Wallinder Charlotta, Sköld Christian, Sundholm Sara, Guimond Marie-Odile, Yahiaoui Samir, Lindeberg Gunnar, Gallo-Payet Nicole, Hallberg Mathias, Alterman Mathias
Department of Medicinal Chemistry , BMC , Uppsala University , P.O. Box 574 , SE-751 23 Uppsala , Sweden.
Service of Endocrinology , Faculty of Medicine and Health Sciences , University of Sherbrooke , Sherbrooke , J1H 5N4 Quebec , Canada.
Medchemcomm. 2019 Nov 18;10(12):2146-2160. doi: 10.1039/c9md00402e. eCollection 2019 Dec 1.
Rigidification of the isobutyl side chain of drug-like AT receptor agonists and antagonists that are structurally related to the first reported selective AT receptor agonist 1 (C21) delivered bioactive indane derivatives. Four enantiomer pairs were synthesized and the enantiomers were isolated in an optical purity >99%. The enantiomers , , , , , , and bind to the AT receptor with moderate ( = 54-223 nM) to high affinity ( = 2.2-7.0 nM). The enantiomer with positive optical rotation (+) exhibited the highest affinity at the receptor. The indane derivatives and are among the most potent AT receptor antagonists reported so far. As illustrated by the enantiomer pairs / and /, an alteration at the stereogenic center has a pronounced impact on the activation process of the AT receptor, and can convert agonists to antagonists and .
与首个报道的选择性AT受体激动剂1（C21）结构相关的类药物AT受体激动剂和拮抗剂的异丁基侧链刚性化产生了生物活性茚满衍生物。合成了四对对映体，并以>99%的光学纯度分离出对映体。对映体 、 、 、 、 、 、 和 以中等亲和力（ = 54 - 223 nM）至高亲和力（ = 2.2 - 7.0 nM）与AT受体结合。具有正旋光性（+）的对映体在受体上表现出最高亲和力。茚满衍生物 和 是迄今为止报道的最有效的AT受体拮抗剂。如对映体对 / 和 / 所示，手性中心的改变对AT受体的激活过程有显著影响，并且可以将激动剂转化为拮抗剂 。
