Crinetics Pharmaceuticals, Inc. — Department of Health and Human Services SBIR Phase II: NICHD

Description

DESCRIPTION provided by applicant During the past decade the discovery of kisspeptin peptides and their cognate receptor KISS R 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 or prolonged menstrual periods acne aberrant hair growth due to associated hyperandrogenism insulin resistance and obesity can all occur in women with PCOS Commonly menstrual abnormality signals the onset of 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 andquot gatekeeperandquot of the HPG axis and GnRH pulsatility KISS R is an attractive new mechanism for treating the neuroendocrine cause of PCOS KISS R antagonists should dampen GnRH pulsatility and offer the first possibility of treating the disease at the hypothalamic level while minimizing the potential risk of hypoestrogenemia During our Phase I program we were able to develop the medicinal chemistry strategy and pharmacologic methodology to determine the activity of KISS R antagonists This resulted in non peptides with good potency and none of the physicochemical liabilities of the only series of previously published antagonists We were able to extend the goals of our Phase I program to include an initial characterization of selectivity pharmacokinetics and pharmacodynamics of a lead molecule Our Phase II plan is to use pharmacology receptor structural models and medicinal chemistry to further develop these antagonists in terms of potency selectivity oral bioavailability as well as other drug like properties and efficacy in animal models of HPG axis control and pulsatility If successful his project will result in the selection of a drug candidate for pre IND enabling toxicology studies to support first in human studies Ultimately this molecule would be evaluated in later stage clinical trials as a potential First In Class treatment for women with PCOS and other reproductive disorders PUBLIC HEALTH RELEVANCE This project entails the further development and optimization of kisspeptin receptor antagonists that will be evaluated in models of reproductive axis control I ultimately successful this work will provide a drug candidate that will be tested in clinical trias for efficacy in reproductive disorders especially PCOS