Discovery of 9-(1-phenoxyethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as oral PI3Kβ inhibitors, useful as antiplatelet agents

Giordanetto, Fabrizio; Barlaam, Bernard; Berglund, Susanne; Edman, K. A. P.; Karlsson, Olle; Lindberg, Jimmy; Nylander, Sven; Inghardt, Tord

doi:10.1016/j.bmcl.2014.07.007

Cited by 22 publications

(12 citation statements)

References 36 publications

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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%

Platelets Are Critical Key Players in Sepsis

Vardon-Bounes

Ruiz

Gratacap

et al. 2019

IJMS

124

100

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Host defense against infection is based on two crucial mechanisms: the inflammatory response and the activation of coagulation. Platelets are involved in both hemostasis and immune response. These mechanisms work together in a complex and synchronous manner making the contribution of platelets of major importance in sepsis. This is a summary of the pathophysiology of sepsis-induced thrombocytopenia, microvascular consequences, platelet-endothelial cells and platelet–pathogens interactions. The critical role of platelets during sepsis and the therapeutic implications are also reviewed.

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Section: Therapeutic Implicationsmentioning

confidence: 99%

Platelets Are Critical Key Players in Sepsis

Vardon-Bounes

Ruiz

Gratacap

et al. 2019

IJMS

124

100

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“…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%

Synthesis and in vitro antiplatelet aggregation screening of novel fluorinated diethyl-2-(benzylthio)-2,3-dihydro-1H-imidazole-4,5-dicarboxylate derivatives

et al. 2014

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Seven fluorinated derivatives of diethyl-2-(benzylthio)-2,3-dihydro-1H-imidazole-4,5-dicarboxylate (a-g) as well as a nitro and chloro derivative (h-i) were prepared in five steps from glycine, ethyl formate, diethyl oxalate, potassium thiocyanate and substituted benzyl bromides. The structures of the synthesised compounds were elucidated and verified using 1 H, 13 C and 2D NMR spectroscopy where appropriate. The synthesised compounds exhibited concentration dependent antiplatelet aggregation activity on both the thrombin and ADP-induced platelet aggregation. The 4-nitro and 4-fluoro compounds exhibited the highest activity from the compounds tested, with IC 50 values of 1.06 and 1.20 mM for the thrombininduced assay and 18.57 and 12.91 mM in the ADP-induced platelet aggregation assay respectively. Three of the compounds, the 3 00 ,4 00 -difluoro (6c), 4 00 -nitro (6h) and 3 00 -chloro (6i) derivatives, have reasonable activity in both of the assays and could have potential as broad spectrum antiplatelet inhibitors. With the exception of 6c, the fluoro derivatives were not as active as the nitro and chloro compounds.

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“…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%

Design, Synthesis and Biological Evaluation of Novel Benzothiazole Derivatives as Selective PI3Kβ Inhibitors

Cao

Cao²,

Liu

et al. 2016

Molecules

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Abstract:A novel series of PI3Kβ (Phosphatidylinositol-3-kinases beta subunit) inhibitors with the structure of benzothiazole scaffold have been designed and synthesized. All the compounds have been evaluated for inhibitory activities against PI3Kα, β, γ, δ and mTOR (Mammalian target of rapamycin). Two superior compounds have been further evaluated for the IC 50 values against PI3Ks/mTOR. The most promising compound 11 displays excellent anti-proliferative activity and selectivity in multiple cancer cell lines, especially in the prostate cancer cell line. Docking studies indicate the morpholine group in 2-position of benzothiazole is necessary for the potent antitumor activity, which confirms our design is reasonable.

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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

Cited by 22 publications

References 36 publications

Platelets Are Critical Key Players in Sepsis

Platelets Are Critical Key Players in Sepsis

Synthesis and in vitro antiplatelet aggregation screening of novel fluorinated diethyl-2-(benzylthio)-2,3-dihydro-1H-imidazole-4,5-dicarboxylate derivatives

Design, Synthesis and Biological Evaluation of Novel Benzothiazole Derivatives as Selective PI3Kβ Inhibitors

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