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

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 <b>1</b> (<i>K</i>_i = 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 <b>2</b> (<i>K</i>_i = 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 <b>2</b> that is best defined as a nonideal type-I′ β-turn. Compound <b>2</b> is 24% orally bioavailable in both rats and monkeys. Despite its potency, in vitro and in gastric emptying studies, <b>2</b> did not induce growth hormone (GH) release in rats, thus demarcating the GH versus GI pharmacology of GRLN