Optimization of the potency and pharmacokinetic properties of a macrocyclic ghrelin receptor agonist (Part I): Development of ulimorelin (TZP-101) from hit to clinic
| Autor: | Eric Marsault, Kamel Benakli, Graeme L. Fraser, Annick Landry, Sophie Beauchemin, Mahesh Ramaseshan, Laurence Foucher, Xiaowen Peng, Jean François Pinault, Martin Brassard, Daniel F. Veber, Martin Vezina, René Gagnon, Shridhar Bhat, Hamid R. Hoveyda, Carl Saint-Louis, Mark Peterson, Patrick Bherer, Sylvie Beaubien, Axel Mathieu, Luc Ouellet, Zhigang Wang |
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| Rok vydání: | 2011 |
| Předmět: |
Agonist
Male Cell Membrane Permeability Macrocyclic Compounds Magnetic Resonance Spectroscopy Stereochemistry medicine.drug_class Peptidomimetic Protein Conformation Ulimorelin Administration Oral Biological Availability Pharmacology In Vitro Techniques Crystallography X-Ray Rats Sprague-Dawley Structure-Activity Relationship Pharmacokinetics Drug Discovery medicine Animals Humans Receptor Receptors Ghrelin Chemistry Stereoisomerism In vitro Bioavailability Rats Macaca fascicularis Growth Hormone Microsomes Liver Molecular Medicine Ghrelin Peptidomimetics Caco-2 Cells Oligopeptides |
| Zdroj: | Journal of medicinal chemistry. 54(24) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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