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  3. (Carbonyl)oxyalkyl linker-based amino acid prodrugs of the HIV-1 protease inhibitor atazanavir that enhance oral bioavailability and plasma trough concentration

(Carbonyl)oxyalkyl linker-based amino acid prodrugs of the HIV-1 protease inhibitor atazanavir that enhance oral bioavailability and plasma trough concentration

  • Eur J Med Chem. 2020 Dec 1;207:112749. doi: 10.1016/j.ejmech.2020.112749.
Murugaiah A M Subbaiah 1,  Thangeswaran Ramar 2,  Lakshumanan Subramani 2,  Salil D Desai 3,  Sarmistha Sinha 4,  Sandhya Mandlekar 4,  Susan M Jenkins 5,  Mark R Krystal 6,  Murali Subramanian 4,  Srikanth Sridhar 3,  Shweta Padmanabhan 4,  Priyadeep Bhutani 4,  Rambabu Arla 4,  John F Kadow 7,  Nicholas A Meanwell 7
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry (Prodrug Group), Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore, 560099, India. Electronic address: murugaiah.andappan@syngeneintl.com.
  • 2 Department of Medicinal Chemistry (Prodrug Group), Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore, 560099, India.
  • 3 Department of Biopharmaceutics, Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore, 560099, India.
  • 4 Department of Pharmaceutical Candidate Optimization, Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore, 560099, India.
  • 5 Department of Pharmaceutical Candidate Optimization, Bristol Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
  • 6 Department of Virology, Bristol Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
  • 7 Department of Small Molecule Drug Discovery, Bristol Myers Squibb Research and Development, PO Box 4000, Princeton, NJ, 08543-4000, United States.
PMID: 33065417 DOI: 10.1016/j.ejmech.2020.112749
Abstract

We describe the design, synthesis and pharmacokinetic (PK) evaluation of a series of amino acid-based prodrugs of the HIV-1 protease inhibitor atazanavir (1) derivatized on the pharmacophoric secondary alcohol using a (carbonyl)oxyalkyl linker. Prodrugs of 1 incorporating simple (carbonyl)oxyalkyl-based linkers and a primary amine in the promoiety were found to exhibit low chemical stability. However, chemical stability was improved by modifying the primary amine moiety to a tertiary amine, resulting in a 2-fold enhancement of exposure in rats following oral dosing compared to dosing of the parent drug 1. Further refinement of the linker resulted in the discovery of 22 as a prodrug that delivered the parent 1 to rat plasma with a 5-fold higher AUC and 67-fold higher C24 when compared to oral administration of the parent drug. The PK profile of 22 indicated that plasma levels of this prodrug were higher than that of the parent, providing a more sustained release of 1 in vivo.

Keywords

(carbonyl)oxyalkyl linker; Atazanavir; Drug delivery; HIV-1 protease inhibitor; Oral bioavailability; Prodrug; Sustained exposure; Trough concentration.

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