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Antimicrobial Agents and Chemotherapy, December 1999, p. 2893-2897, Vol. 43, No. 12
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Expanded-Spectrum Nonnucleoside Reverse Transcriptase Inhibitors Inhibit Clinically Relevant Mutant Variants of Human Immunodeficiency Virus Type 1

Jeffrey W. Corbett,* Soo S. Ko, James D. Rodgers, Susan Jeffrey, Lee T. Bacheler, Ronald M. Klabe, Sharon Diamond, Chii-Ming Lai, Shelley R. Rabel, Jo Anne Saye, Stephen P. Adams, George L. Trainor, Paul S. Anderson, and Susan K. Erickson-Viitanen

DuPont Pharmaceuticals Co., Experimental Station, Wilmington, Delaware 19880-0500

Received 14 May 1999/Returned for modification 27 August 1999/Accepted 20 September 1999

A research program targeted toward the identification of expanded-spectrum nonnucleoside reverse transcriptase inhibitors which possess increased potency toward K103N-containing mutant human immunodeficiency virus (HIV) and which maintain pharmacokinetics consistent with once-a-day dosing has resulted in the identification of the 4-cyclopropylalkynyl-4-trifluoromethyl-3,4-dihydro-2(1H)quinazolinones DPC 961 and DPC 963 and the 4-cyclopropylalkenyl-4-trifluoromethyl-3,4-dihydro-2(1H)quinazolinones DPC 082 and DPC 083 for clinical development. DPC 961, DPC 963, DPC 082, and DPC 083 all exhibit low-nanomolar potency toward wild-type virus, K103N and L100I single-mutation variants, and many multiply amino acid-substituted HIV type 1 mutants. This high degree of potency is combined with a high degree of oral bioavailability, as demonstrated in rhesus monkeys and chimpanzees, and with plasma serum protein binding that can result in significant free levels of drug.

* Corresponding author. Mailing address: DuPont Pharmaceuticals Co., Experimental Station, E500/4403A, P.O. Box 80500, Wilmington, DE 19880-0500. Phone: (302) 695-4823. Fax: (302) 695-9673. E-mail: Jeffrey.W.Corbett{at}DuPontPharma.com.

Antimicrobial Agents and Chemotherapy, December 1999, p. 2893-2897, Vol. 43, No. 12
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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