Small molecular inhibitors of integrin alpha2beta1 that prevent pathological thrombus formation via an allosteric mechanism.

Format:

Book

Thesis/Dissertation

Author/Creator:

Miller, Meredith Wetherbee.

Contributor:

University of Pennsylvania.

Language:

English

Subjects (All):

Pharmacology.

0419.

Local Subjects:

0419.

Physical Description:

175 pages

Contained In:

Dissertation Abstracts International 70-01B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

There is a grave need for safer antiplatelet therapeutics to prevent heart attack and stroke. Agents targeting the interaction of platelets with the diseased vessel wall could impact vascular disease specifically with minimal effects on normal hemostasis. We targeted integrin alpha2beta 1, a collagen receptor, because its overexpression is associated with pathological clot formation while its absence does not cause severe bleeding. Structure-activity studies led to the development of highly potent and selective small molecule inhibitors. The responses of integrin alpha2beta 1 mutants to these compounds are consistent with a computational model of their mode of inhibition and shed light on the activation mechanism of I domain-containing integrins. One of the potent compounds was proven efficacious in an animal model of arterial thrombosis, which is the first demonstration of in vivo efficacy for inhibition of this platelet receptor. These results suggest targeting integrin alpha2beta1 could be a potentially safe, effective approach to long term therapy for cardiovascular disease.

Notes:

Source: Dissertation Abstracts International, Volume: 70-01, Section: B, page: 0229.

Adviser: William DeGrado.

Thesis (Ph.D.)--University of Pennsylvania, 2008.

Local Notes:

School code: 0175.

ISBN:

9781109008401

Access Restriction:

Restricted for use by site license.