Scaffold modifications to the 4-(4,4-dimethylpiperidinyl) 2,6-dimethylpyridinyl class of HIV-1 allosteric integrase inhibitors

  • Bioorg Med Chem. 2022 Aug 1;67:116833. doi: 10.1016/j.bmc.2022.116833.
Kyle Parcella  1 ,  Manoj Patel  2 ,  Yong Tu  3 ,  Kyle Eastman  3 ,  Kevin Peese  2 ,  Eric Gillis  2 ,  Makonen Belema  3 ,  Ira B Dicker  2 ,  Brian McAuliffe  2 ,  Bo Ding  2 ,  Paul Falk  2 ,  Jean Simmermacher  2 ,  Dawn D Parker  2 ,  Prasanna Sivaprakasam  3 ,  Javed A Khan  3 ,  Kevin Kish  3 ,  Hal Lewis  3 ,  Umesh Hanumegowda  2 ,  Susan Jenkins  2 ,  John F Kadow  2 ,  Mark Krystal  2 ,  Nicholas A Meanwell  3 ,  B Narasimhulu Naidu  2
Affiliations
  • 1. ViiV Healthcare, 36 East Industrial Road, Branford, CT 06405, USA. Electronic address: [email protected].
  • 2. ViiV Healthcare, 36 East Industrial Road, Branford, CT 06405, USA.
  • 3. Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, NJ 08543-4000, USA(1).
PMID: 35605346 DOI: 10.1016/j.bmc.2022.116833
Abstract

Allosteric integrase inhibitors (ALLINIs) of HIV-1 may hold promise as a novel mechanism for HIV therapeutics and cure. Scaffold modifications to the 4-(4,4-dimethylpiperidinyl) 2,6-dimethylpyridinyl class of ALLINIs provided a series of potent compounds with differentiated 5/6 fused ring systems. Notably, inhibitors containing the 1,2,4-triazolopyridine and imidazopyridine core exhibited single digit nM Antiviral potency and low to moderate clearance after intravenous (IV) dosing in rat pharmacokinetic (PK) studies. The 1,2,4-triazolopyridines showed a higher oral exposure when compared to the imidazopyridines. Further modifications to the C5 substituent of the 1,2,4-triazolopyridines resulted in a new lead compound, which had improved rat IV/PO PK compared to the former lead compound GSK3739936, while maintaining Antiviral potency. Structure-activity relationships (SAR) and rat pharmacokinetic profiles of this series are discussed.

Keywords
ALLINI; Allosteric integrase inhibitors; HIV-1 Integrase; Lipidosis; Vacuolation.
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