ABSTRACT
Activated factor XI (FXIa) inhibitors are anticipated to combine anticoagulant and profibrinolytic effects with a low bleeding risk. This motivated a structure aided fragment based lead generation campaign to create novel FXIa inhibitor leads. A virtual screen, based on docking experiments, was performed to generate a FXIa targeted fragment library for an NMR screen that resulted in the identification of fragments binding in the FXIa S1 binding pocket. The neutral 6-chloro-3,4-dihydro-1H-quinolin-2-one and the weakly basic quinolin-2-amine structures are novel FXIa P1 fragments. The expansion of these fragments towards the FXIa prime side binding sites was aided by solving the X-ray structures of reported FXIa inhibitors that we found to bind in the S1-S1'-S2' FXIa binding pockets. Combining the X-ray structure information from the identified S1 binding 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment and the S1-S1'-S2' binding reference compounds enabled structure guided linking and expansion work to achieve one of the most potent and selective FXIa inhibitors reported to date, compound 13, with a FXIa IC50 of 1.0 nM. The hydrophilicity and large polar surface area of the potent S1-S1'-S2' binding FXIa inhibitors compromised permeability. Initial work to expand the 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment towards the prime side to yield molecules with less hydrophilicity shows promise to afford potent, selective and orally bioavailable compounds.
Subject(s)
Drug Design , Drug Evaluation, Preclinical , Factor XIa/chemistry , Quantitative Structure-Activity Relationship , Serine Proteinase Inhibitors/chemistry , Amino Acid Sequence , Binding Sites , Crystallography, X-Ray , Drug Evaluation, Preclinical/methods , Factor XIa/antagonists & inhibitors , Humans , Ligands , Models, Molecular , Molecular Conformation , Molecular Sequence Data , Nuclear Magnetic Resonance, Biomolecular , Peptide Library , Protein Binding , Serine Proteinase Inhibitors/pharmacologyABSTRACT
[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.
