title: Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors: 3. Evaluation of 5-amino-linked thiazolo[5,4-d]pyrimidine and thiazolo[5,4-b]pyridine derivatives.
abstract: Our aim was to discover RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors that possess strong activity and sufficient oral absorption, and thus, we selected a 5-amino-linked thiazolo[5,4-d]pyrimidine derivative as the lead compound because of its potential kinase inhibitory activities and its desired solubility. The novel tertiary 1-cyano-1-methylethoxy substituent was designed to occupy the hydrophobic region of 'back pocket' of BRAF on the basis of the X-ray co-crystal structure data of BRAF. In addition, we found that N-methylation of the amine linker could control the twisted molecular conformation leading to improved solubility. These approaches produced N-methyl thiazolo[5,4-b]pyridine-5-amine derivative 5. To maximize the in vivo efficacy, we attempted salt formation of 5. Our result indicated that the besylate monohydrate salt form (5c) showed significant improvement of both solubility and oral absorption. Owing to the improved physicochemical properties, compound 5c demonstrated regressive antitumor efficacy in a HT-29 xenograft model.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited: 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. masaaki.hirose@takeda.com
authors.forename: Masaaki
authors.initials: M
authors.lastname: Hirose
authors.forename: Masanori
authors.initials: M
authors.lastname: Okaniwa
authors.forename: Tohru
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Imada
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ohashi
authors.forename: Yuta
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Takeo
authors.initials: T
authors.lastname: Arita
authors.forename: Masato
authors.initials: M
authors.lastname: Yabuki
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Shunichirou
authors.initials: S
authors.lastname: Tsutsumi
authors.forename: Akihiko
authors.initials: A
authors.lastname: Sumita
authors.forename: Terufumi
authors.initials: T
authors.lastname: Takagi
authors.forename: Bi-Ching
authors.initials: BC
authors.lastname: Sang
authors.forename: Jason
authors.initials: J
authors.lastname: Yano
authors.forename: Kathleen
authors.initials: K
authors.lastname: Aertgeerts
authors.forename: Sei
authors.initials: S
authors.lastname: Yoshida
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Ishikawa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D019073:HT29 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D051379:Mice; D008861:Microsomes / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; C039201:thiazolo(3,2-a)perimidine; D040301:Vascular Endothelial Growth Factor Receptor-2