几度吹唤——喜睹内分泌治疗药研发新貌

1选择性雌激素受体调节剂用于防治骨质疏松选择性雌激素受体调节剂(Selective estrogen receptormodulator,SERM)是一类人工合成的非激素制剂,可与雌激素受体结合,选择性地作用于不同组织的雌激素受体,在不同的靶组织分别产生类雌激素或抗雌激素作用。由于不同结构的特点,对各种受体的亲和力可有所差异,从而在组织中发挥不同的生物效应。主要品种有他莫昔芬、雷洛昔芬、屈洛昔芬。与第1代他莫昔芬相比,雷洛昔芬抗雌激素作用更强,雌激素样作用更弱。当雌激素受体被配体如17-β雌二醇激活后,受体-配体复合物形成,并和热休克蛋白脱离后形成二…     

选择性雌激素受体调节剂对绝经后妇女冠心病的作用

选择性雌激素受体调节剂(SERM)可使雌激素对骨骼和心血管系统的有利作用与其对子宫和卵巢的不利作用发生分离。目前上市的SERM有他莫昔芬和雷诺昔芬,他莫昔芬可有效减少绝经后妇女心血管事件的发生。第二代SERM雷诺昔芬,能预防骨质疏松性骨折,对子宫内膜安全并有希望用于预防乳腺癌,但对冠心病的作用还不明确,正在开发的第三代SERM将更为安全和有效。     

选择性雌激素受体调节剂组织选择性作用研究进展

选择性雌激素受体调节剂(SERMs)是作用在雌激素受体上,在不同的靶组织细胞中起激动剂或拮抗剂调节作用的药物。SERMs本身结构特异性及其与不同靶组织中的受体形成复合体的差异决定了其在各类组织选择性的不同。综述了目前临床常见SERMs的结构类型及其在乳腺、骨、心血管、子宫、肝脏、神经等组织选择性作用的研究进展;并且跟踪报道了治疗绝经期综合症及预防绝经后骨质疏松症的一个新方式即由SERMs与雌激素形成的组织选择性雌激素复合物的应用状况。     

新一代选择性雌激素受体调节剂Ospemifene

QuatRx制药公司的ospemifene(OphenaTM)为治疗泌尿生殖系统萎缩的新一代三苯乙烯类选择性雌激素受体调节剂(SERM),目前已进入Ⅲ期临床研究。Ⅰ期和Ⅱ期临床实验表明,该化合物口服安全且耐受性良好。临床前研究发现,ospemifene的副作用少于其他SERMs,如其没有他莫昔芬的肝脏毒性     

选择性雌激素受体调节剂类乳腺癌治疗新药的研究进展

选择性雌激素受体调节剂(SERMs)是一系列结构各异的化合物，能与雌激素受体结合，依据靶组织和激素的内环境不同，表现出雌激素激动剂和(或)雌激素拮抗剂的作用，可用于治疗绝经妇女与雌激素水平有关的一系列疾病。综述治疗乳腺癌的SERMs类新药的构效关系研究与开发。     

选择性雌激素受体调节剂对AD的作用研究进展

雌激素能够改善学习认知功能,防治阿尔茨海默病,但是乳腺癌、子宫内膜癌等生殖系统癌症发病率的增加限制了其临床应用。选择性雌激素受体调节剂(SERMs)是能选择性与雌激素受体结合而发挥类雌激素作用的一类非类固醇类配体,由于其对组织受体选择的特异性,从而减少了雌激素治疗的副作用。本文就近年来选择性雌激素受体调节剂发挥神经保护作用的可能机制进行综述。     

选择性雌激素受体调节剂组织选择性作用研究进展

选择性雌激素受体调节剂（SERMs）是作用在雌激素受体上,在不同的靶组织细胞中起激动剂或拮抗剂调节作用的药物。SERMs本身结构特异性及其与不同靶组织中的受体形成复合体的差异决定了其在各类组织选择性的不同。综述了目前临床常见SERMs的结构类型及其在乳腺、骨、心血管、子宫、肝脏、神经等组织选择性作用的研究进展;并且跟踪报道了治疗绝经期综合症及预防绝经后骨质疏松症的一个新方式即由SERMs与雌激素形成的组织选择性雌激素复合物的应用状况。     

盐酸雷洛昔芬可用于治疗或预防骨质疏松症及降低乳腺癌的风险

礼来公司的选择性雌激素受体调节剂(SERM) 盐酸雷洛昔芬(raloxifene hydrochloride)片(商品名:Evista)于2007年9月获FDA批准用于治疗或预防骨质疏松症及降低罹患乳腺癌的风险.     

