title: Identification of 4-piperazin-1-yl-quinazoline template based aryl and benzyl thioureas as potent, selective, and orally bioavailable inhibitors of platelet-derived growth factor (PDGF) receptor.
abstract: 4-[4-(N-Substituted-thio-carbamoyl)-1-piperazinyl]-6-methoxy-7-alkoxyamino-quinazoline derivatives such as 14 (CT53986) have been identified to be potent and selective inhibitors of the phosphorylation of PDGFR. SAR-investigations are described in the arylamine segment, C-7 appendage, and the thiourea moiety. Bioisosteres of thiourea (cyanoguanidine), and of quinazoline (quinoline-3-carbonitrile) were synthesized and are compared for their in vitro inhibitory activity. PK profiles of the optimized compounds in rat, dog, and cynomolgus monkey are described.
authors.affiliation: Departments of Medicinal Chemistry, Biology, DMPK, and In Vivo Sciences Millennium Pharmaceuticals, Inc., 256 E. Grand Avenue, South San Francisco, CA 94080, USA. jheath@portola.com
authors.forename: Julie A
authors.initials: JA
authors.lastname: Heath
authors.forename: Mukund M
authors.initials: MM
authors.lastname: Mehrotra
authors.forename: Shannon
authors.initials: S
authors.lastname: Chi
authors.forename: Jin-Chen
authors.initials: JC
authors.lastname: Yu
authors.forename: Athiwat
authors.initials: A
authors.lastname: Hutchaleelaha
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Hollenbach
authors.forename: Neill A
authors.initials: NA
authors.lastname: Giese
authors.forename: Robert M
authors.initials: RM
authors.lastname: Scarborough
authors.forename: Anjali
authors.initials: A
authors.lastname: Pandey
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D008252:Macaca fascicularis; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D011799:Quinazolines; D017479:Receptors, Platelet-Derived Growth Factor; D013890:Thiourea