1365993-80-1Relevant articles and documents
Optimization of the potency and pharmacokinetic properties of a macrocyclic ghrelin receptor agonist (Part I): Development of ulimorelin (TZP-101) from Hit to Clinic
Hoveyda, Hamid R.,Marsault, Eric,Gagnon, René,Mathieu, Axel P.,Vézina, Martin,Landry, Annick,Wang, Zhigang,Benakli, Kamel,Beaubien, Sylvie,Saint-Louis, Carl,Brassard, Martin,Pinault, Jean-Fran?ois,Ouellet, Luc,Bhat, Shridhar,Ramaseshan, Mahesh,Peng, Xiaowen,Foucher, Laurence,Beauchemin, Sophie,Bhérer, Patrick,Veber, Daniel F.,Peterson, Mark L.,Fraser, Graeme L.
, p. 8305 - 8320 (2012/01/15)
High-throughput screening of Tranzyme Phar-ma'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. (Figure presented)
