Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors.

SGK1 inhibitors 1 and 2 suffered from poor oral exposure that could be attributed to factors such as high clearance and formation of glucuronic acid conjugates. Incorporation of appropriately-placed substituents was an effective means of reducing clearance and, in some cases, suppressing glucuronidation to provide SGK1 inhibitors with adequate exposure for in vivo studies.