Doug W. Hobbs

Structure-Based Drug Design and Optimization of Mannoside Bacterial FimH Antagonists

FimH-mediated cellular adhesion to mannosylated proteins is critical in the ability of uropathogenic E. coli (UPEC) to colonize and invade the bladder epithelium during urinary tract infection. We describe the discovery and optimization of potent small-molecule FimH bacterial adhesion antagonists based on alpha-d-mannose 1-position anomeric glycosides using X-ray structure-guided drug design. Optimized biarylmannosides display low nanomolar binding affinity for FimH in a fluorescence polarization assay and submicromolar cellular activity in a hemagglutination (HA) functional cell assay of bacterial adhesion. X-ray crystallography demonstrates that the biphenyl moiety makes several key interactions with the outer surface of FimH including pi-pi interactions with Tyr-48 and an H-bonding electrostatic interaction with the Arg-98/Glu-50 salt bridge. Dimeric analogues linked through the biaryl ring show an impressive 8-fold increase in potency relative to monomeric matched pairs and represent the most potent FimH antagonists identified to date. The FimH antagonists described herein hold great potential for development as novel therapeutics for the effective treatment of urinary tract infections.

III. Identification of novel CXCR3 chemokine receptor antagonists with a pyrazinyl-piperazinyl-piperidine scaffold.

The SAR of a novel pyrazinyl-piperazinyl-piperidine scaffold with CXCR3 receptor antagonist activity was explored. Optimization of the DMPK profile and reduction of hERG inhibition is described. Compound 16e with single-digit CXCR3 affinity, good rat PK and hERG profiles has been identified as a lead for further study.

Novel CXCR3 antagonists with a piperazinyl-piperidine core

High-throughput screening of an encoded combinatorial aryl piperazine library led to the identification of a novel series of potent piperazinyl-piperidine based CXCR3 antagonists. Analogs of the initial hit were synthesized via solid and solution phase methods to probe the influence of structure on the CXCR3 binding of these molecules. Various functional groups were found to contribute to the overall potency and essential molecular features were identified.

IV. Discovery of CXCR3 antagonists substituted with heterocycles as amide surrogates: improved PK, hERG and metabolic profiles.

The structure-human CXCR3 binding affinity relationship of a series of pyridyl/pyrazinyl-piperazinyl-piperidine derivatives were explored with a focus to improve PK, hERG and metabolic profiles. Several small heterocycles were identified as amide surrogates, which minimized many potential metabolite issues. During the course of SAR development, we have observed the additive effect of desirable functional groups to improve hERG and PK profiles which lead to the discovery of many clinically developable CXCR3 antagonists with excellent overall profile.

Computational ADME/Tox Modeling: Aiding Understanding and Enhancing Decision Making in Drug Design

With recent estimates of drug development costs on the order of

Non-peptide oxytocin antagonists: identification and synthesis of a potent camphor aminosuccinimide

800 million and increased pressure to reduce consumer drug costs, it is not surprising that the pharmaceutical industry is keenly interested in reducing the overall expense associated with drug development. An analysis of the reasons for attrition during the drug development process found that over half of all failures can be attributed to problems with human or animal pharmacokinetics and toxicity. Discovering pharmacokinetics and toxicity liabilities late within the drug development process results in wasted resource expenditures. This argues dramatically for evaluation of these properties as early as possible, leading to the concept of Fail Early. Computational models provide a low cost, flexible evaluation of compound properties that can be implemented and used prior to chemical synthesis thereby creating an alternative philosophy of Design for Success. Here we review the history and current trends within ADME/Tox modeling and discuss important issues related to development of computational models. In addition, we review some of the commercially available tools to achieve this goal as well as methods developed internally to address these issues from the design stage through development and optimization of drug candidates. In particular, we highlight those features that we feel best exemplify the Design for Success philosophy.

Orally active, nonpeptide oxytocin antagonists

Abstract The structure activity relationships of a series of non-peptide oxytocin antagonists containing a camphor aminosuccinimide as a key structural element were investigated. A potent and selective analog was identified and prepared in diastereomerically pure form starting from aspartic acid.