biostudies-literature00590Unknown5(5)Bhattacharya SKThe 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.ACS medicinal chemistry letters474-9https://www.ebi.ac.uk/biostudies/studies/S-EPMC4027753biostudies-literatureDiscovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate.PMC4027753Saenz JBhattacharya SKJackson VMHepworth DWang GGao HStorer GAndrews KLondregan ATCameron KOOrr STPatel JKosa RELoria PMStock IAVanVolkenburg MVrieze DMcClure KFChen CKong JRose CKhot VDunn MXiao JZhang YFernando DBeveridge RLapham K59falseDiscovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate.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.2014-01-01T00:00:00Z2014 May2021-03-14T09:04:06Z2019-03-27T01:28:35ZS-EPMC40277532490086410.1021/ml400473x