title: 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).
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.
authors.affiliation: Center for Molecular Design, Janssen Pharmaceutica, B-2350 Vosselaar, Belgium.
authors.forename: Paul A J
authors.initials: PA
authors.lastname: Janssen
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lewi
authors.forename: Eddy
authors.initials: E
authors.lastname: Arnold
authors.forename: Frits
authors.initials: F
authors.lastname: Daeyaert
authors.forename: Marc
authors.initials: M
authors.lastname: de Jonge
authors.forename: Jan
authors.initials: J
authors.lastname: Heeres
authors.forename: Luc
authors.initials: L
authors.lastname: Koymans
authors.forename: Maarten
authors.initials: M
authors.lastname: Vinkers
authors.forename: Jérôme
authors.initials: J
authors.lastname: Guillemont
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Pasquier
authors.forename: Mike
authors.initials: M
authors.lastname: Kukla
authors.forename: Don
authors.initials: D
authors.lastname: Ludovici
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: de Béthune
authors.forename: Rudi
authors.initials: R
authors.lastname: Pauwels
authors.forename: Kalyan
authors.initials: K
authors.lastname: Das
authors.forename: Art D
authors.initials: AD
authors.lastname: Clark
authors.forename: Yulia Volovik
authors.initials: YV
authors.lastname: Frenkel
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Hughes
authors.forename: Bart
authors.initials: B
authors.lastname: Medaer
authors.forename: Fons
authors.initials: F
authors.lastname: De Knaep
authors.forename: Hilde
authors.initials: H
authors.lastname: Bohets
authors.forename: Fred
authors.initials: F
authors.lastname: De Clerck
authors.forename: Ann
authors.initials: A
authors.lastname: Lampo
authors.forename: Peter
authors.initials: P
authors.lastname: Williams
authors.forename: Paul
authors.initials: P
authors.lastname: Stoffels
mesh_terms: D000284:Administration, Oral; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D016679:Genome, Viral; D006678:HIV / Q000235:genetics / Q000302:isolation & purification; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D006801:Humans; D033183:Interdisciplinary Communication; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000068696:Rilpivirine
chemical_list: D019380:Anti-HIV Agents; D009570:Nitriles; D011743:Pyrimidines; D000068696:Rilpivirine