In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine)

  • J Med Chem. 2005 Mar 24;48(6):1901-9. doi: 10.1021/jm040840e.
Paul A J Janssen  1 ,  Paul J Lewi ,  Eddy Arnold ,  Frits Daeyaert ,  Marc de Jonge ,  Jan Heeres ,  Luc Koymans ,  Maarten Vinkers ,  Jérôme Guillemont ,  Elisabeth Pasquier ,  Mike Kukla ,  Don Ludovici ,  Koen Andries ,  Marie-Pierre de Béthune ,  Rudi Pauwels ,  Kalyan Das ,  Art D Clark Jr ,  Yulia Volovik Frenkel ,  Stephen H Hughes ,  Bart Medaer ,  Fons De Knaep ,  Hilde Bohets ,  Fred De Clerck ,  Ann Lampo ,  Peter Williams ,  Paul Stoffels
Affiliations
  • 1. Center for Molecular Design, Janssen Pharmaceutica, B-2350 Vosselaar, Belgium.
PMID: 15771434 DOI: 10.1021/jm040840e
Abstract

Ideally, an anti-HIV drug should (1) be highly active against wild-type and mutant HIV without allowing breakthrough; (2) have high oral bioavailability and long elimination half-life, allowing once-daily oral treatment at low doses; (3) have minimal adverse effects; and (4) be easy to synthesize and formulate. R278474, a new diarylpyrimidine (DAPY) non-nucleoside Reverse Transcriptase inhibitor (NNRTI), appears to meet these criteria and to be suitable for high compliance oral treatment of HIV-1 Infection. The discovery of R278474 was the result of a coordinated multidisciplinary effort involving medicinal chemists, virologists, crystallographers, molecular modelers, toxicologists, analytical chemists, pharmacists, and many Others.

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