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

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

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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