Structure-activity relationship of antiestrogens. Studies on 2,3-diaryl-1-benzopyrans

Abstract

A series of 2,3-diaryl-1-benzopyran analogues substituted at position 4 of 2-phenyl with a hydroxy or pyrrolidinoethoxy residue were synthesized as models for (E)-triarylpropenones constrained in the s-trans conformation. The prototypes, belonging to five chemical series, were evaluated for their estrogen receptor affinity and for estrogen agonist-antagonist activities. The 4H-1-benzopyran-4-one, the 2,3-dihydro-4H-1-benzopyran-4-one, the 4H-1-benzopyran, and the 2,3-dihydro-1-benzopyran derivatives were found to be inactive or only marginally activate as receptor ligands or estrogen agonists-antagonists. In the 2H-1-benzopyran category the parent phenol was also inactive whereas the basic ethers 16 and 26 were modest receptor ligands while being quite active as antiestrogens. In a comparative study the benzopyran 16 was found to be more effective antiestrogen than tamoxifen while being as effective as LY-117018. The benzopyrans have thus emerged as a new class of potent antiestrogens.

Selective estrogen receptor modulators regulate stromal proliferation in human benign prostatic hyperplasia by multiple beneficial mechanisms—action of two new agents

“…The benzopyran-core docks in the ligand binding domain of both ER-α and ER-ß, but in opposite orientations, with several-fold ER-ß selectivity [21]. Since ER-ß has been assigned an important regulatory role in prostatic hyperplasia [30], we selected two molecules from the Institute's library of benzopyran-SERMs [22][23][24] that apparently emerged promising subsequent to the characterization of estrogen signaling in male and the discovery of ER-ß in prostate [31]. We selected DL-2-[4-(2-piperidinoethoxy) phenyl]-3-phenyl-2 H-1-benzopyran (BP/CDRI-85/287) from the Institute's SERM library of substituted benzopyrans on the basis of its low ER-α binding affinity (0.3% of estradiol; 23, 32) yet potent anti-implantation activity (which depends on ER-α antagonism).…”

“…Nevertheless, the activity of phyto-SERMs can by potentiated quite appreciably by structural modifications of its ER-ß selective benzopyran moiety [20,21]. Designed synthesis of a series of potent benzopyran-SERMs was carried out at the Central Drug Research Institute [22][23][24], before the discovery of ER-ß, essentially for female contraception. We selected two differently substituted benzopyran structures from the Institute's SERM-library: DL-2-[4-(2-piperidinoethoxy) phenyl]-3-phenyl-2 H-1-benzopyran (CDRI 85/287) and ormeloxifene ( Fig.…”

In vitro anti-resorptive activity and prevention of ovariectomy-induced osteoporosis in female Sprague–Dawley rats by ormeloxifene, a selective estrogen receptor modulator

“…For in vitro antiresorptive assay, female rats were mated to males of proven fertility (day 1: day of sperm positive vaginal smear) and kept individually in plastic cages containing dry rice husk. Ormeloxifene (INN for centchroman) and CDRI-85/287 synthesized [13] at this institute were used. Tamoxifen, 17␣-ethynylestradiol, BGJ b bone culture medium, parathyroid hormone (PTH, aa 1-34, molecular weight 4117.7), bovine serum albumin (fraction V), HEPES, streptomycin, penicillin, DMSO, PPO, POPOP and methoxyethanol were purchased from Sigma Chemical Company, USA.…”

Antioxidant defense system during endometrial receptivity in the guinea pig: effect of ormeloxifene, a selective estrogen receptor modulator

“…Ormeloxifene synthesized at this institute (Saeed et al 1990) was used. All chemicals were purchased from Sigma Chemical Company.…”