Novel Benzimidazole Derivatives as Transient Receptor Potential Channel 6 (TRPC6) Inhibitors

Important Compound Classes

Title

Benzimidazole Derivatives and Their Uses

Patent Publication Number

WO 2020/210597 A1

Publication Date

October 15, 2020

Priority Application

US 62/832,374

Priority Date

April 11, 2019

Inventors

Chakka, N.; Gao, H.; Guzman-Perez, A.; Johnson, B. M.; Kieffer, M.; Malinowski, J.; Schenkel, L.

Assignee Company

Amgen Inc.; USA

Disease Area

Nephrotic syndrome, minimal change disease, focal segmental glomerulosclerosis, collapsing glomerulopathy, membranoproliferative glomerulonephritis, IGA nephropathy, acute renal failure, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension acute lung disorder, acute respiratory distress syndrome (ARDS), heart failure, stroke, malignant tumor, and muscular dystrophy

Biological Target

Transient Receptor Potential Channel 6 (TRPC6) protein

Summary

The TRPC6 protein, a member of Transient Receptor Potential (TRP) family, which is a nonselective cation-permeable channel, is activated by diacylglycerol and the like produced by activation of phospholipase C and exerts physiological and pathophysiological effects. TRPC6 has effects such as cardiac pathological hypertrophy, fibrosis, progression of myocardial damage in the muscular dystrophy, acute pulmonary vasoconstriction, pathological progression in chronic hypoxia-induced pulmonary hypertension, allergic airway response, migration of cells such as neutrophils, increased permeability of endothelial cells on inflammation, pathological flattening of podocytes, progression of glomerular injury, and proliferation of malignant tumors and is diversely distributed in brain, heart, lungs, kidneys, placenta, ovaries, and spleen.

In familial focal segmental glomerulosclerosis (FSGS), gain-of-function mutants of TRPC6 have been identified and in steroid resistant nephrotic syndrome or idiopathic pulmonary arterial hypertension patients, a single nucleotide polymorphism in the promoter region that increases mRNA expression of TRPC6 has been identified. Thus, it is considered that hyperfunction and increased expression of TRPC6 contribute to pathological progression of nephrotic syndrome and pulmonary hypertension. Furthermore, increased expression of TRPC6 has been reported in minimal change nephrotic syndrome, membranous nephropathy, and diabetic nephropathy.

The present application describes a series of novel benzimidazole derivatives as TRPC6 inhibitors and are useful for treatment of nephrotic syndrome, minimal change disease, FSGS, collapsing glomerulopathy, membranoproliferative glomerulonephritis, IGA nephropathy, acute renal failure, chronic renal failure, diabetic nephropathy, sepsis, pulmonary hypertension acute lung disorder, ARDS, heart failure, stroke, malignant tumor, and muscular dystrophy. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

R₁ = halogen, CN, C_1–6 alkoxy;

R₂ and R₃ = halogen;

R₄ = halogen, CN, C_1–6 alkyl, C_1–6 alkoxy;

R₅ and R₆ = H; and

A = CH or N.

Key Structures

Biological Assay

The TRPC6 calcium flux assay was performed. The compounds described in this application were tested for their ability to inhibit TRPC6. The hTRPC6 IC₅₀ (μM) values are shown in the following table.

Biological Data

The table below shows representative compounds were tested for TRPC6 inhibition. The biological data obtained from testing representative examples are listed in the following table.

Claims

Total claims: 9

Compound claims: 4

Pharmaceutical composition claims: 2

Method of treatment claims: 2

Method of modulation claims: 1

Recent Review Articles

• 1.Zhang C.; Fang X.; Zhang H.; Gao W.; Hsu H. J.; Roman R. J.; Fan F.. Physiol. Rep. 2021, 9, e14688.
• 2.Achanta S.; Jordt S.. Ann. N. Y. Acad. Sci. 2020, 1480, 73.
• 3.Huang Q.; Wang X.; Lin X.; Zhang J.; You X.; Shao A.. Biomed. Pharmacother. 2020, 131, 110647.
• 4.Wang H.; Cheng X.; Tian J.; Xiao Y.; Tian T.; Xu F.; Hong X.; Zhu M. X.. Pharmacol. Ther. 2020, 209, 107497.
• 5.Dryer S. E.; Roshanravan H.; Kim E. Y.. Biochim. Biophys. Acta, Mol. Basis Dis. 2019, 1865, 1041.
• 6.Pablo J. L.; Greka A.. Trends Pharmacol. Sci. 2019, 40, 911.

The author declares no competing financial interest.