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Young, Summer

Summer Young, Ph.D. Candidate
Department of Pharmacology
Vanderbilt University Medical Center
RRB 444
2200 Pierce Avenue
Nashville, TN 37232
summer.e.young@vanderbilt.edu

Education:
B.A. Chemisty and Biology, Johns Hopkins University (Baltimore, MD)

Research Interests: 
Thrombin, a key factor in coagulation and inflammation, elicits responses via activation of protease activated receptors (PARs).  PARs are a family of four GPCRs that are uniquely activated by proteolytic cleavage of their N-terminus which results in a new N-terminus serving as the tethered ligand or endogenous agonist for the receptor.  Human platelets which express both PAR1 and PAR4 are activated by thrombin but a key difference between the two receptors is that PAR1 contains a hirudin-like domain which is able to bind thrombin at sub-nanomolar concentrations whereas PAR4 lacks this binding domain and is considered the low affinity thrombin receptor.  PAR1 and PAR4 activation in the platelet causes rapid intracellular calcium mobilization, GPIIbIIIa activation, alpha and dense granule secretion, and production of feed forward signaling molecules including ADP and thromboxane. These activities are necessary for hemostasis and under pathological conditions may lead to thrombus formation and growth resulting in blockade of blood vessels.  PARs are attractive targets for antiplatelet and antithrombotic therapy.  To date many PAR1 antagonists have been synthesized, characterized and one (Vorapaxar, Merck) has been run in phase III clinical trials.  However, Vorapaxar phase III trials were halted for patients presenting with previous stroke due to an association of treatment with an increased risk of intracranial hemorrhage.  Due to the low affinity nature of PAR4 activation and thus differential temporal engagement by thrombin, PAR4 should be considered a viable alternative target.  YD-3 is the first and sole non-peptide PAR4 antagonist.  We sought to test YD-3 as a PAR4 antagonist in our lab to characterize the role of PAR4 in thrombosis and hemostasis.  However, YD-3 is not commercially available, the published synthetic route is of moderate length, and there is formation of an inactive isomer due to tautomerization of the N2- proton in the indazole ring.  We developed a novel two-step synthetic route for PAR4 antagonists built upon an indole scaffold thus effectively eliminating the formation of a second inactive isomer. We also developed a high throughput purified platelet Ca2+ assay in order rapidly determine structure activity relationships of novel compounds.

 

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