Marc Bazin

Tetrahydroquinoline derivatives as CRTH2 antagonists

A series of tetrahydroquinoline-derived inhibitors of the CRTH2 receptor was discovered by a high throughput screen. Optimization of these compounds for potency and pharmacokinetic properties led to the discovery of potent and orally bioavailable CRTH2 antagonists.

Bipiperidinyl carboxylic acid amides as potent, selective, and functionally active CCR4 antagonists.

A cell‐based assay for the chemokine G‐protein‐coupled receptor CCR4 was developed, and used to screen a small‐molecule compound collection in a multiplex format. A series of bipiperidinyl carboxylic acid amides amenable to parallel chemistry were derived that were potent and selective antagonists of CCR4. One prototype compound was shown to be active in a functional model of chemotaxis, making it a useful chemical tool to explore the role of CCR4 in asthma, allergy, diabetes, and cancer.

Selective cell adhesion inhibitors: Barbituric acid based α4β7—MAdCAM inhibitors

A novel series of barbituric acid derivatives were identified as selective inhibitors of alpha4beta7 MAdCAM (mucosal addressin cell adhesion molecule-1) interactions via a high throughput screening exercise. These inhibitors were optimized to submicromolar potencies in whole cell adhesion assays, retaining their selectivity over alpha4beta1 VCAM.

Lead diversification. Application to existing drug molecules: mifepristone 1 and antalarmin 8.

A series of C-H functionalisation plate-based chemical screens and other C-H activation protocols were developed for the chemical diversification of drug molecules. In this Letter, metalloporphyrin and other catalytic oxidation systems are described in addition to chlorination. Mifepristone and antalarmin are used as substrates. The products obtained and the biological data demonstrate the potential utility of this approach.

Efficient Use of the Iron Ortho-Nitrophenylporphyrin Chloride to Mimic Biological Oxidations of Dimethylaminoantipyrine

Major metabolites of dimethylaminoantipyrine have been synthesized using iron ortho‐nitrophenylporphyrin chloride as biomimetic catalyst. Reactivity of iron tetrakis‐ortho‐nitrophenylporphyrin chloride [Fe(TNO2PP)Cl] has been compared with iron tetrakis‐pentafluorophenylporphyrin chloride and iron tetrakis‐2,6‐dichlorophenylporphyrin chloride using various oxidants such as hydrogen peroxide, iodosobenzene, and cumene hydroperoxide in either protic or aprotic solvent. Effect of imidazole has been showed on the reactivity of Fe(TNO2PP)Cl/cumene hydroperoxide system.

Lead Diversification 2: application to P38, gMTP and lead compounds.

Lead Diversification is a new technology platform developed at Pfizer for the functionalization of drug molecules using C-H activation. We describe its application to some drug programs such as P38 and gMTP and the development of some new plate based screens including a fluorination screen.