Expanded-spectrum nonnucleoside reverse transcriptase inhibitors inhibit clinically relevant mutant variants of human immunodeficiency virus type 1.
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.
Corbett
J W
JW
DuPont Pharmaceuticals Co., Experimental Station, Wilmington, Delaware 19880-0500, USA. Jeffrey.W.Corbet@DuPontPharma.com
Ko
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Rodgers
J D
JD
Jeffrey
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Bacheler
L T
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Klabe
R M
RM
Diamond
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Lai
C M
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Rabel
S R
SR
Saye
J A
JA
Adams
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Trainor
G L
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Anderson
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Erickson-Viitanen
S K
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D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics*; D006207:Half-Life; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D009154:Mutation / Q000502:physiology*; D002679:Pan troglodytes; D011485:Protein Binding; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D013237:Stereoisomerism
D019380:Anti-HIV Agents; D001798:Blood Proteins; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase