Inhibitors of HIV-1 maturation: Development of structure-activity relationship for C-28 amides based on C-3 benzoic acid-modified triterpenoids

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• 作者：Jacob J. Swidorski^a ; ^{jacob.swidorski@bms.com" class="auth_mail" title="E-mail the corresponding author} ; Zheng Liu^a ; Sing-Yuen Sit^a ; Jie Chen^a ; Yan Chen^a ; Ny Sin^a ; Brian L. Venables^a ; Dawn D. Parker^b ; Beata Nowicka-Sans^c ; Brian J. Terry^c ; Tricia Protack^c ; Sandhya Rahematpura^b ; Umesh Hanumegowda^b ; Susan Jenkins^b ; Mark Krystal^c ; Ira B. Dicker^c ; Nicholas A. Meanwell^a ; Alicia Regueiro-Ren^a
• 关键词：HIV-1 ; Maturation inhibitor ; Benzoic acid ; C-28 amide ; Betulinic acid ; Triterpenoid
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 April 2016
• 年：2016
• 卷：26
• 期：8
• 页码：1925-1930
• 全文大小：2510 K

文摘

We have recently reported on the discovery of a C-3 benzoic acid (1) as a suitable replacement for the dimethyl succinate side chain of bevirimat (2), an HIV-1 maturation inhibitor that reached Phase II clinical trials before being discontinued. Recent SAR studies aimed at improving the antiviral properties of 2 have shown that the benzoic acid moiety conferred topographical constraint to the pharmacophore and was associated with a lower shift in potency in the presence of human serum albumin. In this manuscript, we describe efforts to improve the polymorphic coverage of the C-3 benzoic acid chemotype through modifications at the C-28 position of the triterpenoid core. The dimethylaminoethyl amides 17 and 23 delivered improved potency toward bevirimat-resistant viruses while increasing C₂₄ in rat oral PK studies.