Synthesis and structure-activity relationships of 7-substituted 3-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-ones as selective inhibitors of pp60(c-src)

• Published in: Journal of medicinal chemistry Vol. 43; no. 16; pp. 3134 - 3147
• Main Authors: Thompson, AM, Rewcastle, GW, Boushelle, SL, Hartl, BG, Kraker, AJ, Lu, GH, Batley, BL, Panek, RL, Showalter, HDH, Denny, WA
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 10.08.2000
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Division - drug effects; Cells, Cultured; Chemistry, Medicinal; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Life Sciences & Biomedicine; Mice; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; Naphthyridines - chemical synthesis; Naphthyridines - chemistry; Naphthyridines - pharmacology; Pharmacology & Pharmacy; Phosphorylation; Proto-Oncogene Proteins pp60(c-src) - antagonists & inhibitors; Proto-Oncogene Proteins pp60(c-src) - chemistry; Proto-Oncogene Proteins pp60(c-src) - metabolism; Receptor Protein-Tyrosine Kinases - chemistry; Receptor Protein-Tyrosine Kinases - metabolism; Receptor, Fibroblast Growth Factor, Type 1; Receptor, Platelet-Derived Growth Factor beta - chemistry; Receptor, Platelet-Derived Growth Factor beta - metabolism; Receptors, Fibroblast Growth Factor - chemistry; Receptors, Fibroblast Growth Factor - metabolism; Science & Technology; Structure-Activity Relationship; Tumor Cells, Cultured; TYROSINE KINASE INHIBITORS; GROWTH-FACTOR RECEPTOR; IN-VITRO; POTENT; ACTIVATION; PRODUCT; DERIVATIVES; 1,8-NAPHTHYRIDINES; DISCOVERY; C-SRC
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000148t

7-Substituted 3-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H) are potent inhibitors of protein tyrosine kinases, with some selectivity for c-Src. The compounds were prepared by condensing 4,6-diaminonicotinaldehyde with 2,6-dichlorophenylacetonitrile and selectively converting the 2- and 7-amino groups of the product to hydroxy and fluoro groups, respectively, by prolonged diazotization in 50% aqueous fluoboric acid. N-Methylation, followed by treatment with aliphatic diamines, aromatic amines, or their derived lithium anions, gave the desired compounds. Selected isomeric 1,8-naphthyridin-2(1H)-ones were also prepared in order to evaluate the relative contributions of both ring A aza atoms of the related pyrido[2,3-d]pyrimidin-7(8H)ones to the inhibitory activity. The compounds were evaluated for their ability to prevent phosphorylation of a model substrate by c-Src, FGF-1 receptor, and PDGF-beta receptor enzymes. Overall, there was a high degree of correlation of the activities against the different kinases, with c-Src being generally the most sensitive to structural changes. 1,6-Naphthyridin-2(1H)one analogues bearing basic aliphatic side chains [7-NH(CH2)(n)NRR, 7-NHPhO(CH2)(n)NRR, or 7-NHPhN(CH2)(4)NMe] were the most potent against c-Src (IC(50)s of 10-80 nM), showing good selectivity with respect to PDGFR (10-300-fold) but less with respect to FGFR.. The 1,6-naphthyridin-2(1H)-ones showed broadly similar activity to the analogous pyrido[2,3-d]pyrimidin-7(8H)-ones, whereas the 1,8-naphthyridin-2(1H)-ones were at least 10(3)-fold less potent. These results, indicating that the 3-aza atom in the pyrido[2,3-d]pyrimidin-7(8H)-ones is mandatory, whereas the 1-aza atom is not, support the published binding model for these compounds to c-Src (J. Med. Chem. 1998, 41, 1752), where the 3-aza and 2-NH atoms form a bidentate H-bond donor-acceptor motif that interacts with Met341 and the 1-aza atom is not involved in specific binding interactions.