- Structure-activity relationships for a novel series of pyrido[2,3- d]pyrimidine tyrosine kinase inhibitors
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Screening of a compound library for inhibitors of the fibroblast growth factor (FGFr) and platelet-derived growth factor (PDGFr) receptor tyrosine kinases led to the development of a novel series of ATP competitive pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors. The initial lead, 1-[2- amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-3-tert-butylurea (4b, PD-089828), was found to be a broadly active tyrosine kinase inhibitor. Compound 4b inhibited the PDGFr, FGFr, EGFr, and c-src tyrosine kinases with IC50 values of 1.11, 0.13, 0.45, and 0.22 μM, respectively. Subsequent SAR studies led to the synthesis of new analogs with improved potency, solubility, and bioavailability relative to the initial lead. For example, the introduction of a [4-(diethylamino)butyl]amino side chain into the 2- position of 4b afforded compound 6c with enhanced potency and bioavafiability. Compound 6c inhibited PDGF-stimulated vascular smooth muscle cell proliferation with an IC50 of 0.3 μM. Furthermore, replacement of the 6-(2,6-dichlorophenyl) moiety of 4b with a 6-(3',5'-dimethoxyphenyl) functionality produced a highly selective FGFr tyrosine kinase inhibitor 4e. Compound 4e inhibited the FGFr tyrosine kinase with an IC50 of 0.060 μM, whereas IC50s for the inhibiton of the PDGFr, FGFr, EGFr, c-src, and InsR tyrosine kinases for this compound (4e) were all greater than 50 μM.
- Hamby, James M.,Connolly, Cleo J. C.,Schroeder, Mel C.,Winters, R. Thomas,Showalter, H. D. Hollis,Panek, Robert L.,Major, Terry C.,Olsewski, Bronislawa,Ryan, Michael J.,Dahring, Tawny,Lu, Gina H.,Keiser, Joan,Amar, Aneesa,Shen, Cindy,Kraker, Alan J.,Slintak, Veronika,Nelson, James M.,Fry, David W.,Bradford, Laura,Hallak, Hussein,Doherty, Annette M.
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- Optimization and Mechanistic Characterization of Pyridopyrimidine Inhibitors of Bacterial Biotin Carboxylase
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A major challenge for new antibiotic discovery is predicting the physicochemical properties that enable small molecules to permeate Gram-negative bacterial membranes. We have applied physicochemical lessons from previous work to redesign and improve the antibacterial potency of pyridopyrimidine inhibitors of biotin carboxylase (BC) by up to 64-fold and 16-fold against Escherichia coli and Pseudomonas aeruginosa, respectively. Antibacterial and enzyme potency assessments in the presence of an outer membrane-permeabilizing agent or in efflux-compromised strains indicate that penetration and efflux properties of many redesigned BC inhibitors could be improved to various extents. Spontaneous resistance to the improved pyridopyrimidine inhibitors in P. aeruginosa occurs at very low frequencies between 10-8 and 10-9. However, resistant isolates had alarmingly high minimum inhibitory concentration shifts (16- to >128-fold) compared to the parent strain. Whole-genome sequencing of resistant isolates revealed that either BC target mutations or efflux pump overexpression can lead to the development of high-level resistance.
- Andrews, Logan D.,Kane, Timothy R.,Dozzo, Paola,Haglund, Cat M.,Hilderbrandt, Darin J.,Linsell, Martin S.,Machajewski, Timothy,McEnroe, Glen,Serio, Alisa W.,Wlasichuk, Kenneth B.,Neau, David B.,Pakhomova, Svetlana,Waldrop, Grover L.,Sharp, Marc,Pogliano, Joe,Cirz, Ryan T.,Cohen, Frederick
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p. 7489 - 7505
(2019/09/03)
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- Discovery and structure-activity studies of a novel series of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors
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The inhibition of tyrosine kinase-mediated signal transduction pathways represents a therapeutic approach to the intervention of proliferative diseases such as cancer, atherosclerosis, and restenosis. A novel series of pyrido[2,3-d]pyrimidine inhibitors of the PDGFr, bFGFr, and c-Src tyrosine kinases was developed from compound library screening and lead optimization.' In addition, highly selective inhibitors of the FGFr tyrosine kinase were also discovered and developed from this novel series of pyrido[2,3-d]pyrimidines. The syntheses, biological evaluation, and structure-activity relationships of this series are reported.
- Connolly, Cleo J. C.,Hamby, James M.,Schroeder, Mel C.,Barvian, Mark,Lu, Gina H.,Panek, Robert L.,Amar, Aneesa,Shen, Cindy,Kraker, Alan J.,Fry, David W.,Klohs, Wayne D.,Doherty, Annette M.
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p. 2415 - 2420
(2007/10/03)
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- Antihypertensive Activity of 6-Arylpyridopyrimidin-7-amine Derivatives
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A series of 51 6-arylpyridopyrimidin-7-amine derivatives was prepared and evaluated for antihypertensive activity in the conscious spontaneously hypertensive rat.A number of these compounds, notably 6-(2,6-dichlorophenyl)-2-methylpyridopyrimidin-7-amine (36), lowered blood pressure in these rats in a gradual and sustained manner to normotensive levels at oral doses of 10-50 mg/kg.Normalized blood pressure levels could then be maintained by single daily oral doses.The effect of structural variation in the 6-aryl group and in the 2 and 4 positions of the pyridopyrimidine ring on activity is reported and discussed.
- Bennett, Lawrence R.,Blankley, C. John,Fleming, Robert W.,Smith, Ronald D.,Tessman, Deirdre K.
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p. 382 - 389
(2007/10/02)
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