title: Inhibitors of HIV-1 attachment. Part 9: an assessment of oral prodrug approaches to improve the plasma exposure of a tetrazole-containing derivative.
abstract: 7-(2H-Tetrazol-5-yl)-1H-indole 3 was found to be a potent inhibitor of HIV-1 attachment but the compound lacked oral bioavailability in rats. The cause of the low exposure was believed to be poor absorption attributed to the acidic nature of the tetrazole moiety and, in an effort to address this liability, three more lipohilic tetrazole analogs, N-acetoxymethyl 4, N-pivaloyloxymethyl 5, and N-methyl 6, were evaluated as potential oral prodrugs in rats. Prodrug 5 was ineffective in improving the plasma concentration of 3 in vivo but compound 4 provided a 15-fold enhancement of the plasma concentration of 3. Most interestingly, oral dosing of analog 6 afforded a substantial increase in the plasma concentration of the parent in rats when compared to dosing of parent. This represents a novel example of a methyl tetrazole that acts as a prodrug for a free NH tetrazole-containing compound.
authors.affiliation: Bristol-Myers Squibb Research & Development, 5 Research Parkway, PO Box 5100, Wallingford, CT 06492, USA. kapsun.yeung@bms.com
authors.forename: Kap-Sun
authors.initials: KS
authors.lastname: Yeung
authors.forename: Zhilei
authors.initials: Z
authors.lastname: Qiu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Lisa
authors.initials: L
authors.lastname: Zadjura
authors.forename: Celia J
authors.initials: CJ
authors.lastname: D'Arienzo
authors.forename: Marc R
authors.initials: MR
authors.lastname: Browning
authors.forename: Steven
authors.initials: S
authors.lastname: Hansel
authors.forename: Xiaohua Stella
authors.initials: XS
authors.lastname: Huang
authors.forename: Betsy J
authors.initials: BJ
authors.lastname: Eggers
authors.forename: Keith
authors.initials: K
authors.lastname: Riccardi
authors.forename: Ping-Fang
authors.initials: PF
authors.lastname: Lin
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.forename: John F
authors.initials: JF
authors.lastname: Kadow
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D053585:Virus Attachment / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D011355:Prodrugs; D013777:Tetrazoles