Tranzyme Pharma Inc., 3001, 12e Avenue Nord, Sherbrooke, QC J1H 5N4, Canada.
J Med Chem. 2011 Dec 22;54(24):8305-20. doi: 10.1021/jm2007062. Epub 2011 Nov 22.
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.
高通量筛选 Tranzyme Pharma 的专有大环文库，使用发光虫荧光素酶 Ca2+生物发光测定法针对人类生长激素释放肽受体 (GRLN)，发现了针对这种 G 蛋白偶联受体的新型激动剂。早期的命中化合物如 1（Ki=86 nM，EC50=134 nM）虽然在体外具有很强的活性，但表现出较差的药代动力学性质，需要进行优化。虽然这些大环化合物不完全符合完全规则五要素，主要是由于它们的分子量和 clogP，但通过构象刚性化，优化它们的药代动力学性质被证明是可行的。广泛的 SAR 导致了 2（Ki=16 nM，EC50=29 nM）的鉴定，也称为 ulimorelin 或 TZP-101，它已进入治疗术后肠梗阻的 III 期人体临床试验。X 射线结构和详细的 NMR 研究表明，2 中的刚性肽模拟部分最好定义为非理想的 I'型β-转角。化合物 2 在大鼠和猴子中分别有 24%和 18%的口服生物利用度。尽管 2 具有很强的效力，但在体外和胃排空研究中，它不会在大鼠中引起生长激素 (GH) 释放，从而区分了 GRLN 的 GH 与 GI 药理学。
