Novel Compounds as Polycystin‑1 Correctors for Treating Autosomal Dominant Polycystic Kidney Disease

Abstract

Provided herein are novel compounds as polycystin-1 (PC1) correctors, pharmaceutical compositions, use of such compounds in treating autosomal dominant polycystic kidney disease (ADPKD), and processes for preparing such compounds.

Important Compound Classes

Title

Compounds for the Treatment of Kidney Disease

Patent Publication Number

WO 2025/096453 A1

URL: https://patents.google.com/patent/WO2025096453A1/en

Publication Date

May 8, 2025

Priority Application

US 63/594,357

Priority Date

October 30, 2023

Inventors

Austin, J. R.; Boyall, D.; Chudyk, E. I.; Deneka, D.; Dodd, J.; Everitt, S. R.; Faust, B. R.; Fraysse, D. J. M.; Gladding, J. A.; Hepburn, H. B.; Keily, S.; Knegtel, R. M.; Maxwell, B. D.; Mui, J. J. B.; Nasrallah, C.; Pinder, J. L.; Rutherford, A. P.; Salman, A. A.; Wright, M.

Assignee Company

Vertex Pharmaceuticals Incorporated, USA

Disease Area

Autosomal dominant polycystic kidney disease (ADPKD)

Biological Target

PC1

Summary

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder in which bilateral cysts develop in the kidneys. The cysts in polycystic kidney disease are noncancerous, fluid-filled sacs. The enlarging cysts can substantially increase kidney size and contribute to the compression, loss of surrounding renal tissue, and progressive decline of kidney function. The damage caused by the enlarging cysts and increase in kidney size ultimately lead to end-stage kidney disease (ESKD), kidney failure, and premature mortality. ADPKD is a heterogeneous renal disease with a high degree of symptom variability, including hypertension, nocturia, polyuria, hematuria, palpable kidneys, kidney stones, abdominal and flank pain, recurrent urinary tract infections, intercranial aneurysms, vascular dissections, valvular heart disease, hepatic and/or pancreatic cysts, diverticulosis, and abdominal wall hernias.

ADPKD is a Mendelian disease most commonly caused by germline loss of function mutations in one allele of the polycystin (PC) genes, PKD1, which encodes polycystin-1 (PC1) or PKD2, which encodes polycystin-2 (PC2). Mutations in either gene cause decreased expression of the PC1-PC2 complex at cell membranes.

The present application describes a series of novel compounds as polycystin-1 (PC1) correctors for the treatment of autosomal dominant polycystic kidney disease (ADPKD). Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

The = a single bond or a double bond, wherein when a single bond is present, X₁ is and X₂ is and when a double bond is present, X₁ is and X₂ is ;

R₁ = H, C₁–C₃ alkyl (substituted with 0–2 groups selected from oxo, hydroxy and amino), C₁–C₃ alkoxy, halogen and cyano;

R₂ = H and C₁–C₃ alkyl; R₃ = H, C₁–C₃ alkyl, halogen and cyano;

R₆ and R₉ = H, C₁–C₃ alkyl, C₁–C₃ alkoxy, halogen and cyano; R₇ = H, C₁–C₃ alkyl and halogen; and

Y = OR₈, N­(R₈)₂ and 3–10 membered heterocyclyl or 3–10 membered heteroaryl, each of which is substituted with 0–2 groups selected from N­(R₈)₂, hydroxyl, oxo, C₁–C₃ alkoxy and C₁–C₃ alkyl.

Key Structures

Biological Assay

The ADPKD/PC1 activity assay was performed. The compounds described in this application were tested for their ability to correct PC1. The PC1 EC₅₀ (μM) values are shown in the following Table.

Biological Data

The Table below shows representative compounds that were tested for PC1 corrections. The biological data obtained from testing representative examples are listed in the following Table. For EC50: ++++ means ≤ 0.05 μM

Claims

Total claims: 35

Compound claims: 32

Pharmaceutical composition claims: 1

Method of treatment claims: 1

Use of compound claims: 1

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The author declares no competing financial interest.