基本情報
- CAS
1218778-77-8- 標準SMILES
Cc1c(C(=O)Nc2ccc(N3C[C@@H](C)O[C@@H](C)C3)nc2)cccc1-c1ccc(OC(F)(F)F)cc1- InChIKey
VZZJRYRQSPEMTK-CALCHBBNSA-N- 分子式
- C26H26F3N3O3
- 平均分子量
- 485.5 g/mol
- 単同位体質量
- 485.19262619
概要
Sonidegib is a member of the classo of biphenyls that is the amide obtained by formal condensation of the carboxy group of 2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxylic acid with the amino group of 6-(2,6-dimethylmorpholin-4-yl)pyridin-3-amine. Used (as its phosphate salt) for treatment of locally advanced basal cell carcinoma. It has a role as a Hedgehog signaling pathway inhibitor, an antineoplastic agent and a SMO receptor antagonist. It is a member of benzamides, a member of biphenyls, an aromatic ether, an organofluorine compound, an aminopyridine, a member of morpholines and a tertiary amino compound.
名称と識別子
- 優先名称
- Sonidegib
- IUPAC
- N-[6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-3-pyridinyl]-2-methyl-3-[4-(trifluoromethoxy)phenyl]benzamide
- 現地名
- ソニデギブ
- 英語名
- NVP-LDE225
- 分子式
- C26H26F3N3O3
- 分子量
- 485.5
名称と別名
ErismodegibSonidegib956697-53-3LDE225NVP-LDE225LDE-225LDE 225NVP-LDE 225sonidegibum0RLU3VTK5MNVP-LDE-225CHEBI:90863
名称をさらに表示
ソニデギブエリスモデギブN-{6-[(2R,6S)-2,6-ジメチルモルホリン-4-イル]ピリジン-3-イル}-2-メチル-4'-(トリフルオロメトキシ)-[1,1'-ビフェニル]-3-カルボキサミドN-[6-(2α,6α-ジメチルモルホリノ)-3-ピリジル]-2-メチル-4′-(トリフルオロメトキシ)-1,1′-ビフェニル-3-カルボアミドCS-65AZP-577Sonidegib HCLSONIDEGIB(LDE225)LDE225 (NVP-LDE225)LDE-225 (SONIDEGIB)
DTXSID501009335N-(6-((cis-2,6-Dimethylmorpholin-4-yl)-3-pyridyl)-2-methyl-3-(4-(trifluoromethoxy)phenyl)benzamideN-(6-((2R,6S)-2,6-Dimethylmorpholin-4-yl)pyridin-3-yl)-2-methyl-4'-(trifluoromethoxy)biphenyl-3-carboxamideN-[6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl]-2-methyl-3-[4-(trifluoromethoxy)phenyl]benzamide(1,1'-BIPHENYL)-3-CARBOXAMIDE, N-(6-((2R,6S)-2,6-DIMETHYL-4-MORPHOLINYL)-3-PYRIDINYL)-2-METHYL-4'-(TRIFLUOROMETHOXY)-, REL-N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridin-3-yl]-2-methyl-4'-(trifluoromethoxy)[1,1'-biphenyl]-3-carboxamideN-{6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl}-2-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxamideN-(6-((2R,6S)-2,6-dimethylmorpholin-4-yl)pyridin-3-yl)-2-methyl-4'-(trifluoromethoxy)-(1,1'-biphenyl)-3-carboxamide
物性
構造計算による物性
- XLogP
- 5.8
- 極性表面積
- 63.7 Ų
- 水素結合供与体数
- 1
- 水素結合受容体数
- 8
- 回転可能結合数
- 5
- 重原子数
- 35
- 形式電荷
- 0
- 複雑度
- 691
実験および物理化学的性質
Drugs
Pharmaceuticals -> Listed in ZINC15
Pharmaceuticals -> Antineoplastic and immunomodulating agents -> Antineoplastic agents
Human Drugs
Breast Feeding; Lactation; Antineoplastic Agents; Enzyme Inhibitors; Hedgehog Pathway Inhibitors; Signal Transduction Inhibitors;
EMA approved medicines: Human medicine
物理化学的性質
- 融点
- 154 · 154-157°C
- 沸点
- 544.5 · 544.5±50.0 °C(Predicted)
- 比重(密度)
- 1.255 · 1.255
- 貯蔵温度
- Refrigerator
- 溶解性
- DMSO（微量）、メタノール（微量）
- 外見
- 白い固体。
- 酸解離定数(Pka)
- 9.53 · 9.53±0.70(Predicted)
- 色
- ライトパープル
- InChIKey
- VZZJRYRQSPEMTK-CALCHBBNNA-N
- SMILES
- C1(C2=CC=C(OC(F)(F)F)C=C2)=CC=CC(C(NC2=CC=C(N3C[C@H](C)O[C@H](C)C3)N=C2)=O)=C1C |&1:24,27,r|
安全と法規制
安全情報は参考情報です。供給元の安全データシート（SDS）、適用法令、専門家による評価に代わるものではありません。
GHS分類
GHS Classification
Warning
H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]
P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)
The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.
