Synthesis and evaluation of 2-pyridinone derivatives as HIV-1 specific reverse transcriptase inhibitors. 1. Phthalimidoalkyl and -alkylamino analogs

• Published in: Journal of medicinal chemistry 1992-10, Vol.35 (21), p.3784-3791
• Main Authors: Hoffman, Jacob M, Wai, John S, Thomas, Craig M, Levin, Rhonda B, O'Brien, Julie A, Goldman, Mark E
• Format: Article
• Language: English
• Subjects: 6-methylpyridin-2(1H)-one; AIDS/HIV; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Cells, Cultured; Chemistry; derivatives; evaluation; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; HIV Reverse Transcriptase; HIV-1 - enzymology; HIV-2 - enzymology; human immunodeficiency virus 1; Hydrolysis; inhibitors; Magnetic Resonance Spectroscopy; Organic chemistry; Phthalimides - chemical synthesis; Phthalimides - chemistry; Phthalimides - pharmacology; Preparations and properties; Pyridones - chemical synthesis; Pyridones - chemistry; Pyridones - pharmacology; Reverse Transcriptase Inhibitors; RNA-directed DNA polymerase; Simian Immunodeficiency Virus - enzymology; synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00099a006

A potent (IC50 = 30 nM), specific nonnucleoside HIV-1 reverse transcriptase (RT) inhibitor 3-[N-(phthalimidomethyl)amino]-5-ethyl-6-methylpyridin-2(1H) -one (1), was discovered through an in vitro screening program. This compound did not inhibit (IC50 > 300 microns) other DNA and RNA polymerases, including HIV-2 RT and SIV-RT. Unfortunately, hydrolytic instability of this (aminomethyl)phthalimide precluded use as an antiviral agent. In the first paper of this series, preliminary development efforts are described which produced ethylphthalimide 20, a hydrolytically stable compound with reduced (100-fold) HIV-1 RT inhibitory activity and weak (CIC95 = 40 microM) antiviral activity in H9 cells. Structure-activity studies demonstrated the importance of the 5-ethyl, 6-methyl substituent pattern on the pyridinone ring and the need for a flexible two-atom linker between the pyridinone and phthalimide heterocycles. These leads, 1 and 20, provided a basis for the further development of this structural class of inhibitors from which several compounds, the subject of accompanying reports, were selected for clinical evaluation.