2. Academic Validation
  3. C-3 benzoic acid derivatives of C-3 deoxybetulinic acid and deoxybetulin as HIV-1 maturation inhibitors

C-3 benzoic acid derivatives of C-3 deoxybetulinic acid and deoxybetulin as HIV-1 maturation inhibitors

  • Bioorg Med Chem. 2016 Apr 15;24(8):1757-70. doi: 10.1016/j.bmc.2016.03.001.
Zheng Liu 1,  Jacob J Swidorski 2,  Beata Nowicka-Sans 3,  Brian Terry 3,  Tricia Protack 3,  Zeyu Lin 3,  Himadri Samanta 3,  Sharon Zhang 3,  Zhufang Li 3,  Dawn D Parker 4,  Sandhya Rahematpura 4,  Susan Jenkins 4,  Brett R Beno 5,  Mark Krystal 3,  Nicholas A Meanwell 2,  Ira B Dicker 3,  Alicia Regueiro-Ren 6
Affiliations

Affiliations

  • 1 Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: Zheng.Liu@bms.com.
  • 2 Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
  • 3 Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
  • 4 Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
  • 5 Department of Computer-Assisted Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
  • 6 Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: Alicia.regueiroren@bms.com.
PMID: 26968652 DOI: 10.1016/j.bmc.2016.03.001
Abstract

A series of C-3 phenyl- and heterocycle-substituted derivatives of C-3 deoxybetulinic acid and C-3 deoxybetulin was designed and synthesized as HIV-1 maturation inhibitors (MIs) and evaluated for their Antiviral activity and cytotoxicity in Cell Culture. A 4-subsituted benzoic acid moiety was identified as an advantageous replacement for the 3'3'-dimethylsuccinate moiety present in previously disclosed MIs that illuminates new aspects of the topography of the pharmacophore. The new analogs exhibit excellent in vitro Antiviral activity against wild-type (wt) virus and a lower serum shift when compared with the prototypical HIV-1 MI bevirimat (1, BVM), the first MI to be evaluated in clinical studies. Compound 9a exhibits comparable Cell Culture potency toward wt virus as 1 (WT EC50=16 nM for 9a compared to 10nM for 1). However, the potency of 9a is less affected by the presence of human serum, while the compound displays a similar pharmacokinetic profile in rats to 1. Hence 9a, the 4-benzoic acid derivative of deoxybetulinic acid, represents a new starting point from which to explore the design of a 2nd generation MI.

Keywords

Antiviral; Betulinic acid; HIV-1; Maturation inhibitors; Triterpene.

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