Potent achiral agonists of the growth hormone secretagogue (ghrelin) receptor. Part 2: Lead optimisation

Cognitive enhancing effects of ghrelin receptor agonists

“…There was no treatment effect on swim speed on either of the test days. Data expressed as means±SEM (n=10) Patchett et al 1995;Heightman et al 2007;Witherington et al 2008), the aim of these studies was to determine if structurally diverse small-molecule ghrelin receptor agonists are also pro-cognitive.…”

“…The "drug-like" properties of these molecules were subsequently enhanced in a series of lead optimisation steps, which ultimately led to the identification of GSK894490A, an orally bioavailable and selective nonpeptide GHS-R agonist (Witherington et al 2008). We therefore sought to determine whether two non-peptide ghrelin receptor agonists (CP-464709-18 and GSK894490A) were capable of reproducing the pro-cognitive effects reported with ghrelin peptide itself.…”

Ghrelin Receptor Modulators and Their Therapeutic Potential

“…The derivatives of general structure 13, particularly compounds 13a and 13b, possessed robust performance in a rat feeding assay (Table 6). They retained a good selectivity profile over the 5-HT1B receptor and displayed encouraging pharmacokinetic properties with low blood clearance and excellent bioavailability [97,98].…”

Developments and Advances in Gastrointestinal Prokinetic Agents

“…Subsequent optimization, which included ring opening of the indoline, use of an intramolecular H-bond to maintain permeability, and optimization of the sulfonamide group, led to the identification of GSK-894490A, 29. This compound is a potent, orally bioavailable full agonist (F 75% in rat) which was shown to stimulate an increase in food intake in rat at 3 mg/kg following oral dosing [71]. In a more recent publication from the same group, the spacer between the sulfonyl group and the basic piperazine has been investigated and has led to the discovery of a 3-amino-pyrrolidinyl amide derivative, 30, that has an encouraging i.v.…”