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)
- Janssen, Paul A J
- Lewi, Paul J
- Arnold, Eddy
- Daeyaert, Frits
- de Jonge, Marc
- Heeres, Jan
- Koymans, Luc
- Vinkers, Maarten
- Guillemont, Jérôme
- Pasquier, Elisabeth
- Kukla, Mike
- Ludovici, Don
- Andries, Koen
- de Béthune, Marie-Pierre
- Pauwels, Rudi
- Das, Kalyan
- Clark, Art D
- Frenkel, Yulia Volovik
- Hughes, Stephen H
- Medaer, Bart
- De Knaep, Fons
- Bohets, Hilde
- De Clerck, Fred
- Lampo, Ann
- Williams, Peter
- Stoffels, Paul
DOIAbstract
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.status: ...
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