title: Anti-AIDS agents. 78. Design, synthesis, metabolic stability assessment, and antiviral evaluation of novel betulinic acid derivatives as potent anti-human immunodeficiency virus (HIV) agents.
abstract: In a continuing study of potent anti-HIV agents, seventeen 28,30-disubstituted betulinic acid (BA, 1) derivatives and seven novel 3,28-disubstituted BA analogues were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, compound 21 showed an improved solubility and equal anti-HIV potency (EC(50) = 0.09 microM) when compared to HIV entry inhibitors 3b (IC9564, (3R,4S)-N'-[N-[3beta-hydroxy-lup-20(29)-en-28-oyl]-8-aminooctanoyl]-4-amino-3-hydroxy-6-methylheptanoic acid) and 4 (A43-D, [[N-[3beta-O-(3',3'-dimethylsuccinyl)-lup-20(29)-en-28-oyl]-7-aminoheptyl]carbamoyl]methane). Using a cyclic secondary amine to form the C-28 amide bond increased the metabolic stability of the derivatives significantly in pooled human liver microsomes. The most potent compounds 47 and 48 displayed potent anti-HIV activity with EC(50) values of 0.007 and 0.006 microM, respectively. These results are slightly better than that of bevirimat (2, 3',3'-dimethylsuccinylbetulinic acid), which is currently in phase IIb clinical trials. Compounds 47 and 48 should serve as attractive promising leads to develop next generation, metabolically stable, 3,28-disubstituted bifunctional HIV-1 inhibitors as clinical trials candidates.
authors.affiliation: Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Keduo
authors.initials: K
authors.lastname: Qian
authors.forename: Donglei
authors.initials: D
authors.lastname: Yu
authors.forename: Chin-Ho
authors.initials: CH
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Nitz
authors.forename: Karl
authors.initials: K
authors.lastname: Salzwedel
authors.forename: Mary
authors.initials: M
authors.lastname: Reddick
authors.forename: Graham P
authors.initials: GP
authors.lastname: Allaway
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D004355:Drug Stability; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D012995:Solubility; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000094062:Betulinic Acid
chemical_list: D019380:Anti-HIV Agents; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D000094062:Betulinic Acid