SSR240612 is a new, potent, and orally active specific non-peptide bradykinin B1 receptor antagonist, which inhibited Lys0-desAr9-BK (10nM)-induced inositol monophosphate formation in human fibroblast MRC5, with an IC50 of 1.9nM[1]. Bradykinin B1 Receptor (B1R) is a G-protein-coupled receptor with low expression level in normal tissues, but it can be induced to express in pathological states such as inflammation, diabetes, ischemia/reperfusion injury, and participate in inflammation and pain signal transmission[2]. SSR240612 displaced the binding of [3H]Lys0-des-Arg9-BK to the B1 receptors in human fibroblast MRC5 and to recombinant human B1 receptor expressed in human embryonic kidney cells with inhibition constants (Ki ) of 0.48 and 0.73nM, respectively. The affinity of SSR240612 for B2 receptors labeled with [3H]BK was much lower with a Ki of 481nM for guinea pig ileum membranes and a Ki of 358nM for membrane preparations of CHO cells expressing human B2 receptors[1]. SSR240612 is usually used for research in inflammatory, immune, and metabolic diseases[3][4][5].
In vitro, treatment of M. tuberculosis-infected RAW 264.7 cells with SSR240612 (10μM) for 4 days displayed a marked inhibitory effect on CFU counts[6].
In vivo, oral administration of SSR240612 (10 and 30mg/kg) for 3h blocked tactile and cold allodynia without affecting plasma glucose and insulin, insulin resistance (HOMA index) and aortic superoxide anion production in glucose-fed rat compared with control rat[7].
References:
[1] Gougat, J., Ferrari, B., Sarran, L., Planchenault, C., Poncelet, M., Maruani, J., Alonso, R., Cudennec, A., Croci, T., Guagnini, F., Urban-Szabo, K., Martinolle, J. P., Soubrié, P., Finance, O., & Le Fur, G. (2004). SSR240612 [(2R)-2-[((3R)-3-(1,3-benzodioxol-5-yl)-3-[[(6-methoxy-2-naphthyl)sulfonyl]amino]propanoyl)amino]-3-(4-[[2R,6S)-2,6-dimethylpiperidinyl]methyl]phenyl)-N-isopropyl-N-methylpropanamide hydrochloride], a new nonpeptide antagonist of the bradykinin B1 receptor: biochemical and pharmacological characterization. The Journal of pharmacology and experimental therapeutics, 309(2), 661–669.
[2] Campos, M. M., Leal, P. C., Yunes, R. A., & Calixto, J. B. (2006). Non-peptide antagonists for kinin B1 receptors: new insights into their therapeutic potential for the management of inflammation and pain. Trends in pharmacological sciences, 27(12), 646–651.
[3] Tidjane, N., Hachem, A., Zaid, Y., Merhi, Y., Gaboury, L., Girolami, J. P., & Couture, R. (2015). A primary role for kinin B1 receptor in inflammation, organ damage, and lethal thrombosis in a rat model of septic shock in diabetes. European journal of inflammation, 13(1), 40–52.
[4] Costa, R., Fernandes, E. S., Menezes-de-Lima, O., Jr, Campos, M. M., & Calixto, J. B. (2006). Effect of novel selective non-peptide kinin B(1) receptor antagonists on mouse pleurisy induced by carrageenan. Peptides, 27(11), 2967–2975.
[5] El Akoum, S., Haddad, Y., & Couture, R. (2017). Impact of pioglitazone and bradykinin type 1 receptor antagonist on type 2 diabetes in high-fat diet-fed C57BL/6J mice. Obesity science & practice, 3(3), 352–362.
[6] Rodrigues-Junior, V. S., Pail, P. B., Villela, A. D., Falcão, V. C. A., Dadda, A. S., Abbadi, B. L., Pesquero, J. B., Santos, D. S., Basso, L. A., & Campos, M. M. (2018). Effect of the bradykinin 1 receptor antagonist SSR240612 after oral administration in Mycobacterium tuberculosis-infected mice. Tuberculosis (Edinburgh, Scotland), 109, 1–7.
[7] Dias, J. P., Ismael, M. A., Pilon, M., de Champlain, J., Ferrari, B., Carayon, P., & Couture, R. (2007). The kinin B1 receptor antagonist SSR240612 reverses tactile and cold allodynia in an experimental rat model of insulin resistance. British journal of pharmacology, 152(2), 280–287.
SSR240612是一种新的、有效的、具有口服活性的特异性非肽慢激肽B1受体拮抗剂，可抑制Lys0-desAr9-BK (10nM) 诱导的人成纤维细胞MRC5中肌醇单磷酸的形成，IC50为1.9nM[1]。缓激肽B1受体（Bradykinin B1 Receptor, B1R）是一种G蛋白偶联受体，在正常组织中表达水平较低，但在炎症、糖尿病、缺血/再灌注损伤等病理状态下可诱导表达，参与炎症和疼痛信号传递[2]。SSR240612抑制了[3H]Lys0-des-Arg9-BK与人成纤维细胞MRC5中B1受体和人胚胎肾细胞中表达的重组人B1受体的结合，抑制常数（Ki）分别为0.48和0.73nM。SSR240612对[3H]BK标记的B2受体的亲和力更低，对豚鼠回肠膜的Ki为481nM，对表达人B2受体的CHO细胞的膜制剂的Ki为358nM[1]。SSR240612通常用于炎症、免疫和代谢性疾病的研究[3][4][5]。
在体外，10μM SSR240612 处理感染结核分支杆菌的RAW 264.7细胞4天可显著抑制CFU计数[6]。
在体内，与对照大鼠相比，口服SSR240612(10和30mg/kg) 3h可阻断葡萄糖喂养大鼠的触觉和冷痛觉，而不影响血糖和胰岛素、胰岛素抵抗（HOMA指数）和主动脉超氧阴离子生成[7]。