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Citations since 2016
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Here, we describe the development of a series of highly selective PAR4 antagonists with nanomolar potency and selectivity versus PAR1, derived from the indole-based 3. Of these, 9j (PAR4 IC50 = 445 nM, PAR1 response IC50 >30 μM) and 10h (PAR4 IC50 = 179 nM, PAR1 response IC50 >30 μM) maintained an overall favorable in vitro DMPK profile, encouragin...
Herein we report the discovery and SAR of an indole-based protease activated receptor-4 (PAR-4) antagonist scaffold derived from a similarity search of the Vanderbilt HTS collection, leading to MLPCN probe ML354 (VU0099704). Using a novel PAC-1 fluorescent αIIbβ3 activation assay this probe molecule antagonist was found to have an IC50 of 140nM for...
Protease activated receptor-4 (PAR4) is one of the thrombin receptors on human platelets and is a potential target for the management of thrombotic disorders. We sought to develop potent, selective, and novel PAR4 antagonists to test the role of PAR4 in thrombosis and hemostasis. Development of an expedient three-step synthetic route to access a no...
Several compounds act as partial antagonists of PAR4. Platelets were treated with indicated concentrations of compound for 5 minutes prior to stimulation with 200 µM PAR4-AP. GPIIbIIIa activation was measured via flow cytometric analysis of PAC1 binding. Hits from the second round (A) and third round (B) of optimization are shown. Data is presented...
Compounds display varying degrees of PAR1 off target inhibitory activity. Platelets were treated with 10 µM of indicated antagonist for 5 minutes followed by challenge with 20 µM PAR1-AP. Flow cytometric analysis of PAC1 binding was used to determine GPIIbIIIa activation. Data presented is mean±S.D. n of 2 volunteers. (TIF)
YD-3 inhibits PAR4 mediated GPIIbIIIa activation and p-selectin expression. Platelets were treated with YD-3 for 5 minutes prior to stimulation with 200 µM PAR4-AP. Data represented as raw mean fluorescent intensity values for platelets positive for FITC (A) or PE (B) staining. Mean±S.E.M. n of 3 volunteers is graphically represented. Calculated IC...
With the recent interest of protease-activated receptors (PAR) 1 and PAR4 as possible targets for the treatment of thrombotic disorders, we compared the efficacy of protease-activated receptor (PAR)1 and PAR4 in the generation of procoagulant phenotypes on platelet membranes. PAR4-activating peptide (AP) stimulated platelets promoted thrombin gener...
The C2'-oxidized abasic lesion (C2-AP) is produced in DNA that is subjected to oxidative stress. C2-AP is incised by phosphodiesterases, but is not a substrate for endonuclease III even though a Schiff base is formed (Greenberg, M. M., et al. (2004) Biochemistry 43, 15217). A chemically synthesized oligonucleotide was used to study C2-AP reactivity...