811867-23-9Relevant academic research and scientific papers
Intermediates for macrocyclic compounds
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, (2015/11/30)
The present invention is directed to novel macrocyclic compounds of formula (I) and their pharmaceutically acceptable salts, hydrates or solvates: wherein R1, R2, R3, R4, R5, R6, n1, m, p Z1, Z2, and Z3 are as describe in the specification. The invention also relates to compounds of formula (I) which are antagonists of the motilin receptor and are useful in the treatment of disorders associated with this receptor and with or with motility dysfunction.
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)
