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-1 H -pyrrolo[2,3- b ]pyridin-3-yl)benzoic acid ( 1 ) and {4-[5-(2-naphthalenyl)-1 H -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.