A NEW DRUG FOR DEPRESSION

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.