- Discovery of PF-5190457, a potent, selective, and orally bioavailable ghrelin receptor inverse agonist clinical candidate
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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.
- Bhattacharya, Samit K.,Andrews, Kim,Beveridge, Ramsay,Cameron, Kimberly O.,Chen, Chiliu,Dunn, Matthew,Fernando, Dilinie,Gao, Hua,Hepworth, David,Jackson, V. Margaret,Khot, Vishal,Kong, Jimmy,Kosa, Rachel E.,Lapham, Kimberly,Loria, Paula M.,Londregan, Allyn T.,McClure, Kim F.,Orr, Suvi T. M.,Patel, Jigna,Rose, Colin,Saenz, James,Stock, Ingrid A.,Storer, Gregory,Vanvolkenburg, Maria,Vrieze, Derek,Wang, Guoqiang,Xiao, Jun,Zhang, Yingxin
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- Identification of potent, selective, CNS-targeted inverse agonists of the ghrelin receptor
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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.
- 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
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p. 5410 - 5414
(2013/09/23)
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- 2,3-DIHYDRO-1H-INDEN-1-YL-2,7-DIAZASPIRO[3.5] NONANE DERIVATIVES
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The present invention provides a compound of Formula (I) or a pharmaceutically salt thereof wherein R1, R2, Ra, L, Z, Z1 and Z2 are as defined herein, that act as Ghrelin antagonists or inverse agonists; pharmaceutical compositions thereof; and methods of treating diseases, disorders, or conditions mediated by the antagonism of the Ghrelin receptor.
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