title: Design and synthesis of orally available MEK inhibitors with potent in vivo antitumor efficacy.
abstract: The structure-based design, synthesis, and biological evaluation of two novel series of potent and selective MEK kinase inhibitors are described herein. The elaboration of a lead pyrrole derivative to a bicyclic dihydroindolone core provided compounds with high potency and good drug-like pharmaceutical properties. Further scaffold modification afforded a series of dihydroindolizinone inhibitors, including an orally available advanced preclinical MEK inhibitor with potent in vivo antitumor efficacy.
authors.affiliation: Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States. mark.adams@takedasd.com
authors.forename: Mark E
authors.initials: ME
authors.lastname: Adams
authors.forename: Michael B
authors.initials: MB
authors.lastname: Wallace
authors.forename: Toufike
authors.initials: T
authors.lastname: Kanouni
authors.forename: Nicholas
authors.initials: N
authors.lastname: Scorah
authors.forename: Shawn M
authors.initials: SM
authors.lastname: O'Connell
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyake
authors.forename: Lihong
authors.initials: L
authors.lastname: Shi
authors.forename: Petro
authors.initials: P
authors.lastname: Halkowycz
authors.forename: Lilly
authors.initials: L
authors.lastname: Zhang
authors.forename: Qing
authors.initials: Q
authors.lastname: Dong
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use; D015195:Drug Design; D019073:HT29 Cells; D006801:Humans; D007212:Indolizines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D011758:Pyrroles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D051381:Rats; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007212:Indolizines; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D020930:MAP Kinase Kinase Kinases