Potent inhibitors of the HIV-1 protease incorporating cyclic urea P1-P2 scaffold.
We have developed synthetic approaches to novel analogues of 2-imidazolidinone scaffold 2, which was found to be an effective P1-P2 mimetic in HIV-1 protease inhibitor 4. This enabled a rapid synthesis of analogues of 4 and subsequently allowed us to evaluate and rationalize the SAR. Accordingly, trans relationship of P1 and P2 substituents in the P1-P2 mimetic, as found in a related 2-pyrrolidone-based scaffold 1, was found necessary for high potency against HIV-1 protease. Results of this study provided further rationale towards subsequent optimization of 2-pyrrolidone-based lead 3, which led us to potent and drug-like HIV-1 protease inhibitors described in a follow-on report (Bioorg. Med. Chem. Lett. 2004, 14, in press. ).
GlaxoSmithKline Research, 5 Moore Drive, Research Triangle Park, NC 27709, USA. wieslaw.m.kazmierski@gsk.com
Wieslaw M
WM
Kazmierski
Eric
E
Furfine
Yolanda
Y
Gray-Nunez
Andrew
A
Spaltenstein
Lois
L
Wright
D003500:Cyclization; D015195:Drug Design; D016333:HIV Protease / Q000187:drug effects*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D048289:Imidazolidines / Q000138:chemical synthesis; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology
D017320:HIV Protease Inhibitors; D006571:Heterocyclic Compounds; D048289:Imidazolidines; D014508:Urea; D016333:HIV Protease