选择性雌激素受体调节剂

对选择性雌激素受体调节剂（ＳＥＲＭ）的定义、作用机制及其临床研究应用进行了概述,介绍了ＳＥＲＭ在不同的靶组织可以表现为雌激素激动剂和（或）拮抗剂的作用,雌激素的作用模型及其与ＳＥＲＭ的不同作用靶位,各类ＳＥＲＭ的临床应用情况和发展前景。     

骨质疏松症治疗药物近况

骨质疏松症治疗药物按主要作用机制可分为抑制骨吸收药物、促进骨形成药物和骨健康基本补充剂三大类.本文对双膦酸盐、选择性雌激素受体调节剂(SERM)、甲状旁腺素(PTH)等药物的作用及其不良反应等作一简要介绍.     

抗雌激素活性化合物及其构效关系研究

抗雌激素疗法是雌激素受体依赖性乳腺癌内分泌疗法的重要手段之一。抗雌激素化合物按作用机制分类可分为选择性雌激素受体调节剂和纯抗雌激素剂,其结构类型主要包括取代雌二醇衍生物、三苯乙烯、苯骈杂环类及多酚类天然化合物。本文重点综述近年来抗雌激素化合物的作用机制、构效关系及其研究进展。     

Selectively targeting estrogen receptors for cancer treatment

Estrogens regulate growth and development through the action of two distinct estrogen receptors (ERs), ERα and ERβ, which mediate proliferation and differentiation of cells. For decades, ERα mediated estrogen signaling has been therapeutically targeted to treat breast cancer, most notably with the selective estrogen receptor modulator (SERM) tamoxifen. Selectively targeting ERs occurs at two levels: tissue selectivity and receptor subtype selectivity. SERMs have been developed with emphasis on tissue selectivity to target ER signaling for breast cancer treatment. Additionally, new approaches to selectively target the action of ERα going beyond ligand-dependent activity are under current investigation. As evidence of the anti-proliferative role of ERβ accumulates, selectively targeting ERβ is an attractive approach for designing new cancer therapies with the emphasis shifted to designing ligands with subtype selectivity. This review will present the mechanistic and structural features of ERs that determine tissue and subtype selectivity with an emphasis on current approaches to selectively target ERα and ERβ for cancer treatment.     

Bazedoxifene and bazedoxifene combined with conjugated estrogens for the management of postmenopausal osteoporosis

Bazedoxifene acetate (WAY-140424; TSE-424) is an investigational non-steroidal indole-based selective estrogen receptor modulator (SERM) – also classified as an estrogen agonist/antagonist – that is being developed as a daily oral drug for the prevention and treatment of postmenopausal osteoporosis (PMO). Clinical studies have shown favorable effects on the skeleton, with prevention of bone loss in postmenopausal women without osteoporosis and reduction in vertebral fracture risk in women with PMO, without stimulation of endometrium or breast. Bazedoxifene combined with conjugated estrogens is an investigational tissue-selective estrogen complex, the first in a new class of therapeutic agents that pairs a selective estrogen receptor modulator with estrogens. Clinical trials with bazedoxifene/conjugated estrogens in postmenopausal women have shown skeletal benefit with improvement in menopausal vasomotor symptoms and little or no stimulation of endometrial or breast tissue. Bazedoxifene/conjugated estrogens is a potential agent for the prevention of PMO and control of menopausal symptoms.     

Bazedoxifene: a new selective estrogen receptor modulator for the treatment of postmenopausal osteoporosis

Bazedoxifene acetate (WAY-140424; TSE-424) is an oral, nonsteroidal, indole-based selective estrogen receptor modulator (SERM) being developed for the prevention and treatment of osteoporosis. Preclinical studies on bazedoxifene have demonstrated estrogen agonist effects on the skeleton and lipid metabolism but not on breast and uterine endometrium. In combination with estrogen, bazedoxifene antagonizes the stimulatory action of estrogens on proliferation of breast cancer cells and endometrium. Phase III clinical studies have shown favorable effects on the skeleton without stimulation of endometrium and breast. Bazedoxifene prevents bone loss in postmenopausal women without osteoporosis and reduces vertebral fractures in women with postmenopausal osteoporosis. In women at high risk of fracture with multiple risk factors, bazedoxifene reduces nonvertebral fracture risk in post-hoc analysis. Bazedoxifene in combination with conjugated estrogens represents a new form of therapeutic agents for the treatment of postmenopausal symptoms and prevention of postmenopausal osteoporosis. Clinical trials with bazedoxifene/conjugated estrogens have shown beneficial effects on bone mineral density and bone turnover markers with improvement in vasomotor symptoms and little or no stimulation of breast and endometrium.     

