Kynurenic acid derivatives inhibit the binding of nerve growth factor (NGF) to the low-affinity p75 NGF receptor.

The ability of a series of substituted kynurenic acids, thienopyridinonecarboxylic acids, and related compounds to inhibit the binding of nerve growth factor (NGF) to the p75 NGF receptor (NGFR) was evaluated in a radioligand binding assay that utilized a biotinylated derivative of the extracellular domain of p75 NGFR (p75ext) fixed to streptavidin-coated plastic wells. Two compounds, 6-aminokynurenic acid (5h) and the 3-methyl ester of 4,7-dihydro-2-methyl-7-oxothieno[3,2-b]pyridine-3,5-dicarboxylic acid (16), were found to inhibit the binding of [125I]NGF to p75ext with IC50 values in the low micromolar range. Other amino-substituted kynurenic acids also possessed activity at slightly higher concentrations. Several structural features seem to be essential, including the carboxylic acid, a polar group on the benzene ring (or thiophene ring, in the case of analogues of 16), and the C-4 carbonyl group in the pyridinone ring. These compounds were also found to inhibit the binding of [125I]NGF to its receptors in membranes from PC12 cells (which express p75 as well as trka receptors for NGF) and DG44-CHO cells (transfected with full length p75 NGFR). The available data for 5h and 16 do not allow the determination of whether the effects of these compounds are mediated by their interaction with NGF or the NGF receptors.

Synthesis and antimicrobial evaluation of a series of 7-[3-amino (or aminomethyl)-4-aryl (or cyclopropyl)-1-pyrrolidinyl]-4-quinolone- and -1,8-naphthyridone-3-carboxylic acids.

A series of 6-fluoroquinolone- and 6-fluoro-1,8-naphthyridone-3-carboxylic acids possessing a [3-amino (or aminomethyl)-4-aryl (or cyclopropyl)-1-pyrrolidinyl] group at C-7 were synthesized and evaluated for their antimicrobial activity. The effect of the relative stereochemistry of the pyrrolidinyl substituents, as well as the presence of different functional groups on the 4-aryl (or cyclopropyl) moiety, was investigated in conjunction with their attachment to several quinolone or naphthyridone nuclei. In general, the incorporation of substituents on the aryl (or cyclopropyl) ring decreased in vitro and in vivo activity, regardless of the nature and relative position of the substituent. Bulky, lipophilic groups and substitution at the 2- and 3-position of the aromatic ring were particularly deleterious. Within a limited subset of derivatives, cis substitution of the pyrrolidine ring was less favorable than trans substitution. The majority of these effects were more apparent against the Enterobacteriaceae than against any other Gram-negative or Gram-positive organism and could be associated with negative interactions related to permeability or transport factors.

Quinolone antibacterials: preparation and activity of bridged bicyclic analogues of the C7-piperazine.

A series of quinolone and naphthyridine antibacterial agents possessing as the C7-heterocycle bicyclic 2,5-diazabicyclo[n.2.m]alkanes, where n = 2, 3 and m = 1, 2, and a series including 4-aminopiperidine and 3-amino-8-azabicyclo[3.2.1]octanes have been prepared and evaluated in vitro and in vivo for antibacterial activity against a variety of Gram-negative and Gram-positive organisms. These compounds were also tested against the target enzyme bacterial DNA gyrase. All the examples investigated are nearly equipotent with the parent 7-piperazinyl analogues. Only endo-7-(3-amino-8-azabicyclo[3.2.1]oct-8-yl)-1-cyclopropyl-6,8-difluoro- 1,4- dihydro-4-oxo-3-quinolinecarboxylic acid displays activity that surpasses that of the piperazine parent.