A small series of compounds is described in which a narrow SAR has identified N,N-dimethyl-3,4-diphenyl-1H-pyrazole-1-propanamine, 3, as a potential antidepressant with reduced side effects. The isomeric N,N-dimethyl-4,5-diphenyl-1H-pyrazole-1-propanamine was completely inactive in the primary antidepressant screens. Compounds were synthesized by Michael addition of acrylonitrile to diphenylpyrazole followed by reductive alkylation of the resultant diphenylpyrazolepropionitriles. Compound 3 was equipotent with imipramine in standard antidepressant assays in animals but showed no significant anticholinergic action and did not antagonize the antihypertensive effects of clonidine and guanethidine.

The potential of octenidine hydrochloride (WIN 41464-2) as a topical microbicide was measured both by in vitro death kinetics and reductions in numbers of bacteria on the skin of cynomolgus monkeys. Semilogarithmic survial curves were plotted to measure the microbicidal activity of various concentrations of octenidine against Staphylococcus aureus. The microbicidal activity of octenidine was also determined for Staphylococcus epidermidis, Proteus mirabilis, Streptococcus pyogenes, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Serratia marcescens, and Candida albicans. Death rates for the same microbial strains were compared with those obtained by using chlorhexidine gluconate. Octenidine concentrations of <1.5 ,LM (0.94 ,ug/ml) caused a greater than 99% reduction of each microbial population within 15 min. Staphylococcus epidermidis was the most susceptible of the test organisms, and E. coli and C. albicans were the least susceptible. Octenidine was more active than chlorhexidine against each test strain. Skin-degerming activities of aqueous and formulated octenidine and formulated chlorhexidine were compared in single and multiple applications of these agents to the hand and foot surfaces of monkeys by using a glove-juice extraction procedure to measure the skin microflora. Aqueous octenidine, at a concentration of 0.2 to 1.6% reduced resident microflora populations from 90 to 99.98%, depending on the concentration and number of applications. Octenidine formulated at 2% in a surfactant-based vehicle exhibited significantly better skin-degerming activity than did either a nonmedicated vehicle or the Hibiclens brand of 4% chlorhexidine gluconate.

A series of N,N'-polyalkylenebis[4-(substituted-amino)pyridines] has been prepared, and members have been evaluated as potential anti-dental plaque agents. From among the most active members of the series, one compound, N,N'-[1,10-decanediyldi-1(4H)-pyridinyl-4-ylidene]bis(1-octanam ine) dihydrochloride, octenidine, was selected as a candidate for clinical study.

A series of novel 3-quinolinecarboxylic acid derivatives have been prepared and their antibacterial activity evaluated. These derivatives are characterized by fluorine attached to the 6-position and substituted amino groups appended to the 1- and 7-positions. Structure-activity relationship studies indicate that antibacterial potency is greatest when the 1-substituent is methylamino and the 7-substituent is either 4-methyl-1-piperazinyl, 16, or 1-piperazinyl, 21. Derivatives 16 and 21, the 1-methylamino analogues of pefloxacin and norfloxacin, respectively, show comparable in vitro and in vivo antibacterial potency to these two known agents. The activity (vs. Escherichia coli Vogel) of 16 (amifloxacin) is the following: in vitro MIC (microgram/mL) = 0.25; in vivo (mice) PD50 (mg/kg) = 1.0 (po), 0.6 (sc).

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