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
  • 1. Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: [email protected].
  • 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.