Zhi L, Tegley C M, Kallel E A, Marschke K B, Mais D E, Gottardis M M, Jones T K
Department of Medicinal Chemistry, Ligand Pharmaceuticals, Inc., San Diego, California 92121, USA.
J Med Chem. 1998 Jan 29;41(3):291-302. doi: 10.1021/jm9705768.
The development of a novel class of nonsteroidal human progesterone receptor (hPR) agonists, 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines 2, is described. The introduction of a 5-aryl group into the 1,2-dihydrocoumarino[3,4-f]quinoline core 1 is the key for progestational activities. The structure-activity relationship (SAR) studies of the 5-aryl substituents generated a series of potent hPR agonists, which exhibited similar biological activity (EC50 = 8-30 nM) to the natural hormone progesterone (EC50 = 2.9 nM) in cell-based assays with efficacies ranging from 28% to 96%. Most of the analogues displayed similar or greater binding affinity (Ki = 0.41-3.6 nM) than progesterone (Ki = 3.5 nM). Three representative analogues (13, 15, and 24) demonstrated in vivo activities in mammary gland morphology/uterine wet weight assay in ovariectomized rats.
本文描述了一类新型非甾体类人孕酮受体（hPR）激动剂——5-芳基-1,2-二氢-5H-色烯并[3,4-f]喹啉2的研发情况。在1,2-二氢香豆素并[3,4-f]喹啉核心结构1中引入5-芳基基团是产生孕激素活性的关键。对5-芳基取代基的构效关系（SAR）研究产生了一系列强效hPR激动剂，在基于细胞的测定中，它们表现出与天然激素孕酮（EC50 = 2.9 nM）相似的生物活性（EC50 = 8 - 30 nM），效力范围为28%至96%。大多数类似物表现出与孕酮（Ki = 3.5 nM）相似或更高的结合亲和力（Ki = 0.41 - 3.6 nM）。三种代表性类似物（13、15和24）在去卵巢大鼠的乳腺形态/子宫湿重测定中显示出体内活性。
