Optimization of the Potency and Pharmacokinetic Properties of a Macrocyclic Ghrelin Receptor Agonist (Part I): Development of Ulimorelin (TZP-101) from Hit to Clinic

Abstract

High-throughput screening of Tranzyme Pharma's proprietary macrocycle library using the aequorin Ca2+-bioluminescence assay against the human ghrelin receptor (GRLN) led to the discovery of novel agonists against this G-protein coupled receptor. Early hits such as 1 (Ki=86 nM, EC50=134 nM) though potent in vitro displayed poor pharmacokinetic properties that required optimization. While such macrocycles are not fully rule-of-five compliant, principally due to their molecular weight and clogP, optimization of their pharmacokinetic properties proved feasible largely through conformational rigidification. Extensive SAR led to the identification of 2 (Ki=16 nM, EC50=29 nM), also known as ulimorelin or TZP-101, which has progressed to phase III human clinical trials for the treatment of postoperative ileus. X-ray structure and detailed NMR studies indicated a rigid peptidomimetic portion in 2 that is best defined as a nonideal type-I' β-turn. Compound 2 is 24% orally bioavailable in both rats and monkeys. Despite its potency, in vitro and in gastric emptying studies, 2 did not induce growth hormone (GH) release in rats, thus demarcating the GH versus GI pharmacology of GRLN.

Analysis of the ghrelin receptor-independent vascular actions of ulimorelin

“…At rat and human ghrelin receptors, ulimorelin has an EC 50 in the range of 1-2 nM (Hoveyda et al, 2011;. For relaxation of preconstricted arteries, the EC 50 of ulimorelin was 0.5-5 mM and for contraction the EC 50 was 10-30 mM, providing further evidence that these effects are not mediated by the ghrelin receptor.…”

“…Ulimorelin, also known as TPZ101, is a macrocyclic molecule that is a potent agonist of the ghrelin receptor (Hoveyda et al, 2011). Due to its ability to stimulate gastrointestinal motility, ulimorelin has been evaluated as a possible treatment in gastroparesis (Ejskjaer et al, 2010), ileus (Fraser et al, 2009) and constipation .…”

Small Molecule Ghrelin Receptor Inverse Agonists and Antagonists

“…One of the lead ghrelin agonist macrocycles is currently in clinic trials. 176 Tranzyme has extended the field of macrocyclic ghrelin modulators to include ghrelin receptor antagonists/ inverse agonists. (e.g., 17, Figure 10).…”

“…(e.g., 17, Figure 10). 176,177 A recent patent application from Tranzyme reported functional antagonism for the claimed compounds in an aequorin functional assay and inverse agonism based on an IP-one homogeneous time-resolved fluorescence (HTRF) assay. 178,179 Given the novel nature of the macrocyclic analogues, the inventors shared a large amount of ADME data.…”

New trisubstituted 1,2,4-triazoles as ghrelin receptor antagonists

“…Ipsen developed ghrelin analogs and identified a competitive GHS-R1a antagonist, BIM 28163, 8 while Tranzyme Pharma has extensively claimed conformationally defined macrocyclic compounds incorporating peptides as modulators of the GHS-R1a, including antagonists. 9 Numerous nonpeptide small molecules such as benzodiazepine, 10 piperazine bisamide, 11 azaquinazolinone 12 and indolinone 13 derivatives have been described as potent antagonists of the ghrelin receptor. 14 In our effort to find new ghrelin receptor ligands, we recently described a family of peptidomimetics based on a decorated 1,2,4-triazole scaffold that led to potent agonists and antagonists of this receptor.…”