Soluble 2-Substituted Aminopyrido[2,3-d]pyrimidin-7-yl Ureas. Structure−Activity Relationships against Selected Tyrosine Kinases and Exploration of in Vitro and in Vivo Anticancer Activity

• Published in: Journal of medicinal chemistry Vol. 44; no. 12; pp. 1915 - 1926
• Main Authors: Schroeder, Mel C, Hamby, James M, Connolly, Cleo J. C, Grohar, Patrick J, Winters, R. Thomas, Barvian, Mark R, Moore, Charles W, Boushelle, Stacey L, Crean, Sheila M, Kraker, Alan J, Driscoll, Denise L, Vincent, Patrick W, Elliott, William L, Lu, Gina H, Batley, Brian L, Dahring, Tawny K, Major, Terry C, Panek, Robert L, Doherty, Annette M, Showalter, H. D. Hollis
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 07.06.2001; Amer Chemical Soc
• Subjects: 3T3 Cells; Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Division - drug effects; Chemistry, Medicinal; Chemotherapy; Colonic Neoplasms; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; ErbB Receptors - antagonists & inhibitors; Glioma; Humans; Indicators and Reagents; Kinetics; Life Sciences & Biomedicine; Medical sciences; Mice; Molecular Conformation; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phosphorylation; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Rats; Receptors, Fibroblast Growth Factor - antagonists & inhibitors; Receptors, Platelet-Derived Growth Factor - antagonists & inhibitors; Recombinant Proteins - antagonists & inhibitors; Science & Technology; src-Family Kinases; Structure-Activity Relationship; Transfection; Tumor Cells, Cultured; Urea - analogs & derivatives; Urea - chemical synthesis; Urea - chemistry; Urea - pharmacology; GROWTH-FACTOR RECEPTOR; POTENT; SERIES; ANGIOGENESIS; INHIBITORS; IDENTIFICATION; COMBINATION; CANCER; DERIVATIVES; FAMILY; Antineoplastic agent; Nitrogen heterocycle; Structure activity relation; Chlorine Organic compounds; Bicyclic compound; Ureas; Colon; Chemical synthesis; Protein-tyrosine kinase; Human; Autophosphorylation; Enzyme; Transferases; Rodentia; Enzyme inhibitor; Malignant tumor; In vitro; In vivo; Vertebrata; Chemotherapy; Experimental disease; Growth factor receptor; Mammalia; Cell line; Treatment; Mouse; Animal; C-Onc gene; Tertiary amine; Digestive diseases
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0004291

In continuing our search for medicinal agents to treat proliferative diseases, we have discovered 2-substituted aminopyrido[2,3-d]pyrimidin-7-yl ureas as a novel class of soluble, potent, broadly active tyrosine kinase (TK) inhibitors. An efficient route was developed that enabled the synthesis of a wide variety of analogues with substitution on several positions of the template. From the lead structure 1, several series of analogues were made that examined the C-6 aryl substituent, a variety of water solublizing substitutents at the C-2 position, and urea or other acyl functionality at the N-7 position. Compounds of this series were competitive with ATP and displayed submicromolar to low nanomolar potency against a panel of TKs, including receptor (platelet-derived growth factor, PDGFr; fibroblast growth factor, FGFr;) and nonreceptor (c-Src) classes. Several of the most potent compounds displayed submicromolar inhibition of PDGF-mediated receptor autophosphorylation in rat aortic vascular smooth muscle cells and low micromolar inhibition of cellular growth in five human tumor cell lines. One of the more thoroughly evaluated members, 32, with IC50 values of 0.21 μM (PDGFr), 0.049 μM (bFGFr), and 0.018 μM (c-Src), was evaluated in in vivo studies against a panel of five human tumor xenografts, with known and/or inferred dependence on the EGFr, PDGFr, and c-Src TKs. Compound 32 produced a tumor growth delay of 14 days against the Colo-205 colon xenograft model.