Comparison of 3D Structures and AT₁ Binding Properties of Pyrazolidine-3,5-diones and Tetrahydropyridazine-3,6-diones with Parent Antihypertensive Drug Irbesartan

A new series of nonpeptide AT1 receptor antagonists were recently developed, based on the structure of irbesartan (Le Bourdonnec et al. J. Med. Chem. 2000, 43, 2685−2697). The lead compound 1 displayed high selectivity for the AT1 receptor subtype but lower binding affinity than irbesartan. As expected from molecular modeling studies, extension of the pyrazolidine-3,5-dione scaffold to the six-membered heterocycle tetrahydropyridazine-3,6-dione led to an enhancement of the binding affinity toward the AT1 receptor

New Pyridinone Derivatives as Potent HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors

Several 5-ethyl-6-methyl-4-cycloalkyloxy-pyridin-2(1<i>H</i>)-ones were synthesized and evaluated for their anti HIV-1 activities against wild-type virus and clinically relevant mutant strains. A racemic mixture (<b>10</b>) with methyl substituents at positions 3 and 5 of the cyclohexyloxy moiety had potent antiviral activity against wild-type HIV-1. Subsequent stereoselective synthesis of a stereoisomer displaying both methyl groups in equatorial position was found to have the best EC₅₀. Further modulations focused on position 3 of the pyridinone ring improved the antiviral activity against mutant viral strains. Compounds bearing a 3-ethyl (<b>22</b>) or 3-isopropyl group (<b>23</b>) had the highest activity against wild-type HIV-1 and displayed low-nanomolar potency against several clinically relevant mutant strains