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. doi:10.1016/j.bmcl.2004.08.039).