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

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

  • Bioorg Med Chem Lett. 2016 Apr 15;26(8):1925-30. doi: 10.1016/j.bmcl.2016.03.019.
Jacob J Swidorski 1,  Zheng Liu 2,  Sing-Yuen Sit 2,  Jie Chen 2,  Yan Chen 2,  Ny Sin 2,  Brian L Venables 2,  Dawn D Parker 3,  Beata Nowicka-Sans 4,  Brian J Terry 4,  Tricia Protack 4,  Sandhya Rahematpura 3,  Umesh Hanumegowda 3,  Susan Jenkins 3,  Mark Krystal 4,  Ira B Dicker 4,  Nicholas A Meanwell 2,  Alicia Regueiro-Ren 2
Affiliations

Affiliations

  • 1 Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: jacob.swidorski@bms.com.
  • 2 Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
  • 3 Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
  • 4 Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
PMID: 26988305 DOI: 10.1016/j.bmcl.2016.03.019
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 C24 in rat oral PK studies.

Keywords

Benzoic acid; Betulinic acid; C-28 amide; HIV-1; Maturation inhibitor; Triterpenoid.

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