Arrowsmith J E, Campbell S F, Cross P E, Stubbs J K, Burges R A, Gardiner D G, Blackburn K J
J Med Chem. 1986 Sep;29(9):1696-702. doi: 10.1021/jm00159a022.
A series of dihydropyridines substituted at the 2-position by basic side chains are described and their potencies as calcium antagonists listed. One compound, 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5- methoxycarbonyl-6-methyl-1,4-dihydropyridine (17, amlodipine) was found to be comparable in potency to nifedipine and to have an elimination half-life of 30 h in dogs. Oral bioavailability approached 100%, and hemodynamic responses were gradual in onset and long-lasting in effect. The two enantiomers have been prepared, and the bulk of the activity was found to reside with the (-) isomer, 18. X-ray crystallographic studies, carried out on a close analogue of 17, suggest the existence of a weak hydrogen bond between the side-chain oxygen and the proton on the ring nitrogen.
描述了一系列在2-位被碱性侧链取代的二氢吡啶，并列出了它们作为钙拮抗剂的效力。发现一种化合物，2-[(2-氨基乙氧基)甲基]-4-(2-氯苯基)-3-乙氧羰基-5-甲氧羰基-6-甲基-1,4-二氢吡啶（17，氨氯地平）的效力与硝苯地平相当，在犬体内的消除半衰期为30小时。口服生物利用度接近100%，血流动力学反应起效缓慢且作用持久。已制备出两种对映体，发现大部分活性存在于(-)异构体18中。对17的一种类似物进行的X射线晶体学研究表明，侧链氧与环氮上的质子之间存在弱氢键。
