Campbell S F, Danilewicz J C, Greengrass C W, Plews R M
Department of Discovery Chemistry, Pfizer Central Research, Sandwich, Kent, United Kingdom.
J Med Chem. 1988 Mar;31(3):516-20. doi: 10.1021/jm00398a006.
A series of 4-amino-6,7-dimethoxy-2-[4-(substituted oxyethoxy)piperidino] quinazoline derivatives (2) was synthesized and evaluated for alpha-adrenoceptor affinity and antihypertensive activity. Most compounds showed binding affinities within the nanomolar range for alpha 1-receptors, although 25 and 26 showed enhanced potency (Ki, ca. 1.5 X 10(-10) M), equivalent to that of prazosin. Series 2 also displaced [3H]clonidine from alpha 2-adrenoceptors, but at relatively high doses of 10(-6) M, and selectivity for alpha 1 sites still predominated. In a rabbit pulmonary artery preparation, 12, 16, and 25 were potent antagonists of the alpha 1-mediated, postjunctional vasoconstrictor activity of norepinephrine with no effect at the prejunctional alpha 2 sites which modulate transmitter release. Physicochemical measurements gave a pKa of 7.63 +/- 0.10 for 12, and N-1 protonation will be favored (60%) at physiological pH to provide the alpha 1-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.
合成了一系列4-氨基-6,7-二甲氧基-2-[4-(取代氧乙氧基)哌啶基]喹唑啉衍生物(2)，并对其α-肾上腺素受体亲和力和抗高血压活性进行了评估。大多数化合物对α1受体的结合亲和力在纳摩尔范围内，尽管25和26显示出增强的效力(Ki，约1.5×10(-10)M)，与哌唑嗪相当。系列2也能从α2肾上腺素受体上取代[3H]可乐定，但剂量相对较高，为10(-6)M，对α1位点的选择性仍然占主导。在兔肺动脉制剂中，12、16和25是去甲肾上腺素α1介导的节后血管收缩活性的强效拮抗剂，对调节递质释放的节前α2位点无影响。物理化学测量得出12的pKa为7.63±0.10，在生理pH值下，N-1质子化将占优势(60%)，以提供α1-肾上腺素受体药效团28。对自发性高血压大鼠口服给药后评估系列2的抗高血压活性，并在1小时和6小时后测量血压。化合物12、13、16、23和37在降低血压方面显示出中等疗效和作用持续时间，但16在犬体内的血浆半衰期(约2小时)与人类潜在的每日一次给药不相符。
