Ironwood Pharmaceuticals Inc., 301 Binney Street, Cambridge, MA, 02142, USA.
Eur J Pharmacol. 2010 Dec 15;649(1-3):328-35. doi: 10.1016/j.ejphar.2010.09.019. Epub 2010 Sep 20.
Linaclotide is a first-in-class, orally administered 14-amino acid peptide that is in development for the treatment of irritable bowel syndrome with constipation and chronic constipation. We have characterized the solution structure of linaclotide, the in vitro binding and agonist activity to guanylate cyclase C receptors, the stability of linaclotide under conditions mimicking the gastric environment, oral bioavailability, and the pharmacodynamic effects in rat models of gastrointestinal transit and intestinal secretion. Nuclear magnetic resonance spectroscopy analysis determined that the molecular structure of linaclotide is stabilized by three intramolecular disulfide bridges. Linaclotide exhibited high affinity and pH-independent binding (K(i): 1.23-1.64 nM) to guanylate cyclase C receptors on human colon carcinoma T84 cells and concomitantly, linaclotide binding resulted in a significant, concentration-dependent accumulation of intracellular cyclic guanosine-3', 5'-monophosphate (cGMP) (EC₅₀:99 nM). Linaclotide was stable after 3 h incubation in simulated gastric fluid (pH 1) and similarly, was completely resistant to hydrolysis by pepsin. Pharmacokinetic analysis of linaclotide showed very low oral bioavailability (0.1%). Orally administered linaclotide elicited a significant, dose-dependent increase in gastrointestinal transit rates in rats at doses of ≥5 μg/kg. Exposure of surgically ligated small intestinal loops to linaclotide induced a significant increase in fluid secretion, accompanied by a significant increase in intraluminal cGMP levels. These results suggest that the guanylate cyclase C agonist linaclotide elicits potent pharmacological responses locally in the gastrointestinal tract, and that orally administered guanylate cyclase C agonists may be capable of improving bowel habits in patients suffering from irritable bowel syndrome with constipation and chronic constipation.
利那洛肽是一种首创的、口服的 14 个氨基酸肽，正在开发用于治疗便秘型肠易激综合征和慢性便秘。我们已经对利那洛肽的溶液结构、与鸟苷酸环化酶 C 受体的体外结合和激动活性、在模拟胃环境条件下的稳定性、口服生物利用度以及在大鼠胃肠道转运和肠道分泌模型中的药效学作用进行了描述。核磁共振波谱分析确定，利那洛肽的分子结构由三个分子内二硫键稳定。利那洛肽与人结肠癌细胞 T84 上的鸟苷酸环化酶 C 受体具有高亲和力和 pH 无关的结合（K(i)：1.23-1.64 nM），同时，利那洛肽结合导致细胞内环鸟苷酸-3'，5'-单磷酸（cGMP）的显著、浓度依赖性积累（EC₅₀：99 nM）。利那洛肽在模拟胃液（pH 1）中孵育 3 小时后保持稳定，并且同样完全抵抗胃蛋白酶的水解。利那洛肽的药代动力学分析显示口服生物利用度非常低（0.1%）。口服给予利那洛肽可使大鼠胃肠道转运率显著、剂量依赖性增加，剂量≥5μg/kg。给予结扎的小肠环利那洛肽可引起明显的液体分泌增加，并伴有腔内 cGMP 水平的显著增加。这些结果表明，鸟苷酸环化酶 C 激动剂利那洛肽在胃肠道局部引起强烈的药理学反应，口服给予鸟苷酸环化酶 C 激动剂可能能够改善便秘型肠易激综合征和慢性便秘患者的排便习惯。
