Steven John Taylor

Structure-Based Optimization of Arylamides as Inhibitors of Soluble Epoxide Hydrolase

Inhibition of soluble epoxide hydrolase (sEH) is hypothesized to lead to an increase in circulating levels of epoxyeicosatrienoic acids, resulting in the potentiation of their in vivo pharmacological properties. As part of an effort to identify inhibitors of sEH with high and sustained plasma exposure, we recently performed a high throughput screen of our compound collection. The screen identified N-(3,3-diphenyl-propyl)-nicotinamide as a potent inhibitor of sEH. Further profiling of this lead revealed short metabolic half-lives in microsomes and rapid clearance in the rat. Consistent with these observations, the determination of the in vitro metabolic profile of N-(3,3-diphenyl-propyl)-nicotinamide in rat liver microsomes revealed extensive oxidative metabolism and a propensity for metabolite switching. Lead optimization, guided by the analysis of the solid-state costructure of N-(3,3-diphenyl-propyl)-nicotinamide bound to human sEH, led to the identification of a class of potent and selective inhibitors. An inhibitor from this class displayed an attractive in vitro metabolic profile and high and sustained plasma exposure in the rat after oral administration.

Design and synthesis of substituted nicotinamides as inhibitors of soluble epoxide hydrolase

A series of potent nicotinamide inhibitors of soluble epoxides hydrolase (sEH) is disclosed. This series was designed using structure-based deconstruction and a combination of two HTS hit series, resulting in hybrid analogs that retained the optimal potency from one series, and acceptable in vitro metabolic stability from the other. Structure-guided optimization of these analogs gave rise to nanomolar inhibitors of human sEH that had acceptable plasma exposure to qualify them as probes to determine the in vivo phenotypic consequences of sEH inhibition.

Discovery of Potent, Selective Chymase Inhibitors via Fragment Linking Strategies

Chymase plays an important and diverse role in the homeostasis of a number of cardiovascular processes. Herein, we describe the identification of potent, selective chymase inhibitors, developed using fragment-based, structure-guided linking and optimization techniques. High-concentration biophysical screening methods followed by high-throughput crystallography identified an oxindole fragment bound to the S1 pocket of the protein exhibiting a novel interaction pattern hitherto not observed in chymase inhibitors. X-ray crystallographic structures were used to guide the elaboration/linking of the fragment, ultimately leading to a potent inhibitor that was >100-fold selective over cathepsin G and that mitigated a number of liabilities associated with poor physicochemical properties of the series it was derived from.

Integrated strategies for identifying leads that target the NS3 helicase of the hepatitis C virus.

Future treatments for individuals infected by the hepatitis C virus (HCV) will likely involve combinations of compounds that inhibit multiple viral targets. The helicase of HCV is an attractive target with no known drug candidates in clinical trials. Herein we describe an integrated strategy for identifying fragment inhibitors using structural and biophysical techniques. Based on an X-ray structure of apo HCV helicase and in silico and bioinformatic analyses of HCV variants, we identified that one site in particular (labeled 3 + 4) was the most conserved and attractive pocket to target for a drug discovery campaign. Compounds from multiple sources were screened to identify inhibitors or binders to this site, and enzymatic and biophysical assays (NMR and SPR) were used to triage the most promising ligands for 3D structure determination by X-ray crystallography. Medicinal chemistry and biophysical evaluations focused on exploring the most promising lead series. The strategies employed here can have general utility in drug discovery.

Deconstruction of sulfonamide inhibitors of the urotensin receptor (UT) and design and synthesis of benzylamine and benzylsulfone antagonists

Potent small molecule antagonists of the urotensin receptor are described. These inhibitors were derived via systematically deconstructing a literature inhibitor to understand the basic pharmacophore and key molecular features required to inhibit the protein receptor. The series of benzylamine and benzylsulfone antagonists herein reported display a combination of nanomolar molecular and cellular potency as well as acceptable in vitro permeability and metabolic stability.