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).
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.
Janssen
Paul A J
PA
Center for Molecular Design, Janssen Pharmaceutica, B-2350 Vosselaar, Belgium.
Lewi
Paul J
PJ
Arnold
Eddy
E
Daeyaert
Frits
F
de Jonge
Marc
M
Heeres
Jan
J
Koymans
Luc
L
Vinkers
Maarten
M
Guillemont
Jérôme
J
Pasquier
Elisabeth
E
Kukla
Mike
M
Ludovici
Don
D
Andries
Koen
K
de Béthune
Marie-Pierre
MP
Pauwels
Rudi
R
Das
Kalyan
K
Clark
Art D
AD
Frenkel
Yulia Volovik
YV
Hughes
Stephen H
SH
Medaer
Bart
B
De Knaep
Fons
F
Bohets
Hilde
H
De Clerck
Fred
F
Lampo
Ann
A
Williams
Peter
P
Stoffels
Paul
P
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
D019380:Anti-HIV Agents; D009570:Nitriles; D011743:Pyrimidines; D000068696:Rilpivirine