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

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Hammond M, Washburn DG, Hoang HT, Manns S, Frazee JS, Nakamura H, Patterson JR, Trizna W, Wu C, Azzarano LM, Nagilla R, Nord M, Trejo R, Head MS, Zhao B, Smallwood AM, Hightower K, Laping NJ, Schnackenberg CG, Thompson SK

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

Bioorg Med Chem Lett. 2009 Aug 1;19(15):4441-5. doi: 10.1016/j.bmcl.2009.05.051. Epub 2009 May 18.

PubMed ID
19497745 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
[4-(5-naphthalen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl]acetic acidSerine/threonine-protein kinase Sgk1IC 50 (nM)63N/AN/ADetails
[4-(5-naphthalen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl]acetic acidSerine/threonine-protein kinase Sgk1IC 50 (nM)880N/AN/ADetails
4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acidSerine/threonine-protein kinase Sgk1IC 50 (nM)40N/AN/ADetails
4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acidSerine/threonine-protein kinase Sgk1IC 50 (nM)1300N/AN/ADetails