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

Autor:	Jimmy Kong, Theunis C. Goosen, Kimberly O. Cameron, Samit Kumar Bhattacharya, Suvi T. M. Orr, Dilinie P. Fernando, Peter Cornelius, Eunsun Lee, Meihua Tu, Stefanus J. Steyn, David Austen Perry, Laura Michael, Jana Polivkova, Ann M. Janssen, Margaret Jackson, Jeffrey T. Kohrt, Ruduan Wang, Sylvie Perez, Hirokazu Ueno, Kimberly Lapham, Dawn Kelly-Sullivan, Victoria Bagdasarian, Roger Swartz, Ingrid A. Stock, Yingxin Zhang, Ryan Jones, Erasga Noe Ouano, Kim F. McClure, Wenhua Jiao, Daniel W. Kung, Guoqiang Wang, Hua Gao, Sam Varma
Rok vydání:	2013
Předmět:	Central Nervous System Drug Inverse Agonism Stereochemistry Clinical Biochemistry Indane Pharmaceutical Science Biochemistry Inhibitory Concentration 50 Structure-Activity Relationship chemistry.chemical_compound Isomerism Heterocyclic Compounds Drug Discovery Muscarinic acetylcholine receptor Enzyme-linked receptor Animals Humans Structure–activity relationship Inverse agonist Amino Acid Sequence Receptors Ghrelin Receptor Molecular Biology Binding Sites Molecular Structure Organic Chemistry Rats chemistry Indans Molecular Medicine Ghrelin Protein Binding
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 23:5410-5414
ISSN:	0960-894X
Popis:	The optimization for selectivity and central receptor occupancy for a series of spirocyclic azetidine-piperidine inverse agonists of the ghrelin receptor is described. Decreased mAChR muscarinic M2 binding was achieved by use of a chiral indane in place of a substituted benzylic group. Compounds with desirable balance of human in vitro clearance and ex vivo central receptor occupancy were discovered by incorporation of heterocycles. Specifically, heteroaryl rings with nitrogen(s) vicinal to the indane linkage provided the most attractive overall properties.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f0e6d8033acfd64e2624f92f66f339ad https://doi.org/10.1016/j.bmcl.2013.07.044 Zobrazit plný text záznamu Full Text from ScienceDirect