Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors.
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.
Hammond
Marlys
M
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
Washburn
David G
DG
Hoang
H Tram
HT
Manns
Sharada
S
Frazee
James S
JS
Nakamura
Hiroko
H
Patterson
Jaclyn R
JR
Trizna
Walter
W
Wu
Charlene
C
Azzarano
Leonard M
LM
Nagilla
Rakesh
R
Nord
Melanie
M
Trejo
Rebecca
R
Head
Martha S
MS
Zhao
Baoguang
B
Smallwood
Angela M
AM
Hightower
Kendra
K
Laping
Nicholas J
NJ
Schnackenberg
Christine G
CG
Thompson
Scott K
SK
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
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