934665-53-9

Usage

Functional groups

Carbonyl, Fluorine, Methyl, Phenyl

Configuration

(2S) for the azetidin ring and (2R) for the phenylpropanoyl group

Presence of piperidine and azetidin groups

Commonly found in drugs

Potential applications

Drug development or therapeutic treatments

Structure complexity

Long and detailed, with various functional groups arranged in a specific configuration

Pharmaceutical properties

Likely due to the presence of piperidine and azetidin groups

Stereochemistry

Chiral centers present in the molecule, contributing to its complexity

Ester linkage

Present between the phenylpropanoyl group and the azetidin ring

Amide linkage

Present between the carbonyl group and the piperidine ring

Upstream product

• 934664-27-4 1,1-dimethylethyl 2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate 
• 20445-33-4 (R)-methoxytrifluoromethylphenylacetyl chloride 

Downstream Products

• 934665-56-2 tert-butyl (S)-2-{1-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoyl]-3-hydroxy-3-azetidinyl}perhydropyridine-1-carboxylate 
• 934660-93-2 [14C]-GDC-0973 
• 934666-39-4 1,1-dimethylethyl (2S)-2-(3-hydroxyazetidin-3-yl)piperidine-1-carboxylate 
• 934665-55-1 1,1-dimethylethyl (2S)-2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate 

Relevant academic research and scientific papers

Novel carboxamide-based allosteric MEK inhibitors: Discovery and optimization efforts toward XL518 (GDC-0973)

The ERK/MAP kinase cascade is a key mechanism subject to dysregulation in cancer and is constitutively activated or highly upregulated in many tumor types. Mutations associated with upstream pathway components RAS and Raf occur frequently and contribute to the oncogenic phenotype through activation of MEK and then ERK. Inhibitors of MEK have been shown to effectively block upregulated ERK/MAPK signaling in a range of cancer cell lines and have further demonstrated early evidence of efficacy in the clinic for the treatment of cancer. Guided by structural insight, a strategy aimed at the identification of an optimal diphenylamine-based MEK inhibitor with an improved metabolism and safety profile versus PD-0325901 led to the discovery of development candidate 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S) -piperidin-2-yl]azetidin-3-ol (XL518, GDC-0973) (1). XL518 exhibits robust in vitro and in vivo potency and efficacy in preclinical models with sustained duration of action and is currently in early stage clinical trials.

METHODS OF USING MEK INHIBITORS

The present invention provides methods of treating cancer by administering a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in combination with other cancer treatments.

METHODS OF USING COMBINATIONS OF MEK AND JAK-2 INHIBITORS

A method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a MEK compound of Formula I(M), or a pharmaceutical composition comprising a therapeutically effective amount of a MEK compound of Formula I(M) and a pharmaceutically acceptable carrier, in combination with a therapeutically effective amount of a JAK-2 compound of Formula I(J), or a pharmaceutical composition comprising a therapeutically effective amount of a JAK-2 compound of Formula I(J) and a pharmaceutically acceptable carrier, wherein the MEK compound of Formula I(M) and JAK-2 compound of Formula I(J) are as defined in the specification.