Discovery and Preclinical Pharmacology of a Novel, Potent, Nonsteroidal Estrogen Receptor Agonist/Antagonist, CP-336156, a Diaryltetrahydronaphthalene

Abstract

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Disposition of Lasofoxifene, a Next-Generation Selective Estrogen Receptor Modulator, in Healthy Male Subjects

“…The synthetic reference compounds standards, 5-hydroxy-lasofoxifene (M21A), 7-hydroxy-lasofoxifene (M21B), 5-methoxy-lasofoxifene, 5-hydroxy-6-O-methyl-lasofoxifene, 7-methoxy-lasofoxifene, and 7-hydroxy-6-O-methyl-lasofoxifene, were synthesized at Pfizer Global Research and Development using standard procedures (Rosati et al, 1998).…”

“…Studies have shown that lasofoxifene is an estrogen receptor (ER) agonist in bone and cholesterol regulation and an ER antagonist in the mammary gland and uterus. It binds with high affinity to the human ER␣, has good oral bioavailability in preclinical species (Rosati et al, 1998), prevents bone loss, and maintains bone mass and strength in ovariectomized rats without stimulating the uterus (Ke et al, , 2004. In both nonclinical and clinical human studies, lasofoxifene has shown a favorable safety profile and a proven efficacy in preventing bone loss and lowering cholesterol levels (Gennari et al, 2006), and it is now under submission for regulatory approval.…”

Tetrahydroisoquinoline Phenols: Selective Estrogen Receptor Downregulator Antagonists with Oral Bioavailability in Rat

“…A notable exception is lasofoxifene (2), which exhibits low clearance and high oral bioavailability across species, attributed to its nonplanar topology reducing the rate of gut wall glucuronidation. 3 A further step change in treatment for hormonally driven breast cancer occurred with development of selective estrogen receptor downregulators (SERDs) such as fulvestrant. 4 These molecules are capable of both antagonizing estrogen receptor driven cell proliferation as well as effecting a conformational change resulting in ubiquitinylation and degradation of the receptor.…”

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

“…Lasofoxifene is a diaryltetrahydronaphthalene derivative referred to as CP336156 [113] that has been reported to have high binding affinity for ER and have potent activity in preserving bone density in the rat [114,115]. The structure of CP336156 is reminiscent of the putative antiestrogenic metabolite of nafoxidine [116] that failed to become a breast cancer drug because of unacceptable side effects [117].…”

“…Studies demonstrate that the l enantiomer had twice the bioavailbility of the d enantiomer. The authors [113] ascribed the difference to enantioselective glucuronidation of the d isomer. An evaluation of CP336156 in the prevention and treatment of rat mammary tumors induced by N-nitroso-N-methylurea shows activity similar to that of tamoxifen [118].…”