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 2022/056051 A1

URL:https://patents.google.com/patent/WO2022056051A1/en

Publication Date

March 17, 2022

Priority Application

US 63/076,592

Priority Date

September 10, 2020

Inventors

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

Assignee Company

Merck Sharp & Dohme Corp., USA

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 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. Analysis of blisters arising from acute episodes has shown them 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 angioedema, diabetic macular edema, and diabetic retinopathy. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.

Definitions

X₁ = CH or N;

X₂ = NR₄ or CR₄;

X₃ = N, NO, NR_x, or CO;

X₄ = CH or N;

Y = CR₅R₆ or SO₂;

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, heteroaryl, or SOR_x;

R₂ = H or halo;

R₃ = H, halo, or OR_x.

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 table below.

Biological Data

The table below shows representative compounds tested for PKal inhibition and the biological data obtained from testing representative examples.

Claims

Total claims: 18

Compound claims: 12

Pharmaceutical composition claims: 1

Method of treatment claims: 5

The author declares no competing financial interest.