Evolution of a Highly Selective and Potent 2-(Pyridin-2-yl)-1,3,5-triazine Tie-2 Kinase Inhibitor

Hodous, Brian L.; Geuns‐Meyer, Stephanie; Hughes, Paul E.; Albrecht, Brian K.; Bellon, S.F.; Bready, James; Caenepeel, Sean; Cee, Victor J.; Chaffee, Stuart C.; Coxon, Angela; Emery, Maurice G.; Fretland, Jenne; Gallant, Paul; Gu, Yun; Hoffman, Doug; Johnson, Rebecca; Kendall, Richard; Kim, Joseph L.; Long, Alexander; Morrison, Michael J.; Olivieri, Philip R.; Patel, Vinod F.; Polverino, Anthony; Rose, Paul; Tempest, Paul; Wang, Ling; Whittington, Douglas A.; Zhao, Huilin

doi:10.1021/jm061107l

Cited by 86 publications

(81 citation statements)

References 37 publications

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“…The structures used were 1YWN [29], 2P2H [30], 2P2I [30] for KDR, 1E9H [31] and 1QMZ [32] for CDK2, and 1IEP [33] for ABL.…”

Section: Methodsmentioning

confidence: 99%

Can we use docking and scoring for hit-to-lead optimization?

Enyedy¹,

Egan²

2008

J Comput Aided Mol Des

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Docking and scoring is currently one of the tools used for hit finding and hit-to-lead optimization when structural information about the target is known. Docking scores have been found useful for optimizing ligand binding to reproduce experimentally observed binding modes. The question is, can docking and scoring be used reliably for hit-to-lead optimization? To illustrate the challenges of scoring for hit-to-lead optimization, the relationship of docking scores with experimentally determined IC(50) values measured in-house were tested. The influences of the particular target, crystal structure, and the precision of the scoring function on the ability to differentiate between actives and inactives were analyzed by calculating the area under the curve of receiver operator characteristic curves for docking scores. It was found that for the test sets considered, MW and sometimes ClogP were as useful as GlideScores and no significant difference was observed between SP and XP scores for differentiating between actives and inactives. Interpretation by an expert is still required to successfully utilize docking and scoring in hit-to-lead optimization.

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“…The structures used were 1YWN [29], 2P2H [30], 2P2I [30] for KDR, 1E9H [31] and 1QMZ [32] for CDK2, and 1IEP [33] for ABL.…”

Section: Methodsmentioning

confidence: 99%

Can we use docking and scoring for hit-to-lead optimization?

Enyedy¹,

Egan²

2008

J Comput Aided Mol Des

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“…PI3 K activates Akt which in turn phosphorylates and activates the Forkhead transcription factor FOXO-1 (FKHR-1). FKHR-1 is a strong inducer of Ang-2 expression and inhibits Ang-2 liberation [71][72][73][74][75]. Activation of Akt also stimulates the phosphorylation and thereby the inhibition of pro-apoptotic proteins, including BAD and procaspase-9 [72,76].…”

Section: Endothelial Cell Survival and Maintenancementioning

confidence: 99%

The role of the Angiopoietins in vascular morphogenesis

2009

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The Angiopoietin/Tie system acts as a vascular specific ligand/receptor system to control endothelial cell survival and vascular maturation. The Angiopoietin family includes four ligands (Angiopoietin-1, Angiopoietin-2 and Angiopoietin-3/4) and two corresponding tyrosine kinase receptors (Tie1 and Tie2). Ang-1 and Ang-2 are specific ligands of Tie2 binding the receptor with similar affinity. Tie2 activation promotes vessel assembly and maturation by mediating survival signals for endothelial cells and regulating the recruitment of mural cells. Ang-1 acts in a paracrine agonistic manner inducing Tie2 phosphorylation and subsequent vessel stabilization. In contrast, Ang-2 is produced by endothelial cells and acts as an autocrine antagonist of Ang-1-mediated Tie2 activation. Ang-2 thereby primes the vascular endothelium to exogenous cytokines and induces vascular destabilization at higher concentrations. Ang-2 is strongly expressed in the vasculature of many tumors and it has been suggested that Ang-2 may act synergistically with other cytokines such as vascular endothelial growth factor to promote tumor-associated angiogenesis and tumor progression. The better mechanistic understanding of the Ang/Tie system is gradually paving the way toward the rationale exploitation of this vascular signaling system as a therapeutic target for neoplastic and non-neoplastic diseases.

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“…Even with the sterically hindered 1-naphthylboronic acid, quantitative conversion was achieved in the presence of 0.01 mol % of Pd catalyst (Table 3, entries [13][14][15][16][17][18][19]. Difficult substrates such as the highly basic 4-amino-2-chloropyridine reacted with p-tolyl- boronic acid or 1-naphthylboronic acid to afford quantitative conversions at 0.01 mol % catalyst loading (Table 3, entries 8, 16).…”

Section: Suzuki Cross-coupling Of N-heterocyclesmentioning

confidence: 99%

“…[1][2][3][4][5][6] Consequently, a sizable portion of recent US patents reports on organic process development of aromatic heterocycles. [7,8] A useful synthetic tool for the modification of such compounds is the SuzukiMiyaura coupling, [9,10] which has been applied for the preparation of arylpyridines, [11,12] bipyridines, [11][12][13][14][15] arylpyrimidines, [16][17][18] pyridopyridines [11,12,[19][20][21] and aryltriazines, [22,23] the synthesis of nucleosides [24,25] or the introduction of thiophene, [26,27] benzothiazole [28] or indolyl [29][30][31][32] moieties. Nonetheless, the cross-coupling chemistry of heterocyclic substrates suffers from limitations.…”

Section: Introductionmentioning

confidence: 99%

Highly Efficient Suzuki–Miyaura Coupling of Heterocyclic Substrates through Rational Reaction Design

Fleckenstein

Plenio

2008

Chemistry A European J

120

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A dicyclohexyl(2-sulfo-9-(3-(4-sulfophenyl)propyl)-9H-fluoren-9-yl)phosphonium salt was synthesized in 64% overall yield in three steps from simple commercially available starting materials. The highly water-soluble catalyst obtained from the corresponding phosphine and [Na(2)PdCl(4)] enabled the Suzuki coupling of a broad variety of N- and S-heterocyclic substrates. Chloropyridines (-quinolines) and aryl chlorides were coupled with aryl-, pyridine- or indoleboronic acids in quantitative yields in water/n-butanol solvent mixtures in the presence of 0.005-0.05 mol % of Pd catalyst at 100 degrees C, chloropurines were quantitatively Suzuki coupled in the presence of 0.5 mol % of catalyst, and S-heterocyclic aryl chlorides and aryl- or 3-pyridylboronic acids required 0.01-0.05 mol % Pd catalyst for full conversion. The key to the high activity of the Pd-phosphine catalyst is the rational design of the reaction parameters (i.e., the presence of water in the reaction mixture, good solubility of reactants and catalyst in n-butanol/water (3:1), and the electron-rich and sterically demanding nature of the phosphine ligand).

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Evolution of a Highly Selective and Potent 2-(Pyridin-2-yl)-1,3,5-triazine Tie-2 Kinase Inhibitor

Cited by 86 publications

References 37 publications

Can we use docking and scoring for hit-to-lead optimization?

Can we use docking and scoring for hit-to-lead optimization?

The role of the Angiopoietins in vascular morphogenesis

Highly Efficient Suzuki–Miyaura Coupling of Heterocyclic Substrates through Rational Reaction Design

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