Novel Pyridazinones as TRPC5 Inhibitors for Treating Kidney Diseases

Important Compound Classes

Title

Pyridazinones and Methods of Use Thereof

Patent Publication Number

WO 2020/191056 A1

Publication Date

September 24, 2020

Priority Application

US 62/821,178

Priority Date

March 20, 2019

Inventors

Reilly, J. F.; Walsh, L.; Mundel, P. H.; Westerling-Bui, A. K. D.; Daniels, M. H.; Yu, M.; Ledeboer, M. W.; Harmange, J. P.; Coeffet-Legal, M. Y.; Broxson, M.

Assignee Company

Goldfinch Bio Inc., USA

Disease Area

Kidney diseases

Biological Target

Transient Receptor Potential Channel 5 (TRPC5) protein

Summary

The Transient Receptor Potential Channel 5 (TRPC5) protein is a member of Transient Receptor Potential (TRP) family. Proteinuria is a condition in which an excessive amount of protein in the blood leaks into the urine. Proteinuria can progress from a loss of 30 mg of protein in the urine over a 24 h period (called microalbuminuria) to >300 mg/day (called macroalbuminuria), before reaching levels of 3.5 g of protein or more over a 24 h period. Proteinuria occurs when there is a malfunction in the kidney’s glomeruli, causing fluid to accumulate in the body (edema). Prolonged protein leakage has been shown to result in kidney failure. Nephrotic syndrome (NS) disease accounts for approximately 12% of prevalent end stage renal disease cases at an annual cost in the United States of more than $3 billion. Approximately, 5 out of every 100,000 children are diagnosed with NS every year and 15 out of every 100,000 children are living with it today. For patients who respond positively to the treatment, the relapse frequency is extremely high: 90% of children with NS will respond to the treatment; however, an estimated 75% will relapse.

Mammalian TRP channel proteins form six-transmembrane cation-permeable channels, which may be grouped into six subfamilies based on amino acid sequence homology (TRPC, TRPV, TRPM, TRPA, and TRPML). Recent studies of TRP channels indicate that they are involved in numerous fundamental cell functions and are considered to play an important role in the pathophysiology of many diseases. Many TRPs are expressed in kidney along different parts of the nephron and growing evidence suggest that these channels are involved in hereditary as well as acquired kidney disorders.

The present application describes a series of novel pyridazinones as Transient Receptor Potential Channel 5 (TRPC5) inhibitors and a secondary therapeutic agent and are useful for treatment of kidney diseases. Further, the application discloses compounds and their preparation, use, pharmaceutical composition, and treatment.

Definitions

R₁, R₂ and R₃ = H, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteraryl, halogen, −OH, CN, cycloalkyl, −O-alkyl, −O-cycloalkyl, −O-aryl, aryl-O-aryl, −CF₃, −C(H)F₂, alkylene-CF₃, alkylene-C(H)F₂, −SO₂-alkyl, −O-alkylene-O-alkyl, −heterocyclyl-L-R₄, and heteroaryl-L-R₄;

R₄ = absent or alkyl, cycloalkyl, polycyclyl, aryl, heterocyclyl, heteraryl, −C(O)N(R₅)₂, and CF₃;

R₅ = H or alkyl;

R₆ = alkyl, cycloalkyl, aryl, heterocyclyl, heteraryl, alkylene-aryl, −C(O)N(R₅)₂, and CF₃;

L = absent or selected from the group consisting of methylene, −C(O)–, −SO₂–, CH₂N(Me)–, −N(R₅)(R₆)–, −C(R₅)(R₆)–, and −-O-R₆; and

one and only one R is -heterocyclyl-L-R₄ or -heteroaryl-L-R₄.

Key Structures

Biological Assay

The Transient Receptor Potential Channel 5 (TRPC5) activity assay was performed. The compounds described in this application were tested for their ability to inhibit TRPC5. The TRPC5 IC₅₀ (nM to μM) are shown in the following table.

Biological Data

The table below shows representative compounds were tested for TRPC5 inhibition. The biological data obtained from testing representative examples are listed in the following table.

For IC₅₀: “A” means ≤50 nM; “B” means >50 to ≤500 nM; “C” means >500 to <1 μM; and “D” means ≥1 μM.

Claims

Total claims: 26

Method of treatment claims: 26

Recent Review Articles

• 1.Kanthakumar P.; Adebiyi A.. Curr. Res. Physiol. 2021, 4, 17.
• 2.Van den Eynde C.; Vriens J.; De Clercq K.. Biochim. Biophys. Acta, Mol. Cell Res. 2021, 1868, 118950.
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• 5.Pablo J. L.; Greka A.. Trends Pharmacol. Sci. 2019, 40, 911.
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The author declares no competing financial interest.