Novel Plasma Kallikrein Inhibitors for Treating Hereditary Angioedema, Diabetic Macular Edema, and Diabetic Retinopathy

Abstract

Disease Area. Hereditary angioedema, diabetic macular edema, and diabetic retinopathy Biological Target. Plasma kallikrein Summary. Plasma kallikrein is a zymogen of a trypsin-like serine protease and is present in plasma. The gene structure is like that of Factor XI. Overall, the amino acid sequence of plasma kallikrein has 58% homology to factor XI. The active site of plasma kallikrein is contained in the light chain. The light chain of plasma kallikrein reacts with protease inhibitors. Interestingly, heparin significantly accelerates the inhibition of plasma kallikrein by antithrombin III in the presence of highmolecular-weight kininogen (HMWK). In blood, most of the plasma kallikrein circulates in complex with HMWK.Patients a presenting genetic deficiency on C1-esterase suffer from hereditary angioedema (HAE), a lifelong disease that results in intermittent swelling throughout the body. Blisters arising from acute episodes have been shown to contain high levels of plasma kallikrein. Additionally, the plasma kallikrein− kinin system is abnormally abundant in patients diagnosed with advanced diabetic macular edema (DME). Recent publications have shown that plasma kallikrein contributes to observed retinal vascular leakage and dysfunction in diabetic rodent models.The present application describes a series of novel plasma kallikrein inhibitors for the treatment of hereditary angioede-ma, diabetic macular edema, and diabetic retinopathy. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.

Unveiling Therapeutic Frontiers: DON/DRP-104 as Innovative Plasma Kallikrein Inhibitors Against Carcinoma-Associated Hereditary Angioedema Shocks - A Comprehensive Molecular Dynamics Exploration

“…Management of HAE involves targeting PKa effects, with PKa inhibitors serving as the primary on-demand first-line drug agents [2,8,9]. Besides targeting HAE, PKa inhibitors are under development for the treatment of uncontrolled PKa related conditions, such diabetic retinopathy, macular edema, and sepsis [5,10]. Presently, ecallantide [11], lanadelumab [12], and berotralstat [13] are the Food and Drug Administration (FDA)-approved PKa inhibitor drugs for managing Hereditary Angioedema (HAE).…”