- Synthesis of PF-6870961, a major hydroxy metabolite of the novel ghrelin receptor inverse agonist PF-5190457
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Preclinical and human studies have indicated involvement of the ghrelin system in alcohol-related behaviors illuminating the possibility of using ghrelin receptor blockers as a pharmacological intervention for alcohol use disorder (AUD). Preliminary data from a recently conducted phase 1b human study with a ghrelin receptor inverse agonist, PF-5190457 (2-(2-methylimidazo[2,1-b][1,3thiazol-6-yl)-1-{2-(1R)-5-(6-methylpyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]non-7-ylethanone), provided evidence on the safety and tolerability of this compound when co-administered with alcohol. Furthermore, the study revealed important information on the biotransformation pathways for this compound and prompted the discovery and then synthesis of a newly identified major metabolite, PF-6870961 ((R)-1-(2-(5-(2-hydroxy-6-methylpyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2-methylimidazo[2,1-b]thiazol-6-yl)ethan-1-one). The metabolite was synthesized and fully characterized through a design that enabled it to be prepared in useful quantities. The synthesis provided direct access to the recently discovered PF-6870961 and is allowing researchers to conduct additional and deeper evaluation of its in vitro and in vivo properties.
- Sulima, Agnieszka,Akhlaghi, Fatemeh,Leggio, Lorenzo,Rice, Kenner C.
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- Spiro aryl phosphorus oxide or sulfide
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The invention discloses a spiro aryl phosphorus oxide or sulfide as ALK inhibitor, and in particular discloses a compound shown in a formula (I) as an ALK inhibitor or a pharmaceutically acceptable salt thereof.
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Paragraph 0270; 0271; 0272; 0273
(2016/10/08)
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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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- USE OF GHRELIN RECEPTOR INVERSE AGONISTS OR ANTAGONISTS FOR TREATING SLEEP DISORDERS
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The present invention relates to methods of treating sleep disorders in patients comprising administration of a ghrelin receptor inverse agonist or antagonist. The invention also includes methods of treating sleep disorders comprising the administration of a pharmaceutical composition comprising a ghrelin receptor inverse agonist or antagonist and at least one pharmaceutically acceptable carrier, diluent, or excipient.
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Page/Page column 17; 18
(2014/01/08)
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- One-pot synthesis of chiral azetidines from chloroaldehyde and chiral amines
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A variety of chiral azetidinepiperidines have been synthesized utilizing an expedient one-pot union of piperidine chloroaldehyde with chiral amines. This two step one-pot procedure provides access to an interesting set of compounds that retain the chiral
- Orr, Suvi T.M.,Cabral, Shawn,Fernando, Dilinie P.,Makowski, Teresa
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scheme or table
p. 3618 - 3620
(2011/07/31)
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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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Page/Page column 34
(2011/10/10)
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