2. Academic Validation
  3. Optimization of the potency and pharmacokinetic properties of a macrocyclic ghrelin receptor agonist (Part I): Development of ulimorelin (TZP-101) from hit to clinic

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

  • J Med Chem. 2011 Dec 22;54(24):8305-20. doi: 10.1021/jm2007062.
Hamid R Hoveyda 1,  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 Veber,  Mark L Peterson,  Graeme L Fraser
Affiliations

Affiliation

  • 1 Tranzyme Pharma Inc., 3001, 12e Avenue Nord, Sherbrooke, QC J1H 5N4, Canada. hhoveyda@euroscreen.com
PMID: 22106937 DOI: 10.1021/jm2007062
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.

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