Synthesis and evaluation of analogs of Efavirenz (SUSTIVA) as HIV-1 reverse transcriptase inhibitors.
Efavirenz (SUSTIVA) is a potent non-nucleoside reverse transcriptase inhibitor. Due to the observation of breakthrough mutations of the reverse transcriptase enzyme during Efavirenz therapy, we sought to develop an optimized second generation series. To that end, SAR of the substituents on the aromatic ring was undertaken and the results are summarized here. The 5,6-difluoro (4f) and the 6-methoxy (4m) substituted benzoxazinones were determined to be equipotent, and as a result such substitution patterns will be incorporated in second generation scaffolds.
Patel
M
M
DuPont Pharmaceuticals Company, Experimental Station, Wilmington, DE, USA.
Ko
S S
SS
McHugh
R J
RJ
Markwalder
J A
JA
Srivastava
A S
AS
Cordova
B C
BC
Klabe
R M
RM
Erickson-Viitanen
S
S
Trainor
G L
GL
Seitz
S P
SP
D000480:Alkynes; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D048588:Benzoxazines; D003521:Cyclopropanes; D015497:HIV-1; D015394:Molecular Structure; D010078:Oxazines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D010078:Oxazines; D018894:Reverse Transcriptase Inhibitors; C098320:efavirenz