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

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 19; pp. 5410 - 5414
• Main Authors: McClure, Kim F., Jackson, Margaret, Cameron, Kimberly O., Kung, Daniel W., Perry, David A., Orr, Suvi T.M., Zhang, Yingxin, Kohrt, Jeffrey, Tu, Meihua, Gao, Hua, Fernando, Dilinie, Jones, Ryan, Erasga, Noe, Wang, Guoqiang, Polivkova, Jana, Jiao, Wenhua, Swartz, Roger, Ueno, Hirokazu, Bhattacharya, Samit K., Stock, Ingrid A., Varma, Sam, Bagdasarian, Victoria, Perez, Sylvie, Kelly-Sullivan, Dawn, Wang, Ruduan, Kong, Jimmy, Cornelius, Peter, Michael, Laura, Lee, Eunsun, Janssen, Ann, Steyn, Stefanus J., Lapham, Kimberly, Goosen, Theunis
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-10-2013
• Subjects: Acetylcholine receptors (muscarinic); agonists; Amino Acid Sequence; Animals; Antagonist; Binding Sites; Central Nervous System - drug effects; chemistry; Drug Inverse Agonism; Ghrelin; ghrelin receptors; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; Humans; Indans - chemistry; Indans - pharmacology; Inhibitory Concentration 50; Inverse agonist; Isomerism; Molecular Structure; Muscarinic; nitrogen; Protein Binding - drug effects; Rats; Receptor; Receptor occupancy; Receptors, Ghrelin - antagonists & inhibitors; Structure-Activity Relationship; Muscarinic; Antagonist; Ghrelin; Receptor; Receptor occupancy; Inverse agonist
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.07.044

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.