1 research outputs found
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 Ca<sup>2+</sup>-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><sub>i</sub> = 86 nM, EC<sub>50</sub> = 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><sub>i</sub> = 16 nM, EC<sub>50</sub> = 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