Strategies to lower the Pgp efflux liability in a series of potent indole azetidine MCHR1 antagonists

Kai Lu; Yu Jiang; Bin Chen; Eman M Eldemenky; Gil Ma; Mathivanan Packiarajan; Gamini Chandrasena; Andrew D White; Kenneth A Jones; Boshan Li; Sang-Phyo Hong

doi:10.1016/j.bmcl.2011.07.020

Strategies to lower the Pgp efflux liability in a series of potent indole azetidine MCHR1 antagonists

Bioorg Med Chem Lett. 2011 Sep 15;21(18):5310-4. doi: 10.1016/j.bmcl.2011.07.020. Epub 2011 Jul 14.

Authors

Kai Lu¹, Yu Jiang, Bin Chen, Eman M Eldemenky, Gil Ma, Mathivanan Packiarajan, Gamini Chandrasena, Andrew D White, Kenneth A Jones, Boshan Li, Sang-Phyo Hong

Affiliation

¹ Department of Chemical and Pharmacokinetic Sciences, Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, USA.

PMID: 21802292
DOI: 10.1016/j.bmcl.2011.07.020

Abstract

A series of potent indolyl azetidine rMCHR1 antagonists were found to show poor CNS penetration due to Pgp efflux. We envisioned a strategy which included: lowering basicity; changing the conformational flexibility motif; and removal of a hydrogen bond donor, in an attempt to optimize this property while maintaining target receptor efficacy. This work resulted in mitigation of Pgp efflux, and led us to identify 1-dihydroindolyl azetidine derivatives with CNS penetration and excellent rMCHR1 binding affinity.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / deficiency
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
Animals
Azetidines / chemical synthesis
Azetidines / chemistry
Azetidines / pharmacology*
Hydrogen Bonding
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Mice
Mice, Knockout
Molecular Structure
Rats
Receptors, Somatostatin / antagonists & inhibitors*
Receptors, Somatostatin / metabolism
Stereoisomerism

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Azetidines
Indoles
MCHR1 protein, rat
Receptors, Somatostatin
indole