Novel spirocyclic pyrrolidones as P2/P1 mimetics in potent inhibitors of HIV-1 protease.
We have developed concise and efficient syntheses of novel spirocyclic pyrrolidones 1-3, which involve the alkylation of pyrrolidone precursor 13 with 1,5-dibromopentane, 16 and 15, followed by an in situ lactamization. Conjugates of 1 and 2 with P1'/P2' hydroxy-indanolamine moiety resulted in novel and potent inhibitors of HIV-1 protease 25 and 26, suggesting that 1 and 2 are novel P2/P1 HIV-PI mimetics.
Kazmierski
Wieslaw M
WM
GlaxoSmithKline, Research Triangle Park, NC 27709, USA. wieslaw.m.kazmierski@gsk.com
Furfine
Eric
E
Spaltenstein
Andrew
A
Wright
Lois L
LL
D000478:Alkylation; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D007769:Lactams / Q000737:chemistry; D011760:Pyrrolidinones / Q000737:chemistry* / Q000494:pharmacology*; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D007769:Lactams; D011760:Pyrrolidinones; D013141:Spiro Compounds