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Phosphodiesterase Type IV (PDE4) Isoform Selective Allosteric Modulators For…

Award Information

Agency:
Department of Health and Human Services
Branch:
N/A
Award ID:
Program Year/Program:
2011 / SBIR
Agency Tracking Number:
R43MH091791
Solicitation Year:
2011
Solicitation Topic Code:
NIMH
Solicitation Number:
PA08-142
Small Business Information
TETRA DISCOVERY PARTNERS, LLC
910 ROSEWOOD AVE SE GRAND RAPIDS, MI 49506-3362
View profile »
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
 
Phase 1
Fiscal Year: 2011
Title: Phosphodiesterase Type IV (PDE4) Isoform Selective Allosteric Modulators For Psyc
Agency: HHS
Contract: 1R43MH091791-01
Award Amount: $698,827.00
 

Abstract:

DESCRIPTION (provided by applicant): The broad goal of the SBIR proposal is to understand the pharmacology of phosphodiesterase 4 (PDE4) allosteric modulation in the CNS as it relates to psychiatric disorders. We recently described the discovery of isoform-selective, allosteric modulators of PDE4D that bind to a high affinity site on an N-terminal regulatory domain known as Upstream Conserved Region 2 (UCR2). The allosteric mechanism of action prevents the compounds from completely inhibiting cAMP hydrolysis, thereby reducing target-based toxicity. PDE4D modulators have greatly improved tolerability than earlier compounds such as rolipram. Rolipram previously was shown to have anti-depressant activity in human Phase II clinical trials but was poorly tolerated due to emesis. Three isoforms of PDE4 are expressed in brain (PDE4A, B and D). It previously has not been possible to develop isoform-selective PDE4 inhibitors, since earlier efforts have targeted the catalytic site, which is highly conserved among the PDE4 subtypes; thus, little is known regarding the pharmacology of PDE4 isoform selective compounds. Our immediate goal is to explore the possible clinical benefit of our investigational new drug, DG-071 in animal models of psychiatric disease, particularlydepression. The proposed studies will determine the feasibility of developing DG-071 for the treatment of depression. The second specific aim of the SBIR proposal is to use structural guidance to design PDE4B selective allosteric modulators that distribute to brain. We will explore PDE4B CNS pharmacology, particularly in models of schizophrenia. The structural and medicinal chemistry studies will determine the feasibility in a Phase II SBIR of developing PDE4B selective allosteric modulators for psychiatric disorders. PUBLIC HEALTH RELEVANCE: Severe forms of depression affect 2-5% of the US population, and mood disorders impact 7% of the world's population and rank among the top ten causes of disability. We are seeking to develop a new treatment fordepression based on allosteric modulation of phosphodiesterase 4D.

Principal Investigator:

Mark E. Gurney
616-635-0937
mark@tetradiscovery.com

Business Contact:

Mark E. Gurney
616-635-0937
mgurney@decode.com
Small Business Information at Submission:

TETRA DISCOVERY PARTNERS, LLC
910 ROSEWOOD AVE SE GRAND RAPIDS, MI 49506-3362

EIN/Tax ID: 127399859
DUNS: N/A
Number of Employees: N/A
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No