Discovery of Inositol(1,4,5)trisphosphate Receptor Inhibitors

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$93,749.00
Award Year:
2008
Program:
SBIR
Phase:
Phase I
Contract:
1R43NS049920-01A2
Award Id:
89384
Agency Tracking Number:
NS049920
Solicitation Year:
n/a
Solicitation Topic Code:
n/a
Solicitation Number:
n/a
Small Business Information
675 ARAPEEN DRIVE, SUITE 302, SALT LAKE CITY, UT, 84108
Hubzone Owned:
N
Minority Owned:
N
Woman Owned:
N
Duns:
179151188
Principal Investigator:
() -
Business Contact:
() -
ksauder@echelon-inc.com
Research Institute:
n/a
Abstract
DESCRIPTION (provided by applicant): Stroke has become a significant cause of mortality and morbidity among elderly people in industrialized countries. To address the growing burden of health care costs and the immeasurable emotional toll on families as we ll as affected individuals, new pharmacological agents for prevention and treatment are desperately needed. Oxygen deprivation and oxidative stress lead to release of cytochrome c, which is related in turn to the activation of Ins(1,4,5)P3 receptors (IP3R) controlling calcium release from intracellular stores. Therefore, small molecule antagonists of IP3R would be attractive therapeutic candidates to restore proper calcium signaling pathways and prevent apoptosis. To establish the feasibility of this approa ch, Echelon Biosciences proposes to synthesize and identify potential IP3 antagonists. Specifically, we will use in silico modeling in combination with chemical library synthesis to prepare phosphate-free IP3 mimetics that dock in the ligand binding site, as well as a series of xestospongin (a potent natural IP3R inhibitor) analogs. Candidate compounds will be screened using a medium throughput in-cell fluorescence-based assay in which the time course for calcium release by IP3 in appropriately stimulated c ells is monitored in Fluo-3 plus drug-treated fibroblasts. Activity will be optimized by iterative cycles of modeling and synthesis based on biological activities observed.

* information listed above is at the time of submission.

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