Potent inhibitors of the HIV-1 protease incorporating cyclic urea P1-P2 scaffold

Article abstract of DOI:10.1016/j.bmcl.2004.08.038

We have developed an efficient synthetic approach to analogues of potent HIV-protease inhibitor (PI) 4. Key chemistry includes TFA-mediated deprotection of MOB-protected 16 to precursor 17. Alkylation of 17 enabled the synthesis of many PIs, as exemplified here by 13, 19-21, in excellent yields and purity, and thus overcoming bottlenecks of our prior synthetic approach to these PIs. These results allowed to rapidly evaluate the SAR in P1-P2 cyclic urea-based HIV-1 PIs as well as provided a strong rationale towards P1-P2 pyrrolidone scaffold-based PIs, ultimately leading to subnanomolar PIs (follow-up communication). 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).