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

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$698,827.00
Award Year:
2011
Program:
SBIR
Phase:
Phase I
Contract:
1R43MH091791-01
Award Id:
n/a
Agency Tracking Number:
R43MH091791
Solicitation Year:
2011
Solicitation Topic Code:
NIMH
Solicitation Number:
PA08-142
Small Business Information
910 ROSEWOOD AVE SE, GRAND RAPIDS, MI, 49506-3362
Hubzone Owned:
N
Minority Owned:
N
Woman Owned:
N
Duns:
967529939
Principal Investigator:
MARK GURNEY
(616) 635-0937
mark@tetradiscovery.com
Business Contact:
MARK GURNEY
(616) 635-0937
mgurney@decode.com
Research Institute:
Stub




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.

* information listed above is at the time of submission.

Agency Micro-sites


SBA logo

Department of Agriculture logo

Department of Commerce logo

Department of Defense logo

Department of Education logo

Department of Energy logo

Department of Health and Human Services logo

Department of Homeland Security logo

Department of Transportation logo

Enviromental Protection Agency logo

National Aeronautics and Space Administration logo

National Science Foundation logo
US Flag An Official Website of the United States Government