title: Design, synthesis, anti-HIV activities, and metabolic stabilities of alkenyldiarylmethane (ADAM) non-nucleoside reverse transcriptase inhibitors.
abstract: The alkenyldiarylmethane (ADAM) HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are effective anti-HIV agents in cell culture. However, the potential clinical utility of the ADAMs is expected to be limited by the presence of methyl ester moieties that are likely to be metabolized by nonspecific esterases in blood plasma to biologically inactive carboxylic acid derivatives. The present investigation was therefore undertaken to investigate the anti-HIV activities of the ADAMs versus HIV-1(IIIB) and HIV-2(ROD) in MT-4 cells and the stabilities of the biologically active ADAMs in rat plasma. The ADAMs displayed a wide range of metabolic stabilities in rat plasma, with half-lives ranging from 0.9 to 76.6 min. A wide assortment of structural modifications was tolerated, with 18 of the 32 compounds tested displaying EC(50) values between 0.3 and 3.7 microM versus HIV-1(IIIB) in MT-4 cells, 3 compounds in the EC(50) = 13.2-35.4 microM range, and the remaining compounds inactive. Consistent with the mechanism of action of the ADAMs as NNRTIs, they were inactive or displayed comparatively low activity versus HIV-2(ROD). The replacement of the two aromatic methyl ester substituents in one of the most active ADAMs (EC(50) = 0.6 microM) with two methyl thioester groups resulted in an increase in plasma half-life from 5.8 to 55.3 min, while maintaining the antiviral potency at the EC(50) = 1.8 microM level. At the same time, the bis(thioester) modification was less cytotoxic to uninfected MT-4 cells, with a CC(50) of >224 microM versus 160 microM for the parent compound.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Maximilian A
authors.initials: MA
authors.lastname: Silvestri
authors.forename: Muthukaman
authors.initials: M
authors.lastname: Nagarajan
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
mesh_terms: D000475:Alkenes / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D004355:Drug Stability; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D008697:Methane / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D008958:Models, Molecular; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000475:Alkenes; D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D008697:Methane