CAS: 1184173-73-6; (S)-N-(3-(6-Isopropoxypyridin-3-yl)-1H-Indazol-5-yl)-1-(2-(4-(4-(1-Methyl-1H-1,2,4-Triazol-3-yl)Phenyl)-3,6-Dihydropyridin-1(2H)-yl)-2-Oxoethyl)-3-(Methylthio)Pyrrolidine-3-Carboxamide

英文名称(S)-N-(3-(6-Isopropoxypyridin-3-yl)-1H-Indazol-5-yl)-1-(2-(4-(4-(1-Methyl-1H-1,2,4-Triazol-3-yl)Phenyl)-3,6-Dihydropyridin-1(2H)-yl)-2-Oxoethyl)-3-(Methylthio)Pyrrolidine-3-Carboxamide
中文名称(3S)-1-[2-[3,6-二氢-4-[4-(1-甲基-1H-1,2,4-三唑-3-基)苯基]-1(2H)-吡啶基]-2-氧代乙基]-N-[3-[6-(1-甲基乙氧基)-3-吡啶基]-1H-吲唑-5-基]-3-(甲硫基)-3-吡咯烷甲酰胺
IUPAC名称(S)-N-(3-(6-isopropoxypyridin-3-yl)-1H-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamide
其它别名3-pyrrolidinecarboxamide,1-[2-[3,6-dihydro-4-[4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]-1(2H)-pyridinyl]-2-oxoethyl]-n-[3-[6-(1-methylethoxy)-3-pyridinyl]-1H-indazol-5-yl]-3-(Methylthio)-,(3S)-
CAS编号1184173-73-6
MFCD编号:MFCD31657387
分子式:C37H41N9O3S分子量:691.86
产品CID: 235612
同类组份化合物CAS1184173-73-6 (free base)1951448-73-9 (HCl)1951448-74-0 (HCl hydrate)1951428-60-6 (hydrate)1951428-61-7 (x HCl)
产品分类生物化工 → 抑制剂

相似结构搜索
InChIKey: KPQQGHGDBBJGFA-QNGWXLTQSA-N
InChI=1S/C37H41N9O3S/c1-24(2)49-32-12-9-28(20-38-32)34-30-19-29(10-11-31(30)41-42-34)40-36(48)37(50-4)15-18-45(22-37)21-33(47)46-16-13-26(14-17-46)25-5-7-27(8-6-25)35-39-
计算化学: 氢键受体数9.0氢键供体数2.0可旋转键数10.0

物理性质

密度1.36±0.1 g/cm3(预测)
pKa:11.89±0.40(预测)
LogP:4.3
溶解性Soluble In DMSO
外观形态类白色至浅棕色固体
储存条件2-8°C
产品应用该化合物是一种选择性的,口服生物可获的ERK1/2抑制剂,具有针对活性和非活性ERK1/2的强大活动;它在各癌症细胞线(例如A2058,HT-29,COLO-205)中显示出反扩散效应,并在多种BRAF-变型动物模型中显示出抗突触活动.

上下游产品

(S)-N-(3-(6-Isopropoxypyridin-3-yl)-1H-Indazol-5-yl)-3-(Methylthio)Pyrrolidine-3-Carboxamide 1184174-35-3
3-(6-Isopropoxypyridin-3-yl)-1-Trityl-1H-Indazol-5-Amine 1184174-15-9

合成工艺路线路线简述

合成目标产物 Mk-8353 主要起始原料 Tert-Butyl4-(4-(1-Methyl-1H-1,2,4-Triazol-3-yl)Phenyl)-3,6-Dihydropyridine-1(2H)-Carboxylate
(文献来源)合成步骤主要原料 Tert-Butyl4-(4-(1-Methyl-1H-1,2,4-Triazol-3-yl)Phenyl)-3,6-Dihydropyridine-1(2H)-Carboxylate

📜1-Boc-吡咯烷-3-甲酸甲酯置于l-酒石酸,三乙胺,N,N-二异丙基乙胺,三氟乙酸,N-[(Dimethylamino)-3-Oxo-1H-1,2,3-Triazolo[4,5-B]Pyridin-1-Yl-Methylene]-N-Methylmethanaminium Hexafluorophosphate,Lithium Hydroxide,Lithium Diisopropyl Amide体系中,用四氢呋喃,甲醇,正己烷,二氯甲烷,水,N,N-二甲基甲酰胺用作溶剂,化学反应 42.33H,反应生成(3S)-1-[2-[3,6-二氢-4-[4-(1-甲基-1H-1,2,4-三唑-3-基)苯基]-1(2H)-吡啶基]-2-氧代乙基]-N-[3-[6-(1-甲基乙氧基)-3-吡啶基]-1H-吲唑-5-基]-3-(甲硫基)-3-吡咯烷甲酰胺
参考文献:Mk-8353:口服可生物利用的双机制erk肿瘤抑制剂的发现
标题:Mk-8353:口服可生物利用的双机制erk肿瘤抑制剂的发现
摘要:新的免疫癌症治疗方法的出现和发展引发了人们对发现治疗癌症新途径的兴趣迅速增长.为了实现这一目标,已鉴定出一系列新的吡咯烷衍生物(化合物5)为有效的erk1 / 2抑制剂,具有出色的激酶选择性和双重作用机制,但药代动力学(pk)较差.通过发现新的3(S)-硫代甲基吡咯烷类似物7克服了pk的挑战.通过聚焦的结构-活性关系优化前导,导致发现了适用于每日两次口服给药的mk-8353临床候选药物,作为潜在的新型癌症治疗药物.
Doi:10.1021/acsmedchemlett.8B00220

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主要参考文献

1: Morales-Cabán BM, Cantres-Rosario YM, Tosado-Rodríguez EL, Roche-Lima A, Meléndez LM, Boukli NM, Suarez-Arroyo IJ. SCAMP3-Driven Regulation of ERK1/2 and Autophagy Phosphoproteomics Signatures in Triple-Negative Breast Cancer. Int J Mol Sci. 2025 Oct 1;26(19):9577. doi: 10.3390/ijms26199577.
2: Lakhani NJ, Burris H 3rd, Miller WH Jr, Huang M, Chen LC, Siu LL. A phase 1b study of the ERK inhibitor MK-8353 plus pembrolizumab in patients with advanced solid tumors. Invest New Drugs. 2024 Oct;42(5):581-589. doi: 10.1007/s10637-024-01461-z. Epub 2024 Sep 14.
3: Stathis A, Tolcher AW, Wang JS, Renouf DJ, Chen LC, Suttner LH, Freshwater T, Webber AL, Nayak T, Siu LL. Results of an open-label phase 1b study of the ERK inhibitor MK-8353 plus the MEK inhibitor selumetinib in patients with advanced or metastatic solid tumors. Invest New Drugs. 2023 Jun;41(3):380-390. doi: 10.1007/s10637-022-01326-3. Epub 2023 Apr 11.

合成参考文献

参考文献:10.1007/s10637-022-01326-3
摘要:Stathis A, Tolcher AW, Wang JS, Renouf DJ, Chen LC, Suttner LH, Freshwater T, Webber AL, Nayak T, Siu LL. Results of an open-label phase 1b study of the ERK inhibitor MK-8353 plus the MEK inhibitor selumetinib in patients with advanced or metastatic solid tumors. Invest New Drugs. 2023 Jun;41(3):380–90.