毒性情報
Hepatotoxicity
Most clinical trials of sonidegib included few patients and rates of liver tests abnormalities were often not reported. In isolated trials, serum ALT elevations were reported in 15% to 27% of patients and to rise above 5 times the upper limit of normal (ULN) in 1% to 6%. Rates of serum enzyme elevations were greater with higher doses, and all were apparently transient and resolved either spontaneously or with dose reductions or discontinuation. In these trials, there were no cases of clinically apparent liver injury, hepatitis with jaundice or death from liver failure. The product label for sonidegib mentions serum enzyme elevations as a possible adverse event, but does not mention liver injury with jaundice or hepatic failure. Since its approval and more widespread use, there have been no published cases of hepatotoxicity attributed to sonidegib, but it is an uncommonly used antineoplastic agent. Serum enzyme elevations were also rare with the initial hedgehog inhibitor, vismodegib, which has been implicated in causing at least one case of acute, self-limited cholestatic hepatitis (Case 1 in Vismodegib).
Effects During Pregnancy and Lactation◉ Summary of Use during Lactation
安全データ
- hs_code
- 2934999090
化学と産業
薬理情報
ATC Code
L - Antineoplastic and immunomodulating agents
QL - Antineoplastic and immunomodulating agents
Protein BindingSonidegib is over 97% bound to plasma proteins, and binding is independent of concentration. (2)
Pharmacodynamics
Sonidegib has been shown to inhibit a transmembrane protein called SMO which plays a role in Hh signal transduction. This has resulted in inhibition of Hh signaling as well as antitumour activity in various animal models. In a transgenic mouse model of islet cell neoplasms, tumour volume was reduce by 95% in mice treated with sonidegib when compared with untreated mice. (2)
Mechanism of Action
The hedgehog pathway is involved in many human cancers. Sonidegib effectively inhibits the regulator called smoothened (Smo), preventing the hedgehog pathway from functioning. As a result, tumours that depend on the hedgehog pathway are unable to grow. (1)
Biological Half-LifeHalf-life ~ 28 days (2)
Metabolism/MetabolitesSonidegib is primarily metabolized via oxidation and amide hydrolysis. (1) The enzyme responsible for the majority of metabolism is the cytochrome P450 (CYP) 3A4 enzyme. (2)
FDA Pharmacological Classification
0RLU3VTK5M
SONIDEGIB
Established Pharmacologic Class [EPC] - Hedgehog Pathway Inhibitor
Mechanisms of Action [MoA] - Smoothened Receptor Antagonists
Sonidegib is a Hedgehog Pathway Inhibitor. The mechanism of action of sonidegib is as a Smoothened Receptor Antagonist.
SONIDEGIB
Absorption, Distribution and Excretion
Sonidegib is rapidly absorbed in the fasted state with peak concentrations occurring 2-4 hours after administration. (2) However, the total absorption of Sonidegib is low (roughly 6-7%). (1)
関連反応
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化合物ノート
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