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

• Published in: Journal of medicinal chemistry Vol. 52; no. 10; pp. 3248 - 3258
• Main Authors: Qian, Keduo, Yu, Donglei, Chen, Chin-Ho, Huang, Li, Morris-Natschke, Susan L, Nitz, Theodore J, Salzwedel, Karl, Reddick, Mary, Allaway, Graham P, Lee, Kuo-Hsiung
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.05.2009; Amer Chemical Soc
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - metabolism; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Chemistry, Medicinal; Drug Design; Drug Stability; Humans; Inhibitory Concentration 50; Life Sciences & Biomedicine; Medical sciences; Microsomes, Liver - metabolism; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Solubility; Structure-Activity Relationship; Triterpenes - chemistry; Triterpenes - metabolism; Triterpenes - pharmacology; TRITERPENE DERIVATIVES; ENTRY; BEVIRIMAT; ACTIVE ANTIRETROVIRAL THERAPY; RESISTANCE; INFECTION; INHIBITORS; TYPE-1; IDENTIFICATION; MATURATION; Pentacyclic compound; Terpenoid; HIV-1 virus; Nitrogen heterocycle; Saturated compound; Retroviridae; Lentivirus; In vitro; Virus; Metabolic stability; Structure activity relation; Six membered ring; Triterpene; Antiviral; Carboxamide; Human immunodeficiency virus; Chemical synthesis; Acylate
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm900136j

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 (EC50 = 0.09 μM) when compared to HIV entry inhibitors 3b (IC9564, (3R,4S)-N′-[N-[3β-hydroxy-lup-20(29)-en-28-oyl]-8-aminooctanoyl]-4-amino-3-hydroxy-6-methylheptanoic acid) and 4 (A43-D, [[N-[3β-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 EC50 values of 0.007 and 0.006 μM, 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.