A novel class of 2-acylamino-cycloalkylthiophene-3-carboxylic acid arylamides (AACTs) as potent TMEM16A inhibitors
Transmembrane protein 16A (TMEM16A), also called anoctamin 1 (ANO1), is a Ca2+-activated Cl- channel expressed widely in mammalian epithelia, vascular smooth muscle and electrically excitable cells. Increased TMEM16A expression is associated with COPD and asthma, and TMEM16A is reported as a biomarker for gastrointestinal stromal and esophageal tumors. Pharmacological TMEM16A inhibitors, including the AACT small molecule scaffolds described in this invention, could be used to treat diseases such as inflammatory and reactive airway diseases, hypertension, gastrointestinal hypermotility and some cancers.
The TMEM16A inhibitors developed by UCSF scientists have the following advantages:
The Verkman lab at the University of California, San Francisco has discovered, synthesized and biochemically evaluated of a series of TMEM16A inhibitors. The chemical structure of the 2-acylamino-cycloalkylthiophene-3-carboxylic acid arylamide inhibitor scaffold was refined through medicinal chemistry to identify bromodifluoroacetamide-based inhibitors with enhanced potency and metabolic stability.
To develop & commercialize the TMEM16A inhibitors as therapies for inflammatory and reactive airway diseases, hypertension, gastrointestinal hypermotility and some cancers.
Proof of Concept – in vitro and ex vivo
|Patent Cooperation Treaty||Published Application||WO2018195127||10/25/2018||2017-138|
Thiophene-arylamides, AACT, TMEM16A inhibitors, Ca2+-activated Cl- channel inhibitors