Literature DB >> 24900864

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

Samit K Bhattacharya1, Kim Andrews1, Ramsay Beveridge1, Kimberly O Cameron1, Chiliu Chen1, Matthew Dunn1, Dilinie Fernando1, Hua Gao1, David Hepworth1, V Margaret Jackson1, Vishal Khot1, Jimmy Kong1, Rachel E Kosa1, Kimberly Lapham1, Paula M Loria1, Allyn T Londregan1, Kim F McClure1, Suvi T M Orr1, Jigna Patel1, Colin Rose1, James Saenz1, Ingrid A Stock1, Gregory Storer1, Maria VanVolkenburg1, Derek Vrieze1, Guoqiang Wang1, Jun Xiao1, Yingxin Zhang1.   

Abstract

The identification of potent, highly selective orally bioavailable ghrelin receptor inverse agonists from a spiro-azetidino-piperidine series is described. Examples from this series have promising in vivo pharmacokinetics and increase glucose-stimulated insulin secretion in human whole and dispersed islets. A physicochemistry-based strategy to increase lipophilic efficiency for ghrelin receptor potency and retain low clearance and satisfactory permeability while reducing off-target pharmacology led to the discovery of 16h. Compound 16h has a superior balance of ghrelin receptor pharmacology and off-target selectivity. On the basis of its promising pharmacological and safety profile, 16h was advanced to human clinical trials.

Entities:  

Keywords:  Ghrelin; PF-5190457; diabetes; ghrelin receptor antagonist; ghrelin receptor inverse agonist

Year:  2014        PMID： 24900864      PMCID： PMC4027753          DOI： 10.1021/ml400473x

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  38 in total

Review 1.  Structural modifications that alter the P-glycoprotein efflux properties of compounds.

Authors:  Stephen A Hitchcock
Journal:  J Med Chem       Date:  2012-04-16       Impact factor: 7.446

2.  Physiochemical drug properties associated with in vivo toxicological outcomes.

Authors:  Jason D Hughes; Julian Blagg; David A Price; Simon Bailey; Gary A Decrescenzo; Rajesh V Devraj; Edmund Ellsworth; Yvette M Fobian; Michael E Gibbs; Richard W Gilles; Nigel Greene; Enoch Huang; Teresa Krieger-Burke; Jens Loesel; Travis Wager; Larry Whiteley; Yao Zhang
Journal:  Bioorg Med Chem Lett       Date:  2008-07-24       Impact factor: 2.823

3.  Identification of potent, selective, CNS-targeted inverse agonists of the ghrelin receptor.

Authors:  Kim F McClure; Margaret Jackson; Kimberly O Cameron; Daniel W Kung; David A Perry; Suvi T M Orr; Yingxin Zhang; Jeffrey Kohrt; Meihua Tu; Hua Gao; Dilinie Fernando; Ryan Jones; Noe Erasga; Guoqiang Wang; Jana Polivkova; Wenhua Jiao; Roger Swartz; Hirokazu Ueno; Samit K Bhattacharya; Ingrid A Stock; Sam Varma; Victoria Bagdasarian; Sylvie Perez; Dawn Kelly-Sullivan; Ruduan Wang; Jimmy Kong; Peter Cornelius; Laura Michael; Eunsun Lee; Ann Janssen; Stefanus J Steyn; Kimberly Lapham; Theunis Goosen
Journal:  Bioorg Med Chem Lett       Date:  2013-07-30       Impact factor: 2.823

4.  Azabicyclo[3.1.0]hexane-1-carbohydrazides as potent and selective GHSR1a ligands presenting a specific in vivo behavior.

Authors:  Fabio Maria Sabbatini; Sergio Melotto; Giovanni Bernasconi; Steve M Bromidge; Lucilla D'Adamo; Marilisa Rinaldi; Chiara Savoia; Claudia Mundi; Carla Di Francesco; Laura Zonzini; Vivian J A Costantini; Benedetta Perini; Enzo Valerio; Alfonso Pozzan; Elisabetta Perdonà; Filippo Visentini; Mauro Corsi; Romano Di Fabio
Journal:  ChemMedChem       Date:  2011-08-10       Impact factor: 3.466

5.  Dose-dependent inhibition by ghrelin of insulin secretion in the mouse.

Authors:  Martina Kvist Reimer; Giovanni Pacini; Bo Ahrén
Journal:  Endocrinology       Date:  2003-03       Impact factor: 4.736

6.  Pharmacologic inhibition of ghrelin receptor signaling is insulin sparing and promotes insulin sensitivity.

Authors:  Kenneth A Longo; Elizabeth K Govek; Anna Nolan; Thomas McDonagh; Soratree Charoenthongtrakul; Derek J Giuliana; Kristen Morgan; Jeffrey Hixon; Chaoseng Zhou; Bruce Kelder; John J Kopchick; Jeffrey O Saunders; Manuel A Navia; Rory Curtis; Peter S DiStefano; Brad J Geddes
Journal:  J Pharmacol Exp Ther       Date:  2011-07-20       Impact factor: 4.030

