Optimization of the Potency and Pharmacokinetic Properties of a Macrocyclic Ghrelin Receptor Agonist (Part I): Development of Ulimorelin (TZP-101) from Hit to Clinic

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• 作者：Hamid R. Hoveyda ; Eric Marsault ; Ren茅 Gagnon ; Axel P. Mathieu ; Martin V茅zina ; Annick Landry ; Zhigang Wang ; Kamel Benakli ; Sylvie Beaubien ; Carl Saint-Louis ; Martin Brassard ; Jean-Fran莽ois Pinault ; Luc Ouellet ; Shridhar Bhat ; Mahesh Ramaseshan ; Xiaowen Peng ; Laurence Foucher ; Sophie Beauchemin ; Patrick Bh茅rer ; Daniel F. Veber ; Mark L. Peterson ; Graeme L. Fraser
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 22, 2011
• 年：2011
• 卷：54
• 期：24
• 页码：8305-8320
• 全文大小：550K
• 年卷期：v.54,no.24(December 22, 2011)
• ISSN：1520-4804

文摘

High-throughput screening of Tranzyme Pharma鈥檚 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 (K_i = 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 (K_i = 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鈥?尾-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.