The optimization of the pharmacokinetic performance of various 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors following oral administration to either beagle dogs or CM-monkeys is described. The molecules described in this work are composed of a 2-pyridone-containing peptidomimetic binding determinant and an alpha,beta-unsaturated ester Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. Modification of the ester contained within these compounds is detailed along with alteration of the P(2) substituent present in the peptidomimetic portion of the inhibitors. The pharmacokinetics of several inhibitors in both dogs and monkeys are described (7 h plasma concentrations after oral administration) along with their human plasma stabilities, stabilities in incubations with human, dog, and monkey microsomes and hepatocytes, Caco-2 permeabilities, and aqueous solubilities. Compounds containing an alpha,beta-unsaturated ethyl ester fragment and either an ethyl or propargyl P(2) moiety displayed the most promising combination of 3C enzyme inhibition (k(obs)/[I] 170 000-223 000 M(-1) s(-1)), antiviral activity (EC(50) = 0.047-0.058 microM, mean vs seven HRV serotypes), and pharmacokinetics following oral administration (7 h dog plasma levels = 0.248-0.682 microM; 7 h CM-monkey plasma levels = 0.057-0.896 microM).

Utilizing the tools of parallel synthesis and structure-based design, a new class of Michael acceptor-containing, irreversible inhibitors of human rhinovirus 3C protease (HRV 3CP) was discovered. These inhibitors are shown to inhibit HRV-14 3CP with rates of inactivation ranging from 886 to 31 400 M(-1) sec(-1). These inhibitors exhibit antiviral activity when tested against HRV-14 infected H1-HeLa cells, with EC(50) values ranging from 1.94 to 0.15 microM. No cytotoxicity was observed at the limits of the assay concentration. A crystal structure of one of the more potent inhibitors covalently bound to HRV-2 3CP is detailed. These compounds were also tested against HRV serotypes other than type 14 and were found to have highly variable activities.

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The syntheses of various azolylalkylquinoline derivatives in which the nature of the linkage between the quinoline and azolylalkyl moieties of the molecule were altered are described. The compounds were tested for cytotoxic activity towards cancer cells and compound 27 was found to exhibit moderate in vivo activity in a murine sarcoma model.

SummaryA novel series of azolylalkyloxy compounds was designed, synthesized and evaluated for antipicornaviral activity. Several of the compounds exhibited in vitro activity comparable to that of Disoxaril. An investigation of qualitative structure-activity relationships indicated that the optimal length of the alkyl chain is six or seven carbon atoms, with seven being marginally superior. The effect of different azole moieties on activity was relatively small, with 3-methylisoxazole and 4-methylthiazole being most effective. The nature of the oxy substituent was found to be extremely important for antipicornaviral activity. The 2-dibenzofuryl group proved to be the most effective oxy substituent for this class of compounds. Compounds 11 and 22, combining dibenzofuran with 3-methylisoxazole and 4-methylthiazole, respectively, were highly effective in vitro against a wide range of human rhinoviruses as well as several enteroviruses.