picolinic Acids/toxicity , Pyrazines/pharmacology , Pyrazines/toxicity , Rats , Solubility , Stereoisomerism , Structure-Activity Relationship , X-Ray DiffractionABSTRACT
[Acyl CoA]monoacylglycerol acyltransferase 2 (MGAT2) is of interest as a target for therapeutic treatment of diabetes, obesity and other diseases which together constitute the metabolic syndrome. In this Letter we report our discovery and optimisation of a novel series of MGAT2 inhibitors. The development of the SAR of the series and a detailed discussion around some key parameters monitored and addressed during the lead generation phase will be given. The in vivo results from an oral lipid tolerance test (OLTT) using the MGAT2 inhibitor (S)-10, shows a significant reduction (68% inhibition relative to naÑve, p<0.01) in plasma triacylglycerol (TAG) concentration.
Subject(s)
Acyltransferases/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/chemistry , Acyltransferases/metabolism , Administration, Oral , Animals , Caco-2 Cells , Cell Membrane Permeability/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Half-Life , Humans , Mice , Nanostructures/chemistry , Povidone/chemistry , Structure-Activity Relationship , Triglycerides/metabolismABSTRACT
A new series of pyrazinecarboxamide DGAT1 inhibitors was designed to address the need for a candidate drug with good potency, selectivity, and physical and DMPK properties combined with a low predicted dose in man. Rational design and optimization of this series led to the discovery of compound 30 (AZD7687), which met the project objectives for potency, selectivity, in particular over ACAT1, solubility, and preclinical PK profiles. This compound showed the anticipated excellent pharmacokinetic properties in human volunteers.
