| abstract |
Novel multi-binding compounds (agents) which bind endothelin receptors are used to treat disorders affecting the cardiovascular, renal, endocrine and nervous systems in mammals that are mediated by the endothelin receptors, such as congestive heart failure, pulmonary hypertension, cerebral vasospasm following subarachnoid hemorrhage, essential hypertension, myocardial infarction, myocardial ischemia, unstable angina, restenosis, renal failure of ischemic origin, portal hypertension, cardiac hypertrophy, atherosclerosis, eclampsia, cerebrovascular disease, vascular disease, migraines, and auto-immune diseases, such as Morbus Wegener and Morbus Raynaud, to name a few. The compounds of this invention comprise a plurality of ligands each of which can bind to such receptors thereby modulating the biological processes/functions thereof. Each of the ligands, which may be the same or different, is covalently attached to a linker or linkers which may be the same or different to provide for the multi-binding compound. The linker is selected such that the multi-binding compound so constructed demonstrates increased modulation of the biological processes mediated by the endothelin receptor than that provided by the ligands in monomeric form. The invention is also directed to pharmaceutical compositions comprising the multi-binding compounds, methods of inhibiting and treating the disorders mediated by endothelin receptors, and methods of preparing multi-binding compounds of the invention. |