Discovery of a Novel, Orally Active Himbacine-Based Thrombin Receptor Antagonist (SCH 530348) with Potent Antiplatelet Activity

Chackalamannil, Samuel; Wang, Yuguang; Greenlee, William J.; Hu, Zhiyong; Yan, Xiaofeng; Ahn, Ho-Sam; Boykow, George; Hsieh, Yunsheng; Palamanda, Jairam; Agans-Fantuzzi, Jacqueline; Kurowski, Stan; Graziano, Michael P.; Chintala, Madhu

doi:10.1021/jm800180e

Cited by 242 publications

(214 citation statements)

References 34 publications

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“…In several preclinical studies, blocking of the thrombin receptor protease-activated receptor 1 by several compounds such as vorapaxar and atopaxar was suggested as a promising adjunct therapy. [46][47][48][49] In our study, apelin was found to mainly inhibit thrombin-and collagen-mediated platelet activation ( Figure 7D), suggesting the potential use of this naturally occurring inhibitor (and/or its derivatives) of platelet activation in therapy. In conclusion, we demonstrate in the present work a new biological function of apelin peptide that inhibits platelet activation and aggregation mainly induced by thrombin and collagen.…”

Section: Discussionmentioning

confidence: 63%

Apelin: an antithrombotic factor that inhibits platelet function

Adam

Khatib

López

et al. 2016

Blood

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Key Points• Apelin plays a key role in maintaining hemostasis through the regulation of platelet function.• Treatment of platelets with apelin inhibits aggregation and thrombus formation.Apelin peptide and its receptor APJ are directly implicated in various physiological processes ranging from cardiovascular homeostasis to immune signaling. Here, we show that apelin is a key player in hemostasis with an ability to inhibit thrombin-and collagenmediated platelet activation. Mice lacking apelin displayed a shorter bleeding time and a prothrombotic profile. Their platelets exhibited increased adhesion and a reduced occlusion time in venules, and displayed a higher aggregation rate after their activation by thrombin compared with wild-type platelets. Consequently, human and mouse platelets express apelin and its receptor APJ. Apelin directly interferes with thrombin-mediated signaling pathways and platelet activation, secretion, and aggregation, but not with ADP and thromboxane A 2 -mediated pathways. IV apelin administration induced excessive bleeding and prevented thrombosis in mice. Taken together, these findings suggest that apelin and/or APJ agonists could potentially be useful adducts in antiplatelet therapies and may provide a promising perspective for patients who continue to display adverse thrombotic events with current antiplatelet therapies. (Blood. 2016;127(7):908-920)

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Section: Discussionmentioning

confidence: 63%

Apelin: an antithrombotic factor that inhibits platelet function

Adam

Khatib

López

et al. 2016

Blood

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“…It is an experimental pharmaceutical treatment for acute coronary syndrome as a very powerful platelet inhibitor (21).In January 2011, the clinical trial was www.intechopen.com Antiplatelet Therapy in Cardiovascular Disease -Past, Present and Future 5 halted for patients with stroke and mild heart conditions due to safety reasons. It is unknown if it will continue.…”

Section: Proteasa-activated Receptors Antagonistmentioning

confidence: 99%

Antiplatelet Therapy in Cardiovascular Disease – Past, Present and Future

Brizzio¹

2012

Acute Coronary Syndromes

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“…Later, several laboratories have reported a few series of antagonists obtained from HTS of diverse libraries of non-peptide small molecules, followed by optimization [19,30]. The most advanced of these antagonists is SCH-530348 (named vorapaxar, Figure 1), derived from the natural product himbacine, which currently is undergoing Phase III clinical trials in patients with acute coronary syndrome and in patients with atherosclerosis [31][32][33]. Up to now, there is not structural information on the binding sites of these PAR1 antagonists to be used for structure-based design of new antagonists.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of new peptide-based ureas and thioureas as potential antagonists of the thrombin receptor PAR1

Ventosa-Andrés

Valdivielso

Pappos

et al. 2012

European Journal of Medicinal Chemistry

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By applying a diversity oriented synthesis strategy for the search of new antagonists of the thrombin receptor PAR1, a series of peptide-based ureas and thioureas, including analogues of the PAR1 reference antagonist RWJ-58259, has been designed and synthesized. The general synthetic scheme involves reduction of basic amino acid-derived amino nitriles by hydrogen transfer from hydrazine monohydrate in the presence of Raney Ni, followed by reaction with diverse isocyanates and isothiocyanates, and protecting group removal. All new compounds have been evaluated as inhibitors of human platelet aggregation induced by the PAR1 agonist SFLLRN. Some protected peptide-based ureas displayed significant antagonist activity.

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Discovery of a Novel, Orally Active Himbacine-Based Thrombin Receptor Antagonist (SCH 530348) with Potent Antiplatelet Activity

Cited by 242 publications

References 34 publications

Apelin: an antithrombotic factor that inhibits platelet function

Apelin: an antithrombotic factor that inhibits platelet function

Antiplatelet Therapy in Cardiovascular Disease – Past, Present and Future

Design, synthesis and biological evaluation of new peptide-based ureas and thioureas as potential antagonists of the thrombin receptor PAR1

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