2. Academic Validation
  3. Potent Long-Acting Inhibitors Targeting the HIV-1 Capsid Based on a Versatile Quinazolin-4-one Scaffold

Potent Long-Acting Inhibitors Targeting the HIV-1 Capsid Based on a Versatile Quinazolin-4-one Scaffold

  • J Med Chem. 2023 Feb 9;66(3):1941-1954. doi: 10.1021/acs.jmedchem.2c01732.
Eric P Gillis 1,  Kyle Parcella 1,  Michael Bowsher 1,  James H Cook 1,  Christiana Iwuagwu 1,  B Narasimhulu Naidu 1,  Manoj Patel 1,  Kevin Peese 1,  Haichang Huang 2,  Lourdes Valera 2,  Chunfu Wang 2,  Kasia Kieltyka 3,  Dawn D Parker 3,  Jean Simmermacher 3,  Eric Arnoult 4,  Robert T Nolte 5,  Liping Wang 5,  John A Bender 6,  David B Frennesson 7,  Mark Saulnier 6,  Alan Xiangdong Wang 6,  Nicholas A Meanwell 6,  Makonen Belema 6,  Umesh Hanumegowda 3 8,  Susan Jenkins 3,  Mark Krystal 2,  John F Kadow 1,  Mark Cockett 8,  Robert Fridell 2
Affiliations

Affiliations

  • 1 Discovery Chemistry, ViiV Healthcare, Branford, Connecticut 06405, United States.
  • 2 Discovery Biology, ViiV Healthcare, Branford, Connecticut 06405, United States.
  • 3 Discovery Pharmaceutics, DMPK and Toxicology, ViiV Healthcare, Branford, Connecticut 06405, United States.
  • 4 Molecular Design, GSK, Collegeville, Pennsylvania 19426, United States.
  • 5 Protein Cellular and Structural Sciences, GSK, Collegeville, Pennsylvania 19426, United States.
  • 6 Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, Princeton, New Jersey 08543, United States.
  • 7 Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, Cambridge, Massachusetts 02142, United States.
  • 8 ViiV Discovery, ViiV Healthcare, Branford, Connecticut 06405, United States.
PMID: 36719971 DOI: 10.1021/acs.jmedchem.2c01732
Abstract

Long-acting (LA) human immunodeficiency virus-1 (HIV-1) antiretroviral therapy characterized by a ≥1 month dosing interval offers significant advantages over daily oral therapy. However, the criteria for compounds that enter clinical development are high. Exceptional potency and low plasma clearance are required to meet dose size requirements; excellent chemical stability and/or crystalline form stability is required to meet formulation requirements, and new antivirals in HIV-1 therapy need to be largely free of side effects and drug-drug interactions. In view of these challenges, the discovery that capsid inhibitors comprising a quinazolinone core tolerate a wide range of structural modifications while maintaining picomolar potency against HIV-1 Infection in vitro, are assembled efficiently in a multi-component reaction, and can be isolated in a stereochemically pure form is reported herein. The detailed characterization of a prototypical compound, GSK878, is presented, including an X-ray co-crystal structure and subcutaneous and intramuscular pharmacokinetic data in rats and dogs.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-153782
    HIV-1 Inhibitor
    HIV