Novel Azaindole Compounds as Phosphodiesterase 4B Inhibitors for Treating Immune-Inflammatory Diseases or Disorders

Abstract

This application reveals a novel series of azaindole compounds identified as phosphodiesterase 4B (PDE4B) inhibitors. The chemical synthesis, enzymatic inhibitory activity against PDE4B, selectivity over PDE4D, and pharmaceutical compositions are disclosed.

Important Compound Classes

Title

Azaindole compounds and their use as phosphodiesterase inhibitors

Patent Publication Number

WO 2024/118524 Al

URL

https://patents.google.com/patent/WO2024118524A1/en

Publication Date

June 06, 2024

Priority Application

US63/428, 390

Priority Date

November 28, 2022

Inventors

Zhang, D.; Gray, D.; Nguyen, H.; Chappie, T. A.; Chandrasekaran, R. Y.; Helal, C. J.; Lachapelle, E. A.; Patel, N. C.; Sciabola, S.; Verhoest, P. R.; Wager, T. T.

Assignee Company

Cerevel Therapeutics, LLC [US/US]; 222 Jacobs Street, Suite 200, Cambridge, Massachusetts, 02141, United States. Pfizer Inc. [US/US]; 66 Hudson Boulevard East, New York, New York 10001-2192, United States

Disease Area

PDE4B-related diseases, such as metabolic autoimmune, inflammatory, dermatological and fibrotic diseases or disorders.

Biological Target

Phosphodiesterase 4B (PDE4B)

Summary

PDE4, a member of the 11 phosphodiesterase families, is specifically responsible for the hydrolysis of cyclic adenosine monophosphate (cAMP). Four genes encode PDE4 subtypes, including PDE4A, PDE4B, PDE4C, and PDE4D. Among these subtypes, PDE4B is highly expressed in the brain, heart, lungs, and skeletal muscle, where it serves as a key regulator of various physiological processes, highlighting its potential as an important therapeutic target.

PDE4B inhibitors have shown promising therapeutics in the treatment of inflammatory diseases and disorders. A notable selective PDE4B inhibitor, Nerandomilast (currently in phase III trials), has demonstrated significant efficacy in patients with idiopathic pulmonary fibrosis (IPF). However, the clinical use of PDE4B inhibitors is often limited by gastrointestinal side effects, such as nausea and emesis, primarily linked to the inhibition of PDE4D. Thus, selective PDE4B inhibitors with reduced side effects are needed to address these unmet clinical needs.

This patent describes novel azaindole compounds as selective PDE4B inhibitors. These compounds have the potential to improve treatment options for PDE4B-related diseases, such as immune-inflammatory diseases or disorders.

Definitions

X = C or N;

Y = C or N and Z = C or N;

When Y = N, Z = C, the bond between Y and C₂ is a single bond, and the bond between Z and C₂ is a double bond;

When Z = N, Y = C, the bond between Y and C₂ is a double bond, and the bond between Z and C₂ is a single bond;

R₁ = H, halogen, or C_1–3alkyl;

R₂ = H, halogen, C_1–3alkoxy, or −CN;

R₃ = H, halogen, or C_1–3alkoxy;

R₄ = H, C_1–6alkanol, C_3–6cycloalkanol, C_2–6alkyl-O-R₆, C_3–6cycloalkyl, or C_1–6alkyl;

R₅ = H, C_1–6alkanol, C_3–6cycloalkanol, C_2–6alkyl-O-R₆, C_3–6cycloalkyl, or C_1–6alkyl;

R₆ = C_1–25alkyl, C(O)-C_1–25alkyl, C_2–10alkenyl, C_2–10alkynyl, C_3–8cycloalkyl, 5–10 membered heterocyclic groups, C_6–10aryl, C_1–3alkyl-O-C_1–25alkyl, 5–10 membered heteroaryl groups, , and amino acids;

R₇ and R₈ are independently selected from C_1–25alkyl, C_2–10alkenyl, C_2–10alkynyl, C_3–8cycloalkyl, 5–10 membered heterocyclic groups, C_6–10aryl, C_1–25alkyl, C_1–3alkyl, and 5–10 membered heteroaryl groups;

Or R₇ or R₈ = NH₄⁺, Na⁺, or K⁺.

Key Structures

Biological Assay

The PDE4B1 and PDE4D3 enzyme assays were performed using scintillation proximity assay (SPA) technology to assess the in vitro inhibition of human recombinant PDE4B1 and PDE4D3 activities. This method utilizes scintillant-coated beads that bind to the target protein and emit light upon radioligand binding. The emitted light is detected using scintillation counters or plate readers, providing a sensitive measure of enzymatic activity. [³H]-cAMP was used as the substrate to measure PDE4-dependent changes in cAMP levels. The range IC₅₀ values are presented in the table below.

Biological Data

Claims

Total claims: 23

Compound claims: 18

Pharmaceutical composition claims: 2

Method claims: 3

Recent Review Articles

See refs (1−4).

A Recent Review Article

See ref (5).

S.H.L. gratefully acknowledges the support provided, in part, by the NIH grants (AG078058 and AG079956).

The authors declare no competing financial interest.