2006

Pyrazine derivativesR 0550 Orally Bioavailable Highly Potent HIV Protease Inhibitors Against PI-Resistant

Virus. — Replacement of the phenyl group at the S1' pocket of indinavir with aryl het-erocycles together with modifications at the S3 pocket lead to a significant improve-ment of the inhibitory potency against the HIV protease enzyme. The synthesis of the analogues of indinavir is exemplified with the pyridylthiophene analogue (XIII), an ex-tremely potent compound. All compounds reveal much better antiviral activity against mutant isolates than indinavir. Almost a half dozen compounds display substantially better potency against the viral spread of both the wild-type virus (NL4-3) and a number of PI-resistant variants of HIV. Compound (XIII) shows moderate bioavailability and a related analogue, a decent bioavailability. — (LU*, Z.; et al.; Bioorg. Med. Chem. Lett. 15 (2005) 23, 5311-5314; Dep. Basic Chem., Merck Res. Lab., Rahway, NJ 07065, USA; Eng.) — H. Hoennerscheid

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2006