title: Discovery and SAR of a Series of Agonists at Orphan G Protein-Coupled Receptor 139.
abstract: GPR139 is an orphan G-protein coupled receptor (GPCR) which is primarily expressed in the central nervous system (CNS). In order to explore the biological function of this receptor, selective tool compounds are required. A screening campaign identified compound 1a as a high potency GPR139 agonist with an EC50 = 39 nM in a calcium mobilization assay in CHO-K1 cells stably expressing the GPR139 receptor. In the absence of a known endogenous ligand, the maximum effect was set as 100% for 1a. Screening against 90 diverse targets revealed no cross-reactivity issues. Assessment of the pharmacokinetic properties showed limited utility as in vivo tool compound in rat with a poor whole brain exposure of 61 ng/g and a brain/plasma (b/p) ratio of 0.03. Attempts to identify a more suitable analogue identified the des-nitrogen analogue 1s with a reduced polar surface area of 76.7 Å(2) and an improved b/p ratio of 2.8. The whole brain exposure remained low at 95 ng/g due to a low plasma exposure.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu-Chong-Zhi Road, Shanghai 201203, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Shi
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu-Chong-Zhi Road, Shanghai 201203, China.
authors.forename: Jing Kang
authors.initials: JK
authors.lastname: Shen
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu-Chong-Zhi Road, Shanghai 201203, China.
authors.forename: Danqi
authors.initials: D
authors.lastname: Chen
authors.affiliation: Neuroscience Drug Discovery Denmark , H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Copenhagen, Valby, Denmark.
authors.forename: Karina
authors.initials: K
authors.lastname: Fog
authors.affiliation: Neuroscience Drug Discovery Denmark , H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Copenhagen, Valby, Denmark.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Thirstrup
authors.affiliation: Neuroscience Drug Discovery Denmark , H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Copenhagen, Valby, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Hentzer
authors.affiliation: Neuroscience Drug Discovery Denmark , H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Copenhagen, Valby, Denmark.
authors.forename: Jens-Jakob
authors.initials: JJ
authors.lastname: Karlsson
authors.affiliation: Lundbeck Research USA , 215 College Road, Paramus, New Jersey 07652-1431, United States.
authors.forename: Veena
authors.initials: V
authors.lastname: Menon
authors.affiliation: Lundbeck Research USA , 215 College Road, Paramus, New Jersey 07652-1431, United States.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jones
authors.affiliation: Lundbeck Research USA , 215 College Road, Paramus, New Jersey 07652-1431, United States.
authors.forename: Kelli E
authors.initials: KE
authors.lastname: Smith
authors.affiliation: Neuroscience Drug Discovery Denmark , H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Copenhagen, Valby, Denmark.
authors.forename: Garrick
authors.initials: G
authors.lastname: Smith
keywords: CNS; G-protein coupled receptor; Orphan GPR-139; agonists; hydrazinecarboxamide