1312131-45-5Relevant articles and documents
Synthesis of PF-6870961, a major hydroxy metabolite of the novel ghrelin receptor inverse agonist PF-5190457
Sulima, Agnieszka,Akhlaghi, Fatemeh,Leggio, Lorenzo,Rice, Kenner C.
, (2021/10/21)
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.
Identification of potent, selective, CNS-targeted inverse agonists of the ghrelin receptor
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
, p. 5410 - 5414 (2013/09/23)
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.
One-pot synthesis of chiral azetidines from chloroaldehyde and chiral amines
Orr, Suvi T.M.,Cabral, Shawn,Fernando, Dilinie P.,Makowski, Teresa
, p. 3618 - 3620 (2011/07/31)
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
