Literature DB >> 22305493

Discovery of a new class of ghrelin receptor antagonists.

Jeffrey T Mihalic1, Yong-Jae Kim, Mike Lizarzaburu, Xiaoqi Chen, Jeff Deignan, Malgorzata Wanska, Ming Yu, Jiasheng Fu, Xi Chen, Alex Zhang, Richard Connors, Lingming Liang, Michelle Lindstrom, Ji Ma, Liang Tang, Kang Dai, Leping Li.   

Abstract

A series of benzodiazepine antagonists of the human ghrelin receptor GHSR1a were synthesized and their antagonism and metabolic stability were evaluated. The potency of these analogs was determined using a functional aequorin (Euroscreen) luminescent assay measuring the intracellular Ca(2+) concentration, and their metabolic stability was measured using an in vitro rat and human S9 hepatocyte assay. These efforts led to the discovery of a potent ghrelin antagonist with good rat pharmacokinetic properties.
Copyright © 2012 Elsevier Ltd. All rights reserved.

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Year:  2012        PMID： 22305493     DOI： 10.1016/j.bmcl.2012.01.014

Source DB:  PubMed          Journal:  Bioorg Med Chem Lett        ISSN： 0960-894X            Impact factor:   2.823


  5 in total

1.  Scalable and chromatography-free synthesis of 2-(2-formylalkyl)arenecarboxylic acid derivatives through the supramolecularly controlled hydroformylation of vinylarene-2-carboxylic acids.

Authors:  Paweł Dydio; Joost N H Reek
Journal:  Nat Protoc       Date:  2014-04-24       Impact factor: 13.491

2.  G Protein and β-arrestin signaling bias at the ghrelin receptor.

Authors:  Tama Evron; Sean M Peterson; Nikhil M Urs; Yushi Bai; Lauren K Rochelle; Marc G Caron; Larry S Barak
Journal:  J Biol Chem       Date:  2014-09-26       Impact factor: 5.157

3.  Pharmacological characterization of the first in class clinical candidate PF-05190457: a selective ghrelin receptor competitive antagonist with inverse agonism that increases vagal afferent firing and glucose-dependent insulin secretion ex vivo.

Authors:  J Kong; J Chuddy; I A Stock; P M Loria; S V Straub; C Vage; K O Cameron; S K Bhattacharya; K Lapham; K F McClure; Y Zhang; V M Jackson
Journal:  Br J Pharmacol       Date:  2016-03-17       Impact factor: 8.739

4.  Discovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate.

Authors:  Samit K Bhattacharya; Kim Andrews; Ramsay Beveridge; Kimberly O Cameron; Chiliu Chen; Matthew Dunn; Dilinie Fernando; Hua Gao; David Hepworth; V Margaret Jackson; Vishal Khot; Jimmy Kong; Rachel E Kosa; Kimberly Lapham; Paula M Loria; Allyn T Londregan; Kim F McClure; Suvi T M Orr; Jigna Patel; Colin Rose; James Saenz; Ingrid A Stock; Gregory Storer; Maria VanVolkenburg; Derek Vrieze; Guoqiang Wang; Jun Xiao; Yingxin Zhang
Journal:  ACS Med Chem Lett       Date:  2014-02-24       Impact factor: 4.345

5.  Evaluation and synthesis of polar aryl- and heteroaryl spiroazetidine-piperidine acetamides as ghrelin inverse agonists.

Authors:  Suvi T M Orr; Ramsay Beveridge; Samit K Bhattacharya; Kimberly O Cameron; Steven Coffey; Dilinie Fernando; David Hepworth; Margaret V Jackson; Vishal Khot; Rachel Kosa; Kimberly Lapham; Paula M Loria; Kim F McClure; Jigna Patel; Colin Rose; James Saenz; Ingrid A Stock; Gregory Storer; Maria von Volkenburg; Derek Vrieze; Guoqiang Wang; Jun Xiao; Yingxin Zhang
Journal:  ACS Med Chem Lett       Date:  2014-12-14       Impact factor: 4.345
  5 in total

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