ly-73497 and trovirdine

To identify the minimal structural elements necessary for biological activity, the rigid tricyclic nucleus of the known human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor tetrahydroimidazobenzodiazepinthione was subjected to systematic bond disconnection to obtain simpler structures. A rational selection and testing of modeled analogs containing these potential pharmacophoric moieties led to the discovery of a new series of nonnucleoside inhibitors of RT. The lead compound of this new PETT series of nonnucleoside RT inhibitors, N-(2-phenylethyl)-N'-(2-thiazolyl)thiourea (LY73497), was found to inhibit HIV-1 but not HIV-2 or simian immunodeficiency virus in cell culture at micromolar concentrations. This derivative was also found to inhibit HIV-1 RT. Through an integrated effort involving synthesis and molecular modeling, compounds with nanomolar potency against HIV-1 in cell culture were developed. In these studies, LY300046-HCl was identified as a potent nonnucleoside inhibitor of HIV-1 RT possessing favorable pharmacokinetic properties.

Topics: Animals; Antiviral Agents; Base Sequence; Benzodiazepines; Brain; Cattle; Cells, Cultured; DNA-Directed DNA Polymerase; Drug Resistance, Microbial; HIV-1; Humans; Imidazoles; Intercalating Agents; Male; Molecular Sequence Data; Pyridines; Rats; Rats, Inbred F344; Reverse Transcriptase Inhibitors; Structure-Activity Relationship; Thiazoles; Thiourea; Triazoles