Dialkyl-phosphinoyl-alkane (Dapa) compounds and compositions for treatment of lower gastrointestinal tract disorders

Abstract

Heat abstraction from the body's surfaces causes sensations of cold from the skin, orbit, nose, mouth, throat, upper esophagus, airways, and anogenital surfaces. The detection of heat abstraction at these sites is via TRPM8, a neuronal protein linked to nerve membranes. Chemical agents that act on TRPM8 can also produce sensations of cold, but the surface of the lower gastrointestinal tract (LGIT) does not “feel cold”, yet it contains cells with TRPM8. The pharmacology of TRPM8 in the LGIT is an unexplored subject. Menthol has a relaxant effect on gut smooth muscle, but this action is not via TRPM8. Here, a class of selective TRPM8 agonists, called 1-Dialkyl-phosphinoyl-alkanes (Dapa) were synthesized, and the potency and selectivity on TRP channels were characterized. Certain Dapa molecules were shown to inhibit neural signals in isolated vagus nerve and to exert anti-inflammatory effects in a model of heat-injury. When applied to the human colon muscle, a Dapa embodiment inhibited contractions with a median inhibitory concentration of 8 μg/mL. Methods for coating and formulation of Dapa with excipients for delivery to the colonic mucosa are described. The preferred Dapa embodiments are believed useful in treating the muscle spasms and the inflammation of LGIT dysfunction.

Dependencies are inferred from the claim text.