Arzoxifene: the development and clinical outcome of an ideal SERM

Hormone-sensitive tumours are among the most common cancers in women. Specific inhibition of the estrogen receptor by selective estrogen receptor downregulators or selective estrogen receptor modulators (SERMs) is effective for the treatment of breast and endometrial cancers and may be used for the prevention of breast cancer. Due to differential recruitment of co-activators and corepressors, SERMs are tissue specific and may have antiestrogenic effects in some tissues, with estrogen agonist activity in others. The ideal SERM would have antiestrogenic effects on the breast and endometrium, but pro-estrogenic effects on bone and lipids. The SERM, arzoxifene (LY-353381.HCl) meets all of these criteria. This review summarises the development, preclinical studies and the clinical outcome of arzoxifene and places it in context with other modalities in the treatment of hormone receptor-positive tumours.     

Arzoxifene: the development and clinical outcome of an ideal SERM

Hormone-sensitive tumours are among the most common cancers in women. Specific inhibition of the estrogen receptor by selective estrogen receptor downregulators or selective estrogen receptor modulators (SERMs) is effective for the treatment of breast and endometrial cancers and may be used for the prevention of breast cancer. Due to differential recruitment of co-activators and corepressors, SERMs are tissue specific and may have antiestrogenic effects in some tissues, with estrogen agonist activity in others. The ideal SERM would have antiestrogenic effects on the breast and endometrium, but pro-estrogenic effects on bone and lipids. The SERM, arzoxifene (LY-353381.HCl) meets all of these criteria. This review summarises the development, preclinical studies and the clinical outcome of arzoxifene and places it in context with other modalities in the treatment of hormone receptor-positive tumours.     

Lasofoxifene,a new selective estrogen receptor modulator for the treatment of osteoporosis and vaginal atrophy

Selective estrogen receptor modulators (SERMs) represent a class with a growing number of compounds that act as either estrogen receptor (ER) agonists or antagonists in a tissue-specific manner. The purpose of this article is to review the effects of lasofoxifene, a new-generation SERM that has completed the Phase III development program for the prevention and treatment of osteoporosis and vaginal atrophy in postmenopausal women. This compound selectively binds to both ERs with high affinity. Lasofoxifene also has a remarkably improved oral bioavailability with respect to other SERMs such as raloxifene and tamoxifen, owing to increased resistance to intestinal wall glucuronidation. In both preclinical and short-term clinical studies, this compound showed a favorable safety profile and demonstrated a proven efficacy in preventing bone loss and lowering cholesterol levels. More recently, Phase III clinical trials have confirmed the efficacy and safety of this new SERM in the prevention of bone loss and vertebral and nonvertebral fractures. Moreover, in postmenopausal women with osteoporosis, lasofoxifene treatment also reduced ER positive breast cancer risk and the occurrence of vaginal atrophy. With its increased potency and efficacy on the prevention of nonvertebral fractures and its positive effects on the vagina, this new SERM may represent an alternative therapy for osteoporosis in postmenopausal women.     

选择性雌激素受体调节剂研究现状

乳腺癌已经成为危害女性健康的主要恶性肿瘤,选择性雌激素受体调节剂作为治疗乳腺癌的有效药物越来越受到人们的广泛关注。笔者对选择性雌激素受体调节剂的研究现状进行综述。     

Bazedoxifene when paired with conjugated estrogens is a new paradigm for treatment of postmenopausal women

Importance of the field: The concept of the tissue selective estrogen complex (TSEC) combining a selective estrogen receptor modulator (SERM) with one or more estrogens, aims to provide comparable efficacy to combination estrogen and progestin therapy for symptomatic menopausal women with a uterus without the need for a progestin.

Areas covered in this review: Published multi-center randomized blinded clinical trials with bazedoxifene alone and paired in combination with conjugated estrogens show an effect in hot flashes, vaginal atrophy, quality of life measures, sleep, bone density, and breast and uterine safety.

What the reader will gain: A new concept for menopausal women, bazedoxifene with conjugated estrogens (BZA-CE) TSEC, appears to provide the selective benefits of a SERM with additional benefits of estrogen without the need for a progestin. Preclinical studies with bazedoxifene alone showed that it was antagonistic in the uterine and breast tissue while an agonist in the bone. Phase II and III clinical studies of BZA-CE reveal relief from hot flashes and vaginal atrophic changes, and improvement in bone density, quality of life and sleep without breast or uterine stimulation.

Take home message: Bazedoxifene paired with conjugated estrogens in postmenopausal women relieves vasomotor symptoms and vulvovaginal atrophic changes with prevention of bone loss. Adverse events include a twofold increase risk of venous thrombosis. No evidence of stimulation of the breast, uterus or ovary was seen.