Discovery of potent pyrrolidone-based HIV-1 protease inhibitors with enhanced drug-like properties

SAR around the HIV-1 protease inhibitor lead 4, which utilizes the (3S,5R)-3,5-bis(phenylmethyl)-2-pyrrolidinone as P1–P2 scaffold, led to discovery of meta-amino- and meta-hydroxy inhibitors 17b and 19b, which while equipotent to 4, in addition offered an improved aqueous solubility. The SAR was further rationalized with the aid of X-ray crystallography and suggested specific role assumed by the meta-substituent, which can uniquely support high enzyme potency and which can be utilized as a platform for further chemical manipulations to fine–tune other drug-like properties in this series. This finding enables additional chemistry manipulations in search for other potential HIV-1 protease inhibitor drug candidates.