SBIR-STTR Award

Long Term Goals: Serenix Pharmaceuticals (SP) will develop drugs for the treatment of CNS disorders. Strategy: SP acquired a series of vasopressin receptor antagonists from Eli Lilly and Company and has refined these molecules through manipulations of various structural zones. A subset of these antagonists (LEAD SERIES) exhibit reasonable affinity for the vasopressin receptor subtype involved in depression and stress-related affective disorders. The LEAD SERIES requires refinement to optimize affinity (less than 5 .0 nM) and early stage testing to demonstrate biological activity. The platform molecule has four essential structural zones; two of these will be the focus of the proposed research. Phase I objectives are (i) utilize classical and combinatorial chemistry to modify structural zones on the LEAD SERIES to generate ca. 200 compounds, (ii) screen these for target receptor affinity and focus on those with Kds less than 5 nM, and (iii) test the high affinity compounds for in vitro biological activity. The findings, combined with considerations related to affinity, structural diversity, structural attractiveness, and QSAR models, will identify promising compounds for testing in Phase II for oral absorption, stability, metabolism, toxicity, and efficacy. PROPOSED COMMERCIAL APPLICATION: SP will focus on the development of a novel drug for the treatment of depression and stress-related affective disorders. In 1999, the NIMH reported that depression affects over 19,000,000 adults in the United States, making it the most common serious CNS disease. The proposed drug represents a novel pharmacological approach that differs from the tricyclics, SSRIs, and NRIs currently used for these disorders. It therefore may capture significant market share.

Thesaurus Terms:
antidepressant, chemical structure function, combinatorial chemistry, depression, drug design /synthesis /production, hormone inhibitor, vasopressin drug screening /evaluation, hormone receptor, hypothalamic pituitary adrenal axis

Serenix Pharmaceuticals LLC (SRX) will develop drugs for stress-related affective disorders and depression. Serenix acquired a series of vasopressin receptor antagonists from Eli Lilly Company and refined these molecules through manipulations of various structural zones. A subset of these molecules exhibited reasonable affinity for the vasopressin receptor subtype involved in depression. With Phase I support, this series was chemically modified and a candidate that exhibits good binding affinity and blocks biological effects at the target human receptor was identified. The overall goal of Phase II research is to identify additional candidates based on chemical and both in vitro and in vivo biological activity in order to progress toward the filing of Investigational New Drug (IND) applications for two promising candidates. To reach this goal, SRX will pursue the following objectives i) continue classic and combinatorial chemistry based on Phase I findings to produce additional candidate molecules, ii) screen these for target receptor affinity, focus on those with Kds < 10 nM, and test the high affinity compounds for in vitro and in vivo biological activity, and iii) use CROs to conduct tests for oral absorption, bioavailability, metabolism, mutagenicity, and toxicity. The completion of the proposed research will provide data that validates novel drug candidates and meets a portion of the chemical and biological criteria established by the FDA for IND applications.

Thesaurus Terms:
antidepressant, chemical structure function, combinatorial chemistry, depression, drug design /synthesis /production, hormone inhibitor drug metabolism, drug screening /evaluation, hormone receptor, hypothalamic pituitary adrenal axis, pharmacokinetics laboratory mouse