September 24, 2012
Indole derivatives give hope to macular degeneration patients. Age-related macular degeneration (AMD) affects older adults and results in a progressive loss of visual acuity in the macula. The macula is a small, highly pigmented yellow spot ≈5 mm in diam in the center of the retina of the human eye. It is responsible for the sharp vision needed for reading, driving, or recognizing faces.
The less-advanced form of the disease is called dry (or atrophic) AMD; it occurs from the death of atrophic cells of the macula. The disease may advance to a second form known as wet (or neovascular) AMD. Wet AMD is characterized by the abnormal growth of blood vessels under the macula and vascular leakage. Scar tissue forms from the leakage of fluid and blood that may destroy the central retina and can lead to blindness.
The complement system is part of the innate immune system. It consists of several inactive small proteins that are normally found in the blood. The complement proteins may be activated by any of three biochemical pathways: the classical complement pathway, the alternative complement pathway, and the lectin pathway.
Genetic evidence links the activation of the alternative pathway to the pathogenesis of AMD. The inhibition of this activation process may provide an AMD treatment. Factor D is a protein that is involved in the activation of the alternative pathway of the complement system; it activates the complement C3 to C3 protease. Inhibition of factor D is a suitable target for interfering with the complement alternative pathway to treat patients with AMD, diabetic retinopathy, and related ophthalmic diseases.
E. Altmann and co-inventors prepared indole derivatives that inhibit the alternative pathway of the complement system and particularly inhibit factor D. They claim compounds that can modulate and inhibit factor D function and/or factor D–mediated complement pathway activation processes. These compounds may also inhibit or suppress the amplification of the complement system caused by C3 activation irrespective of the initial mechanism of activation.
Structures 1–4 in the figure are examples of the compounds of the invention. The inventors describe 773 specific compounds and report synthesis procedures and IC50 values.
The test compounds were incubated with recombinant human factor D for 1 h at room temperature at pH 7.5. The IC50 values were calculated from the percentage of inhibition of complement factor D activity as a function of test compound concentration.
The application contains a table of IC50 values for the 773 compounds. IC50 values ranged from 1 nM for structure 3 to 24.75 μM for structure 1. (Novartis AG [Basel, Switzerland]. WIPO Publication WO2012093101, July 12, 2012; Ahmed F. Abdel-Magid)
This patent was originally reviewed in ACS Medicinal Chemistry Letters.
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