Excellent Cellular Potency Research Articles

Design and synthesis of dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole oximes as potent dual inhibitors of TIE-2 and VEGF-R2 receptor tyrosine kinases

Fused dihydroindazolopyrrolocarbazole oximes have been identified as low nanomolar, potent dual TIE-2 and VEGF-R2 receptor tyrosine kinase inhibitors with excellent cellular potency. Development of the structure-activity relationships (SAR) led to identification of compounds 35 and 40 as potent, selective dual TIE-2/VEGF-R2 inhibitors with favorable pharmacokinetic properties. Compound 35 was orally active in tumor models with no observed toxicity.

Discovery and biological evaluation of adamantyl amide 11β-HSD1 inhibitors

A series of adamantyl amide 11β-HSD1 inhibitors has been discovered and chemically modified. Selected compounds are selective for 11β-HSD1 over 11β-HSD2 and possess excellent cellular potency in human and murine 11β-HSD1 assays. Good pharmacodynamic characteristics are observed in ex vivo assays.

Novel C-3 N-urea, amide, and carbamate dihydroindazolo[5,4- a]pyrrolo[3,4- c]carbazole analogs as potent TIE-2 and VEGF-R2 dual inhibitors

A novel series of C-3 urea, amide, and carbamate fused dihydroindazolocarbazole (DHI) analogs are reported as highly potent dual inhibitors of TIE-2 and VEGF-R2 receptor tyrosine kinases with excellent cellular potency. Structure–activity relationship (SAR) studies indicate the optimal N-13 alkyl substitutions are n-propyl and i-butyl. The isopropyl carbamate 39 displayed good dual enzyme, cell potency, and rat pharmacokinetic properties for advancement to in vivo evaluation.

Potent and Selective Mitogen-Activated Protein Kinase Kinase (MEK) 1,2 Inhibitors. 1. 4-(4-Bromo-2-fluorophenylamino)-1- methylpyridin-2(1H)-ones

The role of MEK 1,2 in cancer tumorgenesis has been clearly demonstrated preclinically, and two selective inhibitors are currently undergoing clinical evaluation to determine their role in the human disease. We have discovered 4-(4-bromo-2-fluorophenylamino)-1-methylpyridin-2(1H)-ones as a new class of ATP noncompetitive MEK inhibitors. These inhibitors exhibit excellent cellular potency and good pharmacokinetic properties and have demonstrated the ability to inhibit ERK phosphorylation in HT-29 tumors from mouse xenograft studies.

Further Studies on Ethenyl and Ethynyl‐4‐phenylamino‐3‐quinolinecarbonitriles: Identification of a Subnanomolar Src Kinase Inhibitor.

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Further studies on ethenyl and ethynyl-4-phenylamino-3-quinolinecarbonitriles: identification of a subnanomolar Src kinase inhibitor

Several new ethynyl- and ethenyl-4-phenylamino-3-quinolinecarbonitriles were synthesized and tested for Src inhibition. Derivatives bearing an ethenyl or ethynyl substituent at C-6 showed decreased Src inhibitory activity. Incorporation of an ethenylpyridine N-oxide group at C-7 provided 20b, a 0.6 nM inhibitor of Src enzymatic activity with excellent cellular potency.