title: 2,4-Diaminopyrimidine inhibitors of c-Met kinase bearing benzoxazepine anilines.
abstract: Elaboration of the SAR around a series of 2,4-diaminopyrimidines led to a number of c-Met inhibitors in which kinase selectivity was modulated by substituents appended on the C4-aminobenzamide ring and the nature of the C2-aminoaryl ring. Further lead optimization of the C2-aminoaryl group led to benzoxazepine analogs whose pharmaceutical properties were modulated by the nature of the substituent on the benzoxazepine nitrogen. Tumor stasis (with partial regressions) were observed when an orally bioavailable analog was evaluated in a GTL-16 tumor xenograft mouse model. Subsequent PK/PD studies suggested that a metabolite contributed to the overall in vivo response.
authors.affiliation: Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. czificsa@cephalon.com
authors.forename: Craig A
authors.initials: CA
authors.lastname: Zificsak
authors.forename: Jay P
authors.initials: JP
authors.lastname: Theroff
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
authors.forename: Mark S
authors.initials: MS
authors.lastname: Albom
authors.forename: Thelma S
authors.initials: TS
authors.lastname: Angeles
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Brown
authors.forename: Deborah
authors.initials: D
authors.lastname: Galinis
authors.forename: Jennifer V
authors.initials: JV
authors.lastname: Grobelny
authors.forename: Torsten
authors.initials: T
authors.lastname: Herbertz
authors.forename: Jean
authors.initials: J
authors.lastname: Husten
authors.forename: Laura S
authors.initials: LS
authors.lastname: Kocsis
authors.forename: Christine
authors.initials: C
authors.lastname: LoSardo
authors.forename: Sheila J
authors.initials: SJ
authors.lastname: Miknyoczki
authors.forename: Seetha
authors.initials: S
authors.lastname: Murthy
authors.forename: Damaris
authors.initials: D
authors.lastname: Rolon-Steele
authors.forename: Ted L
authors.initials: TL
authors.lastname: Underiner
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Wells-Knecht
authors.forename: Candace S
authors.initials: CS
authors.lastname: Worrell
authors.forename: Kelli S
authors.initials: KS
authors.lastname: Zeigler
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Dorsey
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C017205:2,4-diaminopyrimidine; D019859:Proto-Oncogene Proteins c-met