Patent Watch

March 4, 2013

These TRPV4 antagonists may help treat many medical disorders. C. Brooks and co-inventors disclose spirocarbamate analogues represented by formula 1. These compounds have transient receptor potential vanilloid-4 (TRPV4) antagonist activity and may potentially treat such disorders as pain, cardiovascular disease, and osteoarthritis that are modulated by this receptor.

TRPV4 is a polymodal ion channel that is expressed at high levels in the kidney, liver, lung, heart, and central nervous system. It is activated by a variety of stimuli, including warm temperatures and hypotonicity. TRPV4 is involved in pulmonary edema induced by heart failure. It is also implicated in several physiological and pathophysiological conditions, such as pain, genetic motor neuron disorders, cardiovascular disease, and osteoarthritis.

TRPV4 antagonism may provide significant clinical benefits for many of these disorders. It is being considered as a clinical target for treating ventilator-induced lung injury, inflammatory and neuropathic pain, bladder dysfunctions, congestive heart failure, motor neuron disorders, and osteoarthritis.

The inventors describe 77 compounds of formula 1. Structures 24 are randomly selected representative examples. They were subjected to the following biological assays:

  • ligand-gated assay,
  • hypotonicity assay (baby hamster kidney cells),
  • fluorescent imaging plate reader assay, and
  • patch clamp experiments.

All of the examples described in the patent application exhibited TRPV4 biological activity in the ligand-gated assay. IC50 values ranged from 0.001 nM to 1 μM. (GlaxoSmithKline [Philadelphia]. WIPO Publication 2012174342, Dec. 20, 2012; Ahmed F. Abdel-Magid)

This patent was originally reviewed in ACS Medicinal Chemistry Letters.

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