956697-53-3

Usage

Uses

Used in Pharmaceutical Industry:
NVP-LDE225 is used as an antineoplastic agent for the treatment of locally advanced basal cell carcinoma. It functions as a potent Hedgehog inhibitor, targeting the hedgehog signaling pathway and reducing the growth and progression of cancer cells.
Used in Cancer Research:
NVP-LDE225 is used as a research tool in cancer research to study the role of the hedgehog signaling pathway in various types of cancer. It helps researchers understand the molecular mechanisms underlying the development and progression of cancer and identify potential therapeutic targets for cancer treatment.

Biological Activity

lde225 is a potent and selective inhibitor of smoothened with ic50 values of 1.3nm in mouse and 2.5nm in human, respectively [1].lde225 is screened out from a high-throughput cell-based screen of in-house diversity combinatorial libraries and is developed to be an antagonist of smo. smo is an activator of the hedgehog(hh) signaling pathway and aberrant activation links to tumorigenesis in several cancers. the antitumor efficacy of lde225 has been evaluated in vivo. in the subcutaneous ptch+/-p53-/- medulloblastoma allograft mouse model, lde225 can significantly inhibit tumor growth at a dose of 5mg/kg/day. and in an orthotopic ptch+/-p53-/- medulloblastoma allograft model, lde225 is suggested to penetrate the blood-brain barrier in tumor-bearing animals and cause the tumor growth inhibition after 4 days of treatment. additionally, the preclinical safety assays show that lde225 has no genotoxicity and has good selectivity [1].

references

[1] shifeng pan, xu wu, jiqing jiang, et al. discovery of nvp-lde225, a potent and selective smoothened antagonist. acs med. chem. lett. 2010, 1: 130–134.

Upstream product

• 4214-76-0 5-nitro-pyridin-2-ylamine 
• 99548-54-6 methyl 3-bromo-2-methylbenzoate 
• 1221722-10-6 2-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxyIic acid 
• 76006-33-2 3-bromo-2-methylbenzoic acid 
• 14618-62-3 2R,2'S-bis(ethyl propionate)ether 
• 20753-88-2 meso-((1-hydroxypropan-2-yl)oxy)propan-1-ol 
• 956699-06-2 (2S,6R)-2,6-dimethyl-4-(5-aminopyridin-2-yl)morpholine 
• 260447-04-9 (2S,6R)-2,6-dimethyl-4-(5-nitropyridin-2-yl)morpholine 
• 141-91-3 cis-2,6-dimethylmorpholine 
• 4548-45-2 2-chloro-5-nitropyridine 
• 139301-27-2 4-trifluoromethoxyphenylboronic acid 
• 1221721-86-3 3-bromo-N-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methylbenzamide 
• 7697-26-9 3-bromo-4-methylbenzoic acid 

Downstream Products

• 1218778-77-8 N-[6-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-3-pyridinyl]-2-methyl-4’-(trifluoromethoxy)-[1,1‘-biphenyl]-3-carboxamide diphosphate 

Relevant academic research and scientific papers

Large-steric-hindrance N-heterocyclic carbene palladium complex, preparation method and application thereof, and synthesis method of sonidegib based on large-steric-hindrance N-heterocyclic carbene palladium complex

The invention belongs to the technical field of organic synthesis and chemical catalysis, and discloses a large-steric-hindrance N-heterocyclic carbene palladium complex, a preparation method thereof,an application of the complex in efficient catalysis of a C-N coupling reaction under a room-temperature air condition, and a synthesis method of sonidegib based on the complex. According to the large-steric-hindrance N-heterocyclic carbene palladium complex, diphenyl imidazole serves as a main ligand framework, functionalized allyl serves as an auxiliary ligand, the functionalized allyl is introduced beside a metal center of a catalyst to serve as an auxiliary ligand, the catalytic activity and stability are remarkably improved, the large-steric-hindrance N-heterocyclic carbene palladium complex can be applied to efficient catalysis of a CN coupling reaction, particularly, the CN coupling reaction can be efficiently catalyzed under the room temperature condition, and the yield can reachup to 99%. The invention also provides a method for synthesizing sonidegib by taking aryl/aliphatic amine and aryl chloride as reactants and a three-step method at room temperature under the catalysisof a palladium catalytic system, the synthetic method has few steps, and the total yield can reach 74.5%.

An environmentally responsible 3-pot, 5-step synthesis of the antitumor agent sonidegib using ppm levels of Pd catalysis in water

The current industrial approach to sonidegib utilizes wasteful organic solvents and relies on high loadings of endangered Pd. This anticancer drug can now be synthesized in 5 steps using only 3 pots, along with ppm levels of a Pd catalyst, all done in water at ambient temperatures.

Preparation methods of Sonidegib intermediate and Sonidegib

The invention provides preparation methods of a Sonidegib intermediate and Sonidegib. According to the preparation methods, 2-amino-5-nitropyridine (II) and R-propylene oxide (or S-propylene oxide) are subjected to an epoxy ring-opening substitution react

Preparation method of Sonidegib

The invention discloses a preparation method of Sonidegib, LDE225. An industrial raw material, namely L-lactate, which is easy to obtain is subjected to an intermolecular condensation reaction to obtain cis-2R,2'S-bis(propionate)ether, and the intermediate is subjected to a reduction reaction and a sulfonylation reaction and is then subjected to a cyclization reaction together with N-(6-aminopyridine-3-yl)-2-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-formamide to obtain Sonidegib (I). Raw materials are easy to obtain, the process is simple, and the preparation method is economical, environmentally friendly and suitable for industrial production.

The topical pharmaceutical compositions comprising active agent

The present invention relates to pharmaceutical compositions of 2-Methyl-4′-trifluoromethoxy-biphenyl-3-carboxylic acid [6-(cis-2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide, to the use of such compositions in therapeutic applications and to methods for manufacturing such compositions.

Sonidegib phosphate

Sonidegib phosphate (LDE-225) is a potent, orally bioavailable, selective inhibitor of smoothened protein, a key downstream transducer of the hedgehog signaling pathway. This pathway has been recently associated with cancer development and progression in several tumor types, and components of this pathway have been regarded as targets for the development of new anticancer agents. In preclinical studies, sonidegib bound to smoothened protein with high affinity, leading to dose-related inhibition of hedgehog signaling, ultimately resulting in tumor growth arrest and regression. In early clinical studies, sonidegib showed a favorable safety profile and demonstrated promising antitumor activity, mainly in basal cell carcinoma and medulloblastoma. Ongoing trials are evaluating sonidegib either alone in selected cancer types or in combination with conventional cytotoxic drugs against a broad range of solid tumors.

An efficient continuous flow approach to furnish furan-based biaryls

Suzuki cross-couplings of 5-formyl-2-furanylboronic acid with activated or neutral aryl bromides were performed under continuous flow conditions in the presence of (Bu)4N+F- and the immobilised t-butyl based palladium cata

COMPOUNDS AND COMPOSITIONS AS HEDGEHOG PATHWAY MODULATORS

The invention provides a method for modulating the activity of the hedgehog signaling pathway. In particular, the invention provides a method for inhibiting aberrant growth states resulting from phenotypes such as Ptc loss-of-function, hedgehog gain-of-fu