Anderson Ross C, Newton Claire L, Millar Robert P
Centre for Neuroendocrinology, Department of Physiology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.
Centre for Neuroendocrinology, Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.
Front Endocrinol (Lausanne). 2019 Jan 23;9:757. doi: 10.3389/fendo.2018.00757. eCollection 2018.
The follicle-stimulating hormone receptor (FSHR) has been targeted therapeutically for decades, due to its pivotal role in reproduction. To date, only purified and recombinant/biosimilar FSH have been used to target FSHR in assisted reproduction, with the exception of corifollitropin alfa; a modified gonadotropin in which the FSH beta subunit is joined to the C-terminal peptide of the human choriogonadotropin beta subunit, to extend serum half-life. Assisted reproduction protocols usually entail the trauma of multiple injections of FSH to initiate and promote folliculogenesis, which has prompted the development of a number of orally-available low molecular weight (LMW) chemical scaffolds targeting the FSHR. Furthermore, the recently documented roles of the FSHR in diverse extragonadal tissues, including cancer, fat metabolism, and bone density regulation, has highlighted the potential utility of LMW modulators of FSHR activity. Despite these chemical scaffolds encompassing a spectrum of and activities and pharmacological profiles, none have yet reached the clinic. In this review we discuss the major chemical classes of LMW molecules targeting the FSHR, and document their activity profiles and current status of development, in addition to discussing potential clinical applications.
几十年来，促卵泡激素受体（FSHR）一直是治疗的靶点，因为它在生殖过程中起着关键作用。迄今为止，在辅助生殖中，除了注射用重组人促卵泡激素β（corifollitropin alfa）外，只有纯化的和重组/生物类似物促卵泡激素被用于靶向FSHR；注射用重组人促卵泡激素β是一种改良的促性腺激素，其中促卵泡激素β亚基与人绒毛膜促性腺激素β亚基的C末端肽相连，以延长血清半衰期。辅助生殖方案通常需要多次注射促卵泡激素来启动和促进卵泡生成，这促使人们开发了一些靶向FSHR的口服低分子量（LMW）化学支架。此外，最近有文献记载FSHR在包括癌症、脂肪代谢和骨密度调节在内的多种性腺外组织中的作用，这突出了FSHR活性低分子量调节剂的潜在用途。尽管这些化学支架具有一系列的活性和药理特性，但目前尚无一种进入临床应用。在这篇综述中，我们讨论了靶向FSHR的低分子量分子的主要化学类别，记录了它们的活性特征和当前的开发状况，并讨论了潜在的临床应用。
