Nuclear transport modulators and uses thereof
Inventors
Sandanayaka, Vincent P. • Shechter, Sharon • Shacham, Sharon • McCauley, Dilara • Baloglu, Erkan
Assignees
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Publication Number
US-11318120-B2
Publication Date
2022-05-03
Expiration Date
Abstract
Compounds of formula I: and pharmaceutically acceptable salts, solvates, or hydrates thereof, pharmaceutical compositions comprising the compounds of formula I, and methods of making and using the compounds, salts, solvates, or hydrates and the compositions in the treatment of various disorders associated with CRM1 activity.
Core Innovation
The document describes methods of synthesizing (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid derivatives, including (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-pivaloylacrylohydrazide, by reacting defined (Z)-acrylic acid precursors with corresponding hydrazide reagents. The synthesis is presented with specific chemical entities used to access the triazole-containing (Z)-acrylic acid framework.
The patent also provides pharmacological characterization of CRM1 (XPO1) nuclear export inhibition using RevGFP assays, including U2OS-RevGFP, together with related cellular effects assessed using cytotoxicity/proliferation assays. It reports potency and biological activity readouts for the disclosed compounds.
Further, the document describes pharmacokinetic evaluation including AUCinf and brain:plasma ratios, and reports comparative observations for Formula I compounds showing high AUCinf together with relatively low brain:plasma ratios. The patent additionally describes multiple in vivo disease and mechanistic model studies, and includes mechanistic pathway readouts related to Nrf2 and NF-κB.
Claims Coverage
The provided content includes independent claims directed to a specific chemical conversion pathway centered on (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid and its corresponding (Z)-acrylate precursor, with conversion to the named (Z)-acrylohydrazide derivative.
Synthesis by reacting (Z)-acrylic acid with pivalohydrazide
Reacting (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid with pivalohydrazide to synthesize (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-pivaloylacrylohydrazide.
Synthesis of (Z)-acrylic acid by reacting the (Z)-acrylate with LiOH
Reacting (Z)-isopropyl 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylate with LiOH to synthesize (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid.
The claims define a specific chemical conversion pathway centered on the (Z)-triazolyl acrylic acid framework, with one claim converting the acid to the named (Z)-acrylohydrazide derivative using pivalohydrazide and another converting the (Z)-acrylate to the acid using LiOH.
Stated Advantages
Higher in vivo exposure (AUC) compared with other CRM1 inhibitors.
Reduced brain penetration, reflected by a lower brain:plasma ratio compared with other CRM1 inhibitors.
Documented Applications
Treating disorders associated with abnormal CRM1-mediated nuclear export.
Cancer therapy.
Inflammatory/autoimmune disorders.
Viral diseases.
Ophthalmological disorders.
Neurodegenerative disorders.
Fibrosis.
Metabolic/obesity disorders.
Wounds.
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