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

Important Compound Classes

Title

Plasma Kallikrein Inhibitors

Patent Publication Number

WO 2021/257353 A1

URL: https://patents.google.com/patent/WO2021257353A1/en

Publication Date

December 23, 2021

Priority Application

US 63/039,873

Priority Date

June 16, 2020

Inventors

Jabri, S.; Ogawa, A. K.; Sinz, C. J.; Hicks, J. D.; Cheng, A. C.; Gao, Y.; Yang, S.; Bao, J.; Hayes, D. A. A. W.; Lang, S. B.; Taoka, B. M.; Tian, M.; Shearn-Nance, G. P.; Kuang, R.; Lombardo, M. J.; Wu, Z.; Zhao, Z.

Assignee Company

Merck Sharp & Dohme Corp., USA

Disease Area

Hereditary angioedema, uveitis, posterior uveitis, wet age-related macular edema, diabetic macular edema, diabetic retinopathy, and retinal vein occlusion

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 high molecular weight kininogen (HMWK). In blood, most of the plasma kallikrein circulates in complex with HMWK.

Patients presenting genetic deficiency on C1-esterase suffer from hereditary angioedema (HAE), a lifelong disease that results in intermittent swelling throughout the body. Analyses of blisters arising from acute episodes have shown that the blisters 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 angioedema, uveitis, posterior uveitis, wet age-related macular edema, diabetic macular edema, diabetic retinopathy, and retinal vein occlusion. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment

Definitions

Ring A = , , , , , , or ;

Ring B = or ;

V = CH or N; X = CH or N;

Y = N, NO, NR_x or CO; Z = NR₄ or CR₄;

E = N or CH; Q = N or CH;

G = N or CR₇; J = N or CR₇; L = N or CR₇; M = N or CR₇;

R₁ = H, halo, cyano, R_x, OR_x and SOR_x;

R₂ = H or halo; R₃ = H or halo;

R₅ = H or C_1–3 alkyl, which is optionally substituted with 1–3 substituents selected from halo and hydroxy; and

R₆ = H or C_1–3 alkyl.

Key Structures

Biological Assay

The plasma kallikrein (PKal) assay was performed. The compounds described in this application were tested for their ability to inhibit PKal. The PKal IC₅₀ (nM) are shown in the following table.

Biological Data

The table below shows representative compounds that were tested for PKal inhibition. The biological data obtained from testing representative examples are listed in the following table.

Claims

Total claims: 18

Compound claims: 11

Pharmaceutical composition claims: 2

Method of treatment claims: 5

Recent Review Articles

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The author declares no competing financial interest.