Christophe Claude Parsy

Discovery and structural diversity of the hepatitis C virus NS3/4A serine protease inhibitor series leading to clinical candidate IDX320.

Exploration of the P2 region by mimicking the proline motif found in BILN2061 resulted in the discovery of two series of potent HCV NS3/4A protease inhibitors. X-ray crystal structure of the ligand in contact with the NS3/4A protein and modulation of the quinoline heterocyclic region by structure based design and modeling allowed for the optimization of enzyme potency and cellular activity. This research led to the selection of clinical candidate IDX320 having good genotype coverage and pharmacokinetic properties in various species.

LIPOSOMAL GELS FOR VAGINAL DELIVERY OF THE MICROBICIDE MC-1220: PREPARATION AND IN VIVO VAGINAL TOXICITY AND PHARMACOKINETICS

MC-1220 is a highly potent and selective non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV. The objective is to develop formulations for the vaginal delivery of MC-1220 and characterize them in vitro and in vivo (drug uptake, pharmacokinetics, toxicokinetics and vaginal irritation/inflammation). Due to the low aqueous solubility of MC-1220, emulsion-type and liposomal formulations of MC-1220 were developed. After rheological property adjustment (by gelling agents), the toxicity of two types of vaginal formulations of MC-1220 (emulsion [E] and liposomal [LIP] formulations) at 0.1% (E and LIP) and 0.5% (LIP) drug concentration, towards the vaginal mucosa as well as the absorption of the drug through the vaginal epithelium were investigated, after single and multiple administrations in New Zealand white NZW rabbits, for 10 days. Vaginal irritation was found to be within the acceptable range and always lower compared to the irritation caused by positive control formulation (nonoxynol-9), for all the formulation types (and concentrations evaluated). Pharmacokinetic values measured showed that the 0.1% LIP formulation was faster and better absorbed compared to the similar concentration E formulation, although most differences were not significant due to high variations. In conclusion, both types of formulations can be considered as safe for prolonged vaginal administration of MC-1220 or other drugs.

Discovery of the Aryl-phospho-indole IDX899, a Highly Potent Anti-HIV Non-nucleoside Reverse Transcriptase Inhibitor.

Here, we describe the design, synthesis, biological evaluation, and identification of a clinical candidate non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a novel aryl-phospho-indole (APhI) scaffold. NNRTIs are recommended components of highly active antiretroviral therapy (HAART) for the treatment of HIV-1. Since a major problem associated with NNRTI treatment is the emergence of drug resistant virus, this work focused on optimization of the APhI against clinically relevant HIV-1 Y181C and K103N mutants and the Y181C/K103N double mutant. Optimization of the phosphinate aryl substituent led to the discovery of the 3-Me,5-acrylonitrile-phenyl analogue RP-13s (IDX899) having an EC50 of 11 nM against the Y181C/K103N double mutant.