title: Improvement in oral bioavailability of 2,4-diaminopyrimidine c-Met inhibitors by incorporation of a 3-amidobenzazepin-2-one group.
abstract: The hepatocyte growth factor (HGF)-c-Met signaling axis is involved in the mediation of many biological activities, including angiogenesis, proliferation, cell survival, cell motility, and morphogenesis. Dysregulation of c-Met signaling (e.g., overexpression or increased activation) is associated with the proliferation and metastasis of a wide range of tumor types, including breast, liver, lung, colorectal, gastric, bladder, and prostate, among others. Inhibiting the HGF-c-Met pathway is predicted to lead to anti-tumor effects in many cancers. Elaboration of the SAR around a series of 2,4-diaminopyrimidines led to a number of c-Met inhibitors in which pharmaceutical properties were modulated by substituents appended on the C2-benzazepinone ring. In particular, certain-3-amidobenzazepin-2-one analogs had improved oral bioavailability and were evaluated in PK/PD and efficacy models. Lead compounds demonstrated tumor stasis with partial regressions when evaluated in a GTL-16 tumor xenograft mouse model.
authors.affiliation: Worldwide Discovery Research, Cephalon, Inc. 145 Brandywine Parkway, West Chester, PA 19380-4245, USA. kmilkiew@cephalon.com
authors.forename: Karen L
authors.initials: KL
authors.lastname: Milkiewicz
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: Hong
authors.initials: H
authors.lastname: Chang
authors.forename: Jennifer V
authors.initials: JV
authors.lastname: Grobelny
authors.forename: Jean
authors.initials: J
authors.lastname: Husten
authors.forename: Christine
authors.initials: C
authors.lastname: Losardo
authors.forename: Sheila
authors.initials: S
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: Linda R
authors.initials: LR
authors.lastname: Weinberg
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: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D001552:Benzazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D001682:Biological Availability; D005260:Female; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001552:Benzazepines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C017205:2,4-diaminopyrimidine; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met