title: Discovery of 5-pyrrolopyridinyl-2-thiophenecarboxamides as potent AKT kinase inhibitors.
abstract: A pyrrolopyridinyl thiophene carboxamide 7 was discovered as a tractable starting point for a lead optimization effort in an AKT kinase inhibition program. SAR studies aided by a co-crystal structure of 7 in AKT2 led to the identification of AKT inhibitors with subnanomolar potency. Representative compounds showed antiproliferative activity as well as inhibition of phosphorylation of the downstream target GSK3beta.
authors.affiliation: Oncology Chemistry, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Seefeld
authors.forename: Meagan B
authors.initials: MB
authors.lastname: Rouse
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: McNulty
authors.forename: Lihui
authors.initials: L
authors.lastname: Sun
authors.forename: Jizhou
authors.initials: J
authors.lastname: Wang
authors.forename: Dennis S
authors.initials: DS
authors.lastname: Yamashita
authors.forename: Juan I
authors.initials: JI
authors.lastname: Luengo
authors.forename: Shuyun
authors.initials: S
authors.lastname: Zhang
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Minthorn
authors.forename: Nestor O
authors.initials: NO
authors.lastname: Concha
authors.forename: Dirk A
authors.initials: DA
authors.lastname: Heerding
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D058924:Thienopyridines; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C543087:5-pyrrolopyridinyl-2-thiophenecarboxamide; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D058924:Thienopyridines; D013876:Thiophenes; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt