Fragment Screening of Soluble Epoxide Hydrolase for Lead Generation-Structure-Based Hit Evaluation and Chemistry Exploration.

Soluble epoxide hydrolase (sEH) is involved in the regulation of many biological processes by metabolizing the key bioactive lipid mediator, epoxyeicosatrienoic acids. For the development of sEH inhibitors with improved physicochemical properties, we performed both a fragment screening and a high-throughput screening aiming at an integrated hit evaluation and lead generation. Followed by a joint dose-response analysis to confirm the hits, the identified actives were then effectively triaged by a structure-based hit-classification approach to three prioritized series. Two distinct scaffolds were identified as tractable starting points for potential lead chemistry work. The oxoindoline series bind at the right-hand side of the active-site pocket with hydrogen bonds to the protein. The 2-phenylbenzimidazole-4-sulfonamide series bind at the central channel with significant induced fit, which has not been previously reported. On the basis of the encouraging initial results, we envision that a new lead series with improved properties could be generated if a vector is found that could merge the cyclohexyl functionality of the oxoindoline series with the trifluoromethyl moiety of the 2-phenylbenzimidazole-4-sulfonamide series.

Creating novel activated factor XI inhibitors through fragment based lead generation and structure aided drug design.

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.

Direct AMP-activated protein kinase activators: a review of evidence from the patent literature.

INTRODUCTION: AMP-activated protein kinase (AMPK), a heterotrimeric protein complex with serine/threonine kinase activity has a central role in controlling cellular energy expenditure. Small molecule-based activation of AMPK represents an attractive therapeutic proposition because of AMPK's ability to regulate several anabolic and catabolic pathways that are critical to the development of metabolic disorders and cancer. AREAS COVERED: A comprehensive review of published patents that disclose direct AMPK activators is provided: 26 patents comprising 10 chemical classes, and supporting in vitro and in vivo data are discussed. EXPERT OPINION: AMPK activation holds promise as a possible pharmacological intervention in several disease states. The development of direct, highly specific AMPK activators is necessary to fully realize the opportunities linked to AMPK activation and appreciate the risks associated with it.

A new series of pyridinyl-alkynes as antagonists of the metabotropic glutamate receptor 5 (mGluR5).

Synthesis and some structure-activity relationships for a new series of propargyl ethers as mGluR5 antagonists are reported.

Structure-activity relationships for the linker in a series of pyridinyl-alkynes that are antagonists of the metabotropic glutamate receptor 5 (mGluR5).

Studies of structure-activity relationships for the linker in a new series of metabotropic glutamate receptor 5 antagonists are presented together with in vitro and in vivo pharmacokinetic data.