Discovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate.
ACS Med Chem Lett
; 5(5): 474-9, 2014 May 08.
Article
en En
| MEDLINE
| ID: mdl-24900864
ABSTRACT
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.
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1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
ACS Med Chem Lett
Año:
2014
Tipo del documento:
Article
País de afiliación:
Estados Unidos