A Targeted Approach for Treating Neurodegenerative Diseases with nSMase2 Inhibitