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Heterocycle amide isosteres: An approach to overcoming resistance for HIV-1 integrase strand transfer inhibitors.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2020 Feb 01; Vol. 30 (3), pp. 126784. Date of Electronic Publication: 2019 Nov 09. - Publication Year :
- 2020
-
Abstract
- A series of heterocyclic pyrimidinedione-based HIV-1 integrase inhibitors was prepared and screened for activity against purified integrase enzyme and/or viruses modified with the following mutations within integrase: Q148R, Q148H/G140S and N155H. These are mutations that result in resistance to the first generation integrase inhibitors raltegravir and elvitegravir. Based on consideration of drug-target interactions, an approach was undertaken to replace the amide moiety of the first generation pyrimidinedione inhibitor with azole heterocycles that could retain potency against these key resistance mutations. An imidazole moiety was found to be the optimal amide substitute and the observed activity was rationalized with the use of calculated properties and modeling. Rat pharmacokinetic (PK) studies of the lead imidazole compounds demonstrated moderate clearance and moderate exposure.<br /> (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Binding Sites
Catalytic Domain
Drug Resistance, Viral drug effects
HIV Integrase genetics
HIV Integrase metabolism
HIV Integrase Inhibitors metabolism
HIV Integrase Inhibitors pharmacology
HIV-1 drug effects
Half-Life
Heterocyclic Compounds, 3-Ring metabolism
Heterocyclic Compounds, 3-Ring pharmacology
Humans
Molecular Dynamics Simulation
Mutation
Rats
Structure-Activity Relationship
Amides chemistry
HIV Integrase chemistry
HIV Integrase Inhibitors chemistry
HIV-1 enzymology
Heterocyclic Compounds, 3-Ring chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 30
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 31761656
- Full Text :
- https://doi.org/10.1016/j.bmcl.2019.126784