ORGN 473 |
| Donald W. Ludovici1, Michael J. Kukla1, Barte L. De Corte1, Robert W. Kavash1, Chih Y. Ho1, Hong Ye1, Mark A. Lichtenstein1, Philip P. Grous1, Suma Krishnan1, Henry J. Breslin1, Winston Ho1, Malolm K. Scott1, James D. Rodgers1, Richard Mohrbacher1, Craig J. Diamond1, Milton Miranda1, Cynthia L. Fedde1, Ronald G. Sherrill1, T. Kevin Hitchens1, Koen Andries2, Marie-Pierre de Béthune2, Hilde Azijn2, Henry E. L. Moereels3, Lucien M.H. Koymans3, Marc R. de Jonge3, Koen J.A. Van Aken3, Frederik F.D. Daeyaert3, Paul Lewi3, Kalyan Das4, Edward Arnold4, Erik De Clercq5, Rudi Pauwels2, Jan Heeres3, and Paul A. J. Janssen3. (1) Johnson & Johnson Pharmaceutical Research and Development, Welsh and McKean Roads, Spring House, PA 19477, (2) Tibotec-Virco, Johnson & Johnson Pharmaceutical Research and Development, Generaal De Wittelaan L 11 B3, B-2800, Mechelen, Belgium, (3) Janssen Center for Molecular Design, Johnson & Johnson Pharmaceutical Research and Development, Antwerpsesteenweg 37, B-2350, Vosselaar, Belgium, (4) Center for Advanced Biotechnology and Medicine, Johnson & Johnson Pharmaceutical Research and Development, Rutgers University Chemistry Department, 679 Hoes Lane, Piscataway, NJ 08854, (5) Rega Institute for Medical Research, Johnson & Johnson Pharmaceutical Research and Development, K. U. Leuven, B-3000, Leuven, Belgium |
| The TIBO series, first reported on by J&J/Janssen in Nature in 1990, were the first non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV discovered. Found by screening the Janssen compound collection for anti-HIV activity, this series was optimized to give compounds with single nanomolar potency. Following work on TIBO, analoging of another J&J/Janssen NNRTI screening lead, Loviride, lead to the identification of a number of active scaffolds culminating in the discovery of the diaryltriazines (DATAs), which were found to have an improved potency profile against the mutant strains of reverse transcriptase (RT). SAR developed from the screening of DATA and diarylpyrimidine (DAPY) analogs against a battery of clinically relevant mutant RT stains, molecular modeling and X-ray co-crystallization allowed us to dramatically improve potency against single and double mutants. The fruit of this work is the current clinical candidate TMC-125, a DAPY compound with exceptional potency against the wild type, and a wide variety of single and double mutants of RT. |
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Technical Achievement in Organic Chemistry Awards
8:30 AM-11:25 AM, Wednesday, September 10, 2003 Sheraton New York -- Imperial Ballroom A, Oral
Division of Organic Chemistry |