2014
DOI: 10.1016/j.bmcl.2014.07.007
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Discovery of 9-(1-phenoxyethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as oral PI3Kβ inhibitors, useful as antiplatelet agents

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Cited by 22 publications
(12 citation statements)
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“…Class I phosphoinositide 3-kinase β (PI3Kβ) could be an interesting target for antithrombotic therapy in sepsis. In fact, this PI 3-kinase isoform is shown to play an important role in thrombus formation and stability [77,78,79,80,81]. In vivo, isoform-selective PI3Kβ inhibitors eliminate occlusive thrombus formation but do not prolong bleeding time.…”
Section: Therapeutic Implicationsmentioning
confidence: 99%
“…Class I phosphoinositide 3-kinase β (PI3Kβ) could be an interesting target for antithrombotic therapy in sepsis. In fact, this PI 3-kinase isoform is shown to play an important role in thrombus formation and stability [77,78,79,80,81]. In vivo, isoform-selective PI3Kβ inhibitors eliminate occlusive thrombus formation but do not prolong bleeding time.…”
Section: Therapeutic Implicationsmentioning
confidence: 99%
“…Clopidogrel is a thienopyridine and the choice of drug for the prevention of thrombosis associated with cardiovascular stenting; however, 20-40 % of patients respond poorly to this, and therefore, alternatives such as prasugrel, vicagrel, ticagrelor, cangrelor and elmogrel are being used instead (Zhang and Hollenberg, 2014). Recent developments in platelet aggregation inhibitors have been the identification of a preclinical candidate (SAR216471), an indole-3-carboxamide that irreversibly binds to the P2Y12 receptor involved in adenosine diphosphate (ADP) stimulated platelet activation of the glycoprotein IIb/IIIa (Boldron et al, 2014), 2-phenylpyrimidine-4-carboxamides as orally bioavailable and selective P2Y12 antagonists (Caroff et al, 2014), a pyrimidine-7-carboxamide, an orally bioavailable PI3Kb inhibitor with potent in vivo anti-thrombotic effects (Giordanetto et al, 2014) and a tick peptide YY-39, which was found to inhibit platelet aggregation induced by ADP, thrombin and thromboxane A2(TXA2) (Tang et al, 2014).…”
Section: Introductionmentioning
confidence: 99%
“…Since numerous studies have suggested that the interaction to the hinge region is crucial to PI3K inhibitory activity [18,19], the interaction with VAL848 is essential to all kinds of PI3K inhibitor. In this model (Figure 3), Compound 11 and GDC-0941 can overlap in the position of morpholine group and both of the morpholine groups bond to the hinge region via the main-chain nitrogen of VAL848.…”
Section: Resultsmentioning
confidence: 99%