title: Optimization of the potency and pharmacokinetic properties of a macrocyclic ghrelin receptor agonist (Part I): Development of ulimorelin (TZP-101) from hit to clinic.
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.
authors: Tranzyme Pharma Inc., 3001, 12e Avenue Nord, Sherbrooke, QC J1H 5N4, Canada. hhoveyda@euroscreen.com
authors: Hamid R
authors: HR
authors: Hoveyda
authors: Eric
authors: E
authors: Marsault
authors: René
authors: R
authors: Gagnon
authors: Axel P
authors: AP
authors: Mathieu
authors: Martin
authors: M
authors: Vézina
authors: Annick
authors: A
authors: Landry
authors: Zhigang
authors: Z
authors: Wang
authors: Kamel
authors: K
authors: Benakli
authors: Sylvie
authors: S
authors: Beaubien
authors: Carl
authors: C
authors: Saint-Louis
authors: Martin
authors: M
authors: Brassard
authors: Jean-François
authors: JF
authors: Pinault
authors: Luc
authors: L
authors: Ouellet
authors: Shridhar
authors: S
authors: Bhat
authors: Mahesh
authors: M
authors: Ramaseshan
authors: Xiaowen
authors: X
authors: Peng
authors: Laurence
authors: L
authors: Foucher
authors: Sophie
authors: S
authors: Beauchemin
authors: Patrick
authors: P
authors: Bhérer
authors: Daniel F
authors: DF
authors: Veber
authors: Mark L
authors: ML
authors: Peterson
authors: Graeme L
authors: GL
authors: Fraser
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D013006:Growth Hormone / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D047028:Macrocyclic Compounds; D009842:Oligopeptides; D057786:Peptidomimetics; D054440:Receptors, Ghrelin; D013006:Growth Hormone; C528884:ulimorelin