Sograzepide (Netazepide) is an oral active, selective and potent gastrin/CCK-B antagonist with an IC50 value of 0.1nM. It has inhibitory effects on the activity of gastrin/CCK-A and an IC50 value of 502nM. Sograzepide can specifically bind to the gastrin/CCK-B receptors in the rat brain, cloned canine, and cloned human tissues, with Ki values of 0.068, 0.62, and 0.19nM, respectively[1]. CCK-B is widely expressed throughout the human brain and gastrointestinal tract, and its expression is increased in various tumor cell lines (including gastric, lung, colon and lymphoma cells). Sograzepide can inhibit the expression of Pappalysin 2 in type 1 gastric neuroendocrine tumors and induce their regression, and can be used to treat gastric neuroendocrine tumors and pancreatic cancer caused by chronic autoimmune atrophic gastritis with hypergastrinemia[2].
In vitro, in AGS-E cells, pretreatment with Sograzepide (10-2, 10-1, 1, 10, 100nM) for 48 hours significantly eliminated the gastrin-dependent TFF2 promoter activity in a dose-dependent manner. At concentrations of 10-100nM gastrin, the responses of all TFF2 promoter constructs to gastrin were completely inhibited in the presence of 100nM Sograzepide. And 10-2nM Sograzepide inhibited 50% of the trans-activation effect of 100nM gastrin on the TFF2 promoter in AGS-E cells[3]. After treating AGSGR cells with Sograzepide (100nM) for 48h, the cell responses induced by gastrin, such as DNA synthesis, phosphatidylinositol hydrolysis, and histamine secretion, were all inhibited. Sograzepide has been shown to competitively replace gastrin-I with CCK-B with a higher efficacy than the previously developed CCK-B antagonists[4].
In vivo, by orally administering Sograzepide (2mg/kg/d, 5mg/kg/d) to Swiss mice for 8 days, it completely prevented the pain symptoms and nerve damage caused by vincristine, and had a protective effect on vincristine-induced peripheral neuropathy[2]. Sograzepide (300μM/kg) was subcutaneously injected once a week into Sprague-Dawley rats, which could prevent the increase in gastrin levels caused by proton pump inhibitors (PPI)-induced excessive gastric acid from causing the increase in ECL cell activity and density, gastric mucosa thickness, mucosal histamine decarboxylase (HDC) activity and serum gastrin levels[5].
References:
[1] Boyce M, Dowen S, Turnbull G, van den Berg F, Zhao CM, Chen D, Black J. Effect of Sograzepide, a gastrin/CCK2 receptor antagonist, on gastric acid secretion and rabeprazole-induced hypergastrinaemia in healthy subjects. Br J Clin Pharmacol. 2015 May;79(5):744-55.
[2] Bernard A, Mroué M, Bourthoumieu S, Boyce M, Richard L, Sturtz F, Demiot C, Danigo A. Sograzepide, an Antagonist of Cholecystokinin Type 2 Receptor, Prevents Vincristine-Induced Sensory Neuropathy in Mice. Pharmaceuticals. 2024; 17(2):144.
[3] Tu S, Chi A L, Lim S H, et al. Gastrin regulates the TFF2 promoter through gastrin-responsive cis-acting elements and multiple signaling pathways[J]. American Journal of Physiology-Gastrointestinal and Liver Physiology, 2007, 292(6): G1726-G1737.
[4] Lloyd K A. Investigation of biomarkers associated with hypergastrinaemia and their responses to CCK-2 receptor antagonism[M]. The University of Liverpool (United Kingdom), 2016.
[5] Chen D, Zhao C-M, Norlén P, Björkqvist M, Ding X-Q, Kitano M, Håkanson R: Effect of cholecystokinin-2 receptor blockade on rat stomach ECL cells. Cell Tissue Res 2000, 299:81-95. /Boyce M, Lloyd K A, Pritchard D M. Potential clinical indications for a CCK2 receptor antagonist[J]. Current Opinion in Pharmacology, 2016, 31: 68-75.
Sograzepide (Netazepide)是一种口服活性高、选择性强且效力强的胃泌素/CCK-B拮抗剂，IC50值为 0.1nM，对胃泌素/CCK-A活性具有抑制作用，IC50为502nM。Sograzepide能够与大鼠大脑、克隆的犬类和克隆的人胃泌素/CCK-B受体的特异性结合，其 Ki值分别为 0.068、0.62和 0.19nM[1]。CCK-B在人类整个大脑和胃肠道中均广泛表达，且在多种肿瘤细胞系（包括胃、肺、结肠和淋巴瘤细胞）中观察到其表达量有所增加。Sograzepide可抑制1型胃神经内分泌肿瘤中Pappalysin 2的表达，并能诱导1型胃神经内分泌肿瘤消退，可用于治疗慢性自身免疫性萎缩性胃炎继发高胃泌素血症引起的胃神经内分泌肿瘤和胰腺癌[2]。
在体外，在AGS-E细胞中, Sograzepide(10-2，10-1，1，10，100nM)的预处理48h显著地以剂量依赖的方式消除了胃泌素依赖的TFF2启动子活性。在10-100nM胃泌素浓度下，所有TFF2启动子构建体对胃泌素的反应在100nM的Sograzepide存在的情况下均被完全抑制，10-2nM 的Sograzepide抑制了AGS-E细胞中100nM 胃泌素对TFF2启动子的反式激活作用的 50%[3]。在Sograzepide(100nM)处理AGSGR细胞48h后，胃泌素诱导的细胞反应如DNA合成、磷脂酰肌醇水解、组胺分泌均被抑制。Sograzepide已被证明能以比先前开发的CCK-B拮抗剂更高的效力竞争性地取代胃泌素-I与CCK-B结合[4] 。
在体内，通过口服Sograzepide(2mg/kg/d，5mg/kg/d)治疗Swiss小鼠8天，完全预防了长春新碱引起的疼痛症状和神经损伤，对长春新碱诱导的周围神经病变具有保护作用[2]。Sograzepide(300μM/kg)每周对大鼠皮下注射一次，能够阻止由于质子泵抑制剂(PPI)引起的胃酸过多所导致的胃泌素增多所引发的ECL细胞活性和密度、胃黏膜厚度、黏膜组胺脱羧酶(HDC)活性以及血清胰胃泌素水平的升高[5] 。