Nonpeptide Kisspeptin Antagonists for PCOS and HPG axis control
DESCRIPTION (provided by applicant): During the past decade, the discovery of kisspeptin peptides and their cognate receptor KISS1R (aka GPR54) has expanded our mechanistic understanding of the hypthothalamic-pituitary-gonadal (HPG) axis. The kisspeptin system has been shown to be an integrator of several streams of biological feedback (endocrine, metabolic, circadian) and regulates the pulsatile secretion of GnRH, which subsequently controls the release of the gonadotropins LH and FSH. Gonadotropin activity dictates a host of biological responses, including gonadal development, puberty, fertility, gametogenesis and sex hormone production. Polycystic ovary syndrome (PCOS) is the most common hormonal disorder among women of reproductive age. Infrequent and/orprolonged menstrual periods, aberrant hair growth (due to associated hyperandrogenism), acne and obesity can all occur in women with PCOS. Commonly, menstrual abnormality signals the condition in adolescence, though PCOS may manifest later following unexplained weight gain and/or difficulty becoming pregnant. Current treatments rely on managing the symptoms of the disease rather than the cause. Recent evidence demonstrates that a hallmark of the pathology of PCOS is hyperpulsatility of GnRH secretion. Thus, as the gatekeeper of the HPG-axis and GnRH signaling, KISS1R is an attractive new mechanism for treating the cause of PCOS. KISS1R antagonists should dampen GnRH pulsatility and offer the first possibility of treating the disease at the hypothalamiclevel. To date there are no drug-like, nonpeptide modulators of KISS1R. Our Phase I approach is to develop the pharmacological tools and deploy them in an in vitro assay cascade for the discovery and characterization of drug-like, nonpeptide antagonists of KISS1R. This assay cascade will employ different assays (e.g. whole cell functional, competition binding) such that we will be able to rapidly evaluate nonpeptide compounds and identify those that display insurmountable antagonism and slow dissociation rates from the receptor. We will use this information to guide small molecule medicinal chemistry efforts to characterize a drug-like lead chemical series. We have previously demonstrated that the use of this type of cascade to guide medicinal chemistry efforts can circumvent many common issues that often lead early stage programs astray. If successful, this project will pave the way for the Phase II optimization (pharmacokinetic, pharmacodynamic, and toxicological) and preclinical development of a novel setof KISS1R antagonists capable of being ready for human clinical development for the treatment of PCOS and potentially other reproductive disorders. PUBLIC HEALTH RELEVANCE: This project entails the development of kisspeptin receptor assays that will be used to guide design and synthesis of novel drug-like compounds for the treatment of polycystic ovary syndrome (PCOS). If successful, this work will provide lead molecules that could be optimized for human clinical trials.
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CRINETICS PHARMACEUTICALS, INC.
1428 Caudor St. Leucadia, CA 92024-
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