Field of the Invention
The present invention relates to a biphenyl sulfonamide compound which is a dual angiotensin and endothelin receptor antagonist, to pharmaceutical compositions containing such compound, to methods of manufacturing the pharmaceutical formulations containing such compound, and to methods of using such compound in the treatment of endothelin-dependent or angiotensin II-dependent disorders and other diseases.
Description of the Related Art
Angiotensin II (AngII) and endothelin-1 (ET-1) are two of the most potent endogenous vasoactive peptides currently known and are believed to play a role in controlling both vascular tone and pathological tissue remodeling associated with a variety of diseases including diabetic nephropathy, heart failure, and chronic or persistently elevated blood pressure. Currently, angiotensin receptor blockers (ARBs), which block the activity of AngII, are widely used as a treatment for diabetic nephropathy, heart failure, chronic or persistently elevated blood pressure. In addition, there is a growing body of data that demonstrates the potential therapeutic benefits of ET receptor antagonists (ERAs) in blocking ET-1 activity.
It is also known that AngII and ET-1 work together in blood pressure control and pathological tissue remodeling. For example, ARBs not only block the action of AngII at its receptor, but also limit the production of ET-1. Similarly, ERAs block ET-1 activity and inhibit the production of AngII. Consequently, simultaneously blocking AngII and ET-1 activities may offer better efficacy than blocking either substance alone.
In well-validated rat models of human chronic or persistently elevated blood pressure, the combination of an ARB and an ERA results in a synergistic effect. Furthermore, although ARBs are the standard of care for patients with diabetic nephropathy, improved efficacy with the co-administration of an ERA has been reported in Phase 2 clinical development.
There are preclinical and initial clinical data suggesting that compared to either mechanism alone, simultaneously blocking angiotensin II and endothelin 1 at their respective receptors, ATI and ETA, may provide an improved treatment option for several cardiovascular diseases.