Discovery and optimization of diphenyl ether nonnucleoside inhibitors of HIV reverse transcriptase

MEDI 458

James P. Dunn, james.dunn@roche.com1, Pete Dunten2, Todd R. Elworthy1, Xiaochun Han1, Seth Harris2, Gabrielle Heilek3, Donald R. Hirschfeld1, J. Heather Hogg1, Ann Kaiser1, Denis J. Kertesz1, Woongki Kim1, Klaus Klumpp3, Yu Li3, Taraneh Mirzadegan1, Michael G. Roepel1, Y. David Saito1, Tania M. P. C. Silva1, Steven Swallow1, Zachary K. Sweeney, zachary.sweeney@roche.com1, Jahari L. Tracy1, Armando Villasenor2, Harit Vora1, Mark Smith1, Dimitrios Stefanidis4, Gouping Su3, Alejandra Trejo-Martin1, and Amy Zhou5. (1) Department of Medicinal Chemistry, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, (2) Department of Lead Discovery, Roche Palo Alto, 3431 Hillview Ave, Palo Alto, CA 94304, (3) Department of Viral Biochemistry, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto Ca, 94304, (4) Department of Pharmacetics, Roche Palo Alto LLC, 3431 Hillview Ave, Palo Alto, CA 94304, (5) Department of Drug Metabolism and Pharacokinetics, 3431 Hillview Ave, Palo Alto, CA 94304
A series of diphenyl ether compounds was discovered to inhibit the activity of HIV reverse transcriptase. Structure-based design was used to optimize the potency for both the wild-type and mutantant viruses of this novel series of non-nucleoside reverse transcriptase inhibitors (NNRTIs). This effort led to a 100-fold improvement in potency, and several compounds were discovered that showed excellent activity against both the wild-type virus and NNRTI-resistant viruses. Selected compounds had an IC50 value of <10nM against 92% of the viruses in a panel of 50 clinically derived mutant viruses. Pharmacokinetic studies in rat and dog demonstrated that these compounds have good oral bioavailability in animal species, The structure of a complex between HIV-RT and a pyridazinone inhibitor was also determined and will be described.
 

General Oral Session
9:00 AM-12:20 PM, Thursday, August 23, 2007 BCEC -- 210B, Oral

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007