Inhibition of clinically relevant mutant variants of HIV-1 by quinazolinone non-nucleoside reverse transcriptase inhibitors.
A series of 4-alkenyl and 4-alkynyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones were found to be potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) of human immunodeficiency virus type-1 (HIV-1). The 4-alkenyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones DPC 082 and DPC 083 and the 4-alkynyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones DPC 961 and DPC 963 were found to exhibit low nanomolar potency toward wild-type RF virus (IC(90) = 2.0, 2.1, 2.0, and 1.3 nM, respectively) and various single and many multiple amino acid substituted HIV-1 mutant viruses. The increased potency is combined with favorable plasma serum protein binding as demonstrated by improvements in the percent free drug in human plasma when compared to efavirenz: 3.0%, 2.0%, 1.5%, 2. 8%, and 0.2-0.5% for DPC 082, DPC 083, DPC 961, DPC 963, and efavirenz, respectively.
Corbett
J W
JW
DuPont Pharmaceuticals Company, Experimental Station, Wilmington, Delaware 19880-0500, USA. jeffrey.w.corbett@dupontpharma.com
Ko
S S
SS
Rodgers
J D
JD
Gearhart
L A
LA
Magnus
N A
NA
Bacheler
L T
LT
Diamond
S
S
Jeffrey
S
S
Klabe
R M
RM
Cordova
B C
BC
Garber
S
S
Logue
K
K
Trainor
G L
GL
Anderson
P S
PS
Erickson-Viitanen
S K
SK
D000480:Alkynes; D019380:Anti-HIV Agents / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D048588:Benzoxazines; D001798:Blood Proteins / Q000378:metabolism; D003521:Cyclopropanes; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D015394:Molecular Structure; D009154:Mutation; D010078:Oxazines / Q000097:blood / Q000494:pharmacology; D011485:Protein Binding; D011799:Quinazolines / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D001798:Blood Proteins; D003521:Cyclopropanes; D010078:Oxazines; D011799:Quinazolines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; C098320:efavirenz