Optimization of the potency and pharmacokinetic properties of a macrocyclic ghrelin receptor agonist (Part I): Development of ulimorelin (TZP-101) from Hit to Clinic

Hamid R. Hoveyda, Eric Marsault, René Gagnon, Axel P. Mathieu, Martin Vézina, Annick Landry, Zhigang Wang, Kamel Benakli, Sylvie Beaubien, Carl Saint-Louis, Martin Brassard, Jean François Pinault, Luc Ouellet, Shridhar Bhat, Mahesh Ramaseshan, Xiaowen Peng, Laurence Foucher, Sophie Beauchemin, Patrick Bhérer, Daniel F. VeberMark L. Peterson, Graeme L. Fraser

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

High-throughput screening of Tranzyme Phar-ma's proprietary macrocycle library using the aequorin Ca 2+-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 (K i = 86 nM, EC 50 = 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 (K i = 16 nM, EC 50 = 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. (Figure presented)

Original languageEnglish (US)
Pages (from-to)8305-8320
Number of pages16
JournalJournal of medicinal chemistry
Volume54
Issue number24
DOIs
StatePublished - Dec 22 2011
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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