Abstract
Provided herein are novel AT2R antagonists, pharmaceutical compositions, use of such compounds in treating chronic pain, and processes for preparing such compounds.
Important Compound Classes
Title
AT2R Antagonists and Uses Thereof
Patent Publication Number
WO 2023/224853 A1
Publication Date
November 23, 2023
Priority Applications
US 63/342,828 and US 63/413,691
Priority Dates
May 17, 2022 and October 6, 2022
Inventors
Beauchamp, T. J.; Chen, Z.; Conner, S. E.; Erickson, J. A.; Garcia Paredes, M. C.; Lineswala, J. P.; Sher, E.; Thapa, B.; Winneroski, L. L., II
Assignee Company
Eli Lilly and Company, USA
Disease Area
Chronic pain
Biological Target
AT2R
Summary
Chronic pain is a highly prevalent condition with huge societal impact. Despite the high disease burden and impact on society, management of chronic pain is currently unsatisfactory. The angiotensin 2 receptors (AT2R) are useful in the treatment of chronic pain. Chronic pain can be divided into different categories based on the mechanism: nociceptive, neuropathic, and mixed. Nociceptive pain is caused by stimuli, including inflammation, that potentially or actually cause an injury to non-neuronal tissues. This activates nociceptive receptors in the peripheral sensory system. Pain due to osteoarthritis is a classic example of somatic nociceptive pain. Neuropathic pain is caused by injuries to or disease of the central or peripheral nervous system. Pain due to diabetic peripheral neuropathy is a classic example of peripheral neuropathic pain. Conditions that exhibit features of both nociceptive and neuropathic pain are categorized as mixed pain. Damaged nerves and painful neuromas have higher AT2R expression than normal nerves. AT2R antagonists have been proven to be useful for relieving pain in animal experiments.
The present application describes a series of novel AT2R antagonists for treating chronic pain. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.
Definitions
R1 = C1–C6 alkyl, C3–C6 cycloalkyl, C3–C9 heterocycloalkyl, or C6–C10 aryl, wherein the C1–C6 alkyl, C3–C6 cycloalkyl, C3–C9 heterocycloalkyl, or C6–C10 aryl is optionally substituted with one or more R1a;
R2 = C1–C6 alkyl, C3–C6 cycloalkyl, C3–C9 heterocycloalkyl, or C6–C10 aryl, wherein the C1–C6 alkyl, C3–C6 cycloalkyl, C3–C9 heterocycloalkyl, or C6–C10 aryl is optionally substituted with one or more R2a;
R3 = H or C1–C6 alkyl; and
X = C5–C10 heteroaryl, C6–C10 aryl, or
Key Structures
Biological Assay
The AT2R in vitro binding affinity assay was performed. The compounds described in this application were tested for their ability to inhibit AT2R. The AT2R Ki values (μM) are shown in the following table.
Biological Data
The table below shows representative
compounds that were tested for AT2R inhibition and the
biological data obtained from testing representative examples.
Claims
Total claims: 41
Compound claims: 30
Pharmaceutical composition claims: 1
Method of treatment claims: 5
Use of compound claims: 5
Recent Review Articles
The author declares no competing financial interest.
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