Inhibitors of HIV-1 attachment: The discovery and structure-activity relationships of tetrahydroisoquinolines as replacements for the piperazine benzamide in the 3-glyoxylyl 6-azaindole pharmacophore

  • Bioorg Med Chem Lett. 2016 Jan 1;26(1):160-7. doi: 10.1016/j.bmcl.2015.11.009.
Jacob J Swidorski  1 ,  Zheng Liu  1 ,  Zhiwei Yin  1 ,  Tao Wang  1 ,  David J Carini  1 ,  Sandhya Rahematpura  2 ,  Ming Zheng  2 ,  Kim Johnson  2 ,  Sharon Zhang  3 ,  Pin-Fang Lin  3 ,  Dawn D Parker  2 ,  Wenying Li  2 ,  Nicholas A Meanwell  1 ,  Lawrence G Hamann  1 ,  Alicia Regueiro-Ren  1
Affiliations
  • 1. Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
  • 2. Department of Pharmaceutical Candidate Optimization, 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.
PMID: 26584882 DOI: 10.1016/j.bmcl.2015.11.009
Abstract

6,6-Fused ring systems including tetrahydroisoquinolines and tetrahydropyrido[3,4-d]pyrimidines have been explored as possible replacements for the piperazine benzamide portion of the HIV-1 attachment inhibitor BMS-663068. In initial studies, the tetrahydroisoquinoline compounds demonstrate sub-nanomolar activity in a HIV-1 pseudotype Viral Infection assay used as the initial screen for inhibitory activity. Analysis of SARs and approaches to optimization for an improved drug-like profile are examined herein.

Keywords
Attachment; BMS-663068; Entry; HIV-1; Tetrahydroisoquinoline; Tetrahydropyrido[3,4-d]pyrimidines.