HIV-1 protease inhibitors with a tertiary alcohol containing transition-state mimic and various P2 and P1′ substituents

Abstract

Two series, including in total 18 novel HIV-1 protease inhibitors, comprising a tertiary alcohol as the transition-state mimic have been synthesised and evaluated. Replacement of the previously used, but metabolically unstable, indanol amide group with amino acid derived aliphatic P2–P3 moieties provided potent inhibitors with low Ki- and EC50-values (2.7 nM and 2.0 μM, respectively). The P1′ subunit was varied using 10 different aromatic and heteroaromatic substituents furnishing the corresponding inhibitors with retained activity. Permeability and stability studies showed examples in the same range as Atazanavir. X-Ray crystallographic analysis of two selected inhibitor enzyme co-complexes (9a and 9d) supplied detailed structural information. The binding modes were compared to those of Atazanavir and a previously reported indanol amide containing inhibitor (14). The novel inhibitors with an elongated P1′ side chain enabled a previously unexploited edge-on interaction with Phe53/153. Exchange of the previously used indanol amide P2 moiety, with a tert-leucine derived P2–P3 side chain, furnished small main chain displacements in the S2–S3 pocket. The methyl amide in the P3 position caused a 2 Å shift of the Arg8/108 in comparison to 14, indicating the flexibility of the protease active site.