ABSTRACT
A backup molecule to compound 2 was sought by targeting the most likely metabolically vulnerable site in this molecule. Compound 18 was subsequently identified as a potent P2X(7) antagonist with very low in vivo clearance and high oral bioavailability in all species examined. Some evidence to support the role of P2X(7) in the etiology of pain is also presented.
Subject(s)
Imidazolines/pharmacology , Purinergic Antagonists/pharmacology , Receptors, Purinergic P2X7/drug effects , Administration, Oral , Animals , Biological Availability , Half-Life , Haplorhini , Imidazolines/administration & dosage , Imidazolines/chemistry , Imidazolines/pharmacokinetics , Purinergic Antagonists/administration & dosage , Purinergic Antagonists/chemistry , Purinergic Antagonists/pharmacokinetics , RatsABSTRACT
A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X(7) receptor antagonist. Structure-activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X(7) antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies.
Subject(s)
Amides/pharmacology , Purinergic P2 Receptor Antagonists/pharmacology , Pyrrolidonecarboxylic Acid/chemistry , Receptors, Purinergic P2X7/drug effects , Amides/chemistry , Drug Discovery , Models, Molecular , Purinergic P2 Receptor Antagonists/chemistry , Structure-Activity RelationshipABSTRACT
As part of an on-going lead optimisation effort, a cross screening exercise identified an aryl sulphonyl amide hit that was optimised to afford a highly potent series of ghrelin receptor agonists.
Subject(s)
Chemistry, Pharmaceutical/methods , Ghrelin/chemistry , Receptors, Ghrelin/antagonists & inhibitors , Sulfones/chemistry , Administration, Oral , Animals , Biological Availability , Drug Design , Growth Hormone/chemistry , Male , Models, Chemical , Protein Processing, Post-Translational , Rats , Rats, Sprague-Dawley , Receptors, Ghrelin/chemistry , Structure-Activity RelationshipABSTRACT
A series of small molecule orally bioavailable ghrelin receptor agonists have been identified through systematic optimisation of a high throughput screening hit.
