Amphoteric drugs. 3. Synthesis and antiallergic activity of 3-[(5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11- ylidene)piperidino]propionic acid derivatives and related compounds.
JOURNAL OF MEDICINAL CHEMISTRY(1995)
摘要
An important approach to the design of antiallergic agents with reduced penetration into the central nervous system (CNS) is described. A series of 3-[(5,11-dihydro[1]benzoxepino[4,3-b]-pyridin- 11-ylidene)piperidino]propionic acid derivatives (31-47) and related compounds (48-54) were synthesized and evaluated for antiallergic activity and penetration of a compound into the CNS in comparison with the corresponding 6H-dibenz[b,e]oxepin derivative (3). Combination of zwitterionization and introduction of a pyridine component resulted in an increase in antiallergic activity and a great reduction of penetration into the CNS, which was evaluated by the selectivity (B/A) of antihistaminic activities in the central system [ID50 value (B) for ex vivo H-1 binding to mouse brain membranes] and in the peripheral system [ED(50) value.(A) for inhibitory effect on histamine-induced increase in vascular permeability in mice]. This surprising reduction of penetration into the CNS could be considered on the basis of an increase in hydrophilicity caused by both of the zwitterionization and the introduction of a pyridine component. 3-[4-(8-Fluoro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-ylidene)piperidino]propionic acid (33) exhibited a strong antiallergic effect in various experimental models and very low penetration into the CNS. Compound 33 (HSR-609) is now under clinical trial as a promising antiallergic agent with greatly reduced penetration into the CNS.
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关键词
in vivo,partition coefficient,aromatic compound,amphoteric,chemical synthesis,ex vivo,central nervous system
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