7.  Identification of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor.

Authors:  Daniel W Kung; Steven B Coffey; Ryan M Jones; Shawn Cabral; Wenhua Jiao; Michael Fichtner; Philip A Carpino; Colin R Rose; Richard F Hank; Michael G Lopaze; Roger Swartz; Hou Tommy Chen; Zachary Hendsch; Bruce Posner; Christopher F Wielis; Brian Manning; Jeffrey Dubins; Ingrid A Stock; Sam Varma; Mary Campbell; Demetria DeBartola; Rachel Kosa-Maines; Stefanus J Steyn; Kim F McClure
Journal:  Bioorg Med Chem Lett       Date:  2012-05-17       Impact factor: 2.823

8.  Effects of an oral growth hormone secretagogue in older adults.

Authors:  Heidi K White; Charles D Petrie; William Landschulz; David MacLean; Ann Taylor; Kenneth Lyles; Jeanne Y Wei; Andrew R Hoffman; Roberto Salvatori; Mark P Ettinger; Miriam C Morey; Marc R Blackman; George R Merriam
Journal:  J Clin Endocrinol Metab       Date:  2009-01-27       Impact factor: 5.958

Review 9.  Current and emerging therapies for type 2 diabetes.

Authors:  Jing Xu
Journal:  IDrugs       Date:  2004-03

10.  Ghrelin infusion in humans induces acute insulin resistance and lipolysis independent of growth hormone signaling.

Authors:  Esben Thyssen Vestergaard; Lars Christian Gormsen; Niels Jessen; Sten Lund; Troels Krarup Hansen; Niels Moller; Jens Otto Lunde Jorgensen
Journal:  Diabetes       Date:  2008-09-05       Impact factor: 9.461
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  19 in total

1.  Pd-catalyzed arylation of linear and angular spirodiamine salts under aerobic conditions.

Authors:  Sean W Reilly; Nikaela W Bryan; Robert H Mach
Journal:  Tetrahedron Lett       Date:  2016-12-23       Impact factor: 2.415

2.  Endocrine effects of the novel ghrelin receptor inverse agonist PF-5190457: Results from a placebo-controlled human laboratory alcohol co-administration study in heavy drinkers.

Authors:  Mary R Lee; Mehdi Farokhnia; Enoch Cobbina; Anitha Saravanakumar; Xiaobai Li; Jillian T Battista; Lisa A Farinelli; Fatemeh Akhlaghi; Lorenzo Leggio
Journal:  Neuropharmacology       Date:  2019-09-23       Impact factor: 5.250

3.  Pharmacokinetics and pharmacodynamics of PF-05190457: The first oral ghrelin receptor inverse agonist to be profiled in healthy subjects.

Authors:  William S Denney; Gabriele E Sonnenberg; Santos Carvajal-Gonzalez; Theresa Tuthill; V Margaret Jackson
Journal:  Br J Clin Pharmacol       Date:  2016-10-29       Impact factor: 4.335

4.  Targeting Peripheral CB1 Receptors Reduces Ethanol Intake via a Gut-Brain Axis.

Authors:  Grzegorz Godlewski; Resat Cinar; Nathan J Coffey; Jie Liu; Tony Jourdan; Bani Mukhopadhyay; Lee Chedester; Ziyi Liu; Douglas Osei-Hyiaman; Malliga R Iyer; Joshua K Park; Roy G Smith; Hiroshi Iwakura; George Kunos
Journal:  Cell Metab       Date:  2019-05-16       Impact factor: 27.287

Review 5.  Ghrelin, CCK, GLP-1, and PYY(3-36): Secretory Controls and Physiological Roles in Eating and Glycemia in Health, Obesity, and After RYGB.

Authors:  Robert E Steinert; Christine Feinle-Bisset; Lori Asarian; Michael Horowitz; Christoph Beglinger; Nori Geary
Journal:  Physiol Rev       Date:  2017-01       Impact factor: 37.312

6.  Role of Molybdenum-Containing Enzymes in the Biotransformation of the Novel Ghrelin Receptor Inverse Agonist PF-5190457: A Reverse Translational Bed-to-Bench Approach.

Authors:  Sravani Adusumalli; Rohitash Jamwal; R Scott Obach; Tim F Ryder; Lorenzo Leggio; Fatemeh Akhlaghi
Journal:  Drug Metab Dispos       Date:  2019-06-10       Impact factor: 3.922

7.  Development and validation of an UPLC-MS/MS assay for quantitative analysis of the ghrelin receptor inverse agonist PF-5190457 in human or rat plasma and rat brain.

Authors:  Mwlod Ghareeb; Lorenzo Leggio; Ayman El-Kattan; Fatemeh Akhlaghi
Journal:  Anal Bioanal Chem       Date:  2015-05-07       Impact factor: 4.142

8.  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

Review 9.  Ghrelin as a Survival Hormone.

Authors:  Bharath K Mani; Jeffrey M Zigman
Journal:  Trends Endocrinol Metab       Date:  2017-10-30       Impact factor: 12.015

10.  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
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