Chhabria Mahesh T, Srinivas Sreeramaiah, Rajan Kombu S, Ravikumar Tadiparthy, Rathnam Shivprakash
Department of Pharmaceutical Chemistry, L. M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat, India.
Arzneimittelforschung. 2002;52(11):792-6. doi: 10.1055/s-0031-1299969.
A series of new 4-amino-5,7-dimethyl-2- (substituted)aminopyrido(2,3-d)pyrimidines (5) have been synthesized and tested for selective alpha 1-adrenoreceptor antagonistic activity. Some of the compounds were found to antagonize alpha 1-adrenoreceptor in a competitive and reversible manner. When screened on rat anococcygeus muscle some of the compounds exhibited significant alpha 1-adrenoreceptor antagonistic activity (pA2 values in the range of 5.2-7.8). The most potent compound (5j) was evaluated by an in vivo method and was found to reduce the systolic and diastolic blood pressure of spontaneously hypertensive rats. The percentage reduction in blood pressure by test compound 5j was found to be higher than that of the standard drug prazosin (CAS 19216-56-9) at the same dose level (1 mg/kg p.o.). Chemically, prazosin is a 4-aminoquinazolin derivative. Pyridopyrimidine is a known bioisostere of quinazoline. The study revealed that isosteric replacement of the benzene ring of prazosin by a pyridine ring increases the potency.
一系列新的4-氨基-5,7-二甲基-2-（取代）氨基吡啶并[2,3-d]嘧啶（5）已被合成，并测试了其选择性α1-肾上腺素能受体拮抗活性。发现一些化合物以竞争性和可逆的方式拮抗α1-肾上腺素能受体。当在大鼠肛门尾骨肌上进行筛选时，一些化合物表现出显著的α1-肾上腺素能受体拮抗活性（pA2值在5.2-7.8范围内）。通过体内方法对最有效的化合物（5j）进行了评估，发现其可降低自发性高血压大鼠的收缩压和舒张压。发现在相同剂量水平（1mg/kg口服）下，测试化合物5j的血压降低百分比高于标准药物哌唑嗪（CAS 19216-56-9）。从化学结构上看，哌唑嗪是一种4-氨基喹唑啉衍生物。吡啶并嘧啶是已知的喹唑啉生物电子等排体。该研究表明，用吡啶环对哌唑嗪的苯环进行等排取代可提高效力。
