title: Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors.
abstract: The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}acetic acid (2) suffer from low DNAUC values in rat, due in part to formation and excretion of glucuronic acid conjugates. These PK/glucuronidation issues were addressed either by incorporating a substituent on the 3-phenyl ring ortho to the key carboxylate functionality of 1 or by substituting on the group in between the carboxylate and phenyl ring of 2. Three of these analogs have been identified as having good SGK1 inhibition potency and have DNAUC values suitable for in vivo testing.
authors.affiliation: Department of Chemistry, Metabolic Pathways Centre for Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA. marlys.2.hammond@gsk.com
authors.forename: Marlys
authors.initials: M
authors.lastname: Hammond
authors.forename: David G
authors.initials: DG
authors.lastname: Washburn
authors.forename: H Tram
authors.initials: HT
authors.lastname: Hoang
authors.forename: Sharada
authors.initials: S
authors.lastname: Manns
authors.forename: James S
authors.initials: JS
authors.lastname: Frazee
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nakamura
authors.forename: Jaclyn R
authors.initials: JR
authors.lastname: Patterson
authors.forename: Walter
authors.initials: W
authors.lastname: Trizna
authors.forename: Charlene
authors.initials: C
authors.lastname: Wu
authors.forename: Leonard M
authors.initials: LM
authors.lastname: Azzarano
authors.forename: Rakesh
authors.initials: R
authors.lastname: Nagilla
authors.forename: Melanie
authors.initials: M
authors.lastname: Nord
authors.forename: Rebecca
authors.initials: R
authors.lastname: Trejo
authors.forename: Martha S
authors.initials: MS
authors.lastname: Head
authors.forename: Baoguang
authors.initials: B
authors.lastname: Zhao
authors.forename: Angela M
authors.initials: AM
authors.lastname: Smallwood
authors.forename: Kendra
authors.initials: K
authors.lastname: Hightower
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Laping
authors.forename: Christine G
authors.initials: CG
authors.lastname: Schnackenberg
authors.forename: Scott K
authors.initials: SK
authors.lastname: Thompson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005938:Glucocorticoids / Q000737:chemistry; D020723:Glucuronic Acid / Q000737:chemistry; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D047428:Protein Kinase Inhibitors / Q000037:antagonists & inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D020723:Glucuronic Acid; D017874:Immediate-Early Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases