1. Inhibitors of HIV-1 maturation: Development of structure–activity relationship for C-28 amides based on C-3 benzoic acid-modified triterpenoids.
- Author
-
Swidorski, Jacob J., Liu, Zheng, Sit, Sing-Yuen, Chen, Jie, Chen, Yan, Sin, Ny, Venables, Brian L., Parker, Dawn D., Nowicka-Sans, Beata, Terry, Brian J., Protack, Tricia, Rahematpura, Sandhya, Hanumegowda, Umesh, Jenkins, Susan, Krystal, Mark, Dicker, Ira B., Meanwell, Nicholas A., and Regueiro-Ren, Alicia
- Subjects
- *
BENZOIC acid , *HIV , *ANTI-HIV agents , *STRUCTURE-activity relationship in pharmacology , *TRITERPENOIDS , *CLINICAL trials , *AMIDES , *HIV maturation inhibitors - Abstract
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 C 24 in rat oral PK studies. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF