Journal of Medicinal Chemistry p. 516 - 520 (1988)
Update date:2022-08-05
Topics:
Campbell, Simon F.
Danilewicz, John C.
Greengrass, Colin W.
Plews, Rhona M.
A series of 4-amino-6,7-dimethoxy-2-<4-(substituted oxyethoxy)piperidino>quinazoline derivatives (2) was synthesized and evaluated for α-adrenoceptor affinity and antihypertensive activity.Most compounds showed binding affinities within the nanomolar ranger for α1-receptors, although 25 and 26 showed enhanced potency (Ki, ca. 1.5x10-1o M), equivalent to that of prazosin.Series 2 also displaced <3H>clonidine from α2-adrenoceptors, but at relatively high doses of 10-6 M, and selectivity for α1 sites still predominated.In a rabbit pulmonary artery preparation , 12, 16, and 25 were potent antagonists of the α1-mediated, postjunctional vasoconstrictor activity of norepinephrine with no effect at the prejunctional α2 sites which modulate transmitter release.Physicochemical measurements gave a pKa of 7.63+/-0.10 for 12, and N-1 protonation will be favored (60percent) at physiological pH to provide the α1-adrenoceptor pharmacophore, 28.Antihypertensive activity of series 2 was evaluated following oral administration to spontaneously hypertensive rats, and blood pressure was measured after 1 and 6 h.Compounds 12, 13, 16, 23, and 37 displayed moderate efficacy and duration of action in lowering blood pressure, but the plasma half-life (ca. 2 h) of 16 in dogs was not compatible with potential once-daily administration in humans.
View MoreShanghai PuYi Chem-Tech Co.,Ltd.
Contact:+86-21-57687505-227
Address:3 Floor, Building 11, No 201 MinYi Road, Songjiang District, Shanghai 201612, China
Taizhou Sunny Chemical Co.,Ltd
Contact:+86-523-86920899 +86-13951172783
Address:No.11 Xingyuang road, Gaoyong Chemical Industry Park, Gaogang Jiangsu China
Changzhou Ruiping Chemical Co., Ltd
website:http://www.wishchem.com
Contact:+86-519-82324280
Address:No.288-1 Huacheng Road, Jintan
Zhejiang Haizhou Pharmaceutical Co., Ltd.
website:https://www.haizhoupharma.com/
Contact:+86 576 88221016
Address:No. 19, Donghai 5th Avenue, Yanhai Industrial Zone, Linhai, Zhejiang, China
JIANGXI AIFEIMU TECHNOLOGY CO.,LTD
Contact:+86-570-6040289
Address:FINECHEMICAL PARK,ZIBU TOWN,WANNIAN COUNTY,JIANGXI PROV.,CHINA,ZIP
Doi:10.1016/S0040-4039(00)98767-7
(1985)Doi:10.1021/ja01610a016
(1955)Doi:10.1021/jm401864b
(2014)Doi:10.1016/0040-4020(94)01129-N
(1995)Doi:10.1021/ja00509a062
(1979)Doi:10.1016/S0022-328X(00)81285-1
(1979)