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Discovery of Novel Pyridine-Dimethyl-Phenyl-DAPY Hybrids by Molecular Fusing of Methyl-Pyrimidine-DAPYs and Difluoro-Pyridinyl-DAPYs: Improving the Druggability toward High Inhibitory Activity, Solubility, Safety, and PK.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2022 Feb 10; Vol. 65 (3), pp. 2122-2138. Date of Electronic Publication: 2022 Jan 24. - Publication Year :
- 2022
-
Abstract
- A series of novel heteroaromatic biphenyl-methyl-pyrimidine analogues were designed via hybridization of privileged structures of two HIV-1 inhibitors. Among them, compound 7a containing 4-pyridinyl-phenyl and methyl-pyrimidine fragments revealed excellent wild-type HIV-1 inhibitory activity with low cytotoxicity. 7a had favorable solubility and liver microsome stability; moreover, no apparent CYP enzymatic inhibitory activity or acute toxicity was observed. However, its inhibitory activity toward mutant strains and the pharmacokinetic (PK) profiles were still unsatisfactory. Further optimizations resulted in a highly potent compound 9d without methyl on the pyrimidine but a heteroaromatic dimethyl-biphenyl on the left rings of difluoro-pyridinyl-diarylpyrimidines (DAPYs). A broad-spectrum activity (EC <subscript>50</subscript> = 2.0-57 nM) of 9d against resistant strains was revealed. This compound also exhibited good solubility and safety profiles and a good PK profile with an oral bioavailability of 59% in rats. Collectively, these novel heteroaromatic dimethyl-biphenyl-DAPYs represent promising drug candidates for HIV clinical therapy.
- Subjects :
- Animals
Anti-HIV Agents metabolism
Anti-HIV Agents pharmacokinetics
Anti-HIV Agents pharmacology
Binding Sites
Cell Survival drug effects
Cytochrome P-450 Enzyme System chemistry
Cytochrome P-450 Enzyme System metabolism
Drug Design
Drug Resistance, Viral drug effects
Drug Stability
Female
HIV Reverse Transcriptase antagonists & inhibitors
HIV Reverse Transcriptase genetics
HIV Reverse Transcriptase metabolism
HIV-1 genetics
Half-Life
Humans
Mice
Molecular Docking Simulation
Mutation
Solubility
Structure-Activity Relationship
Anti-HIV Agents chemistry
Pyridines chemistry
Pyrimidines chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 65
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 35073089
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.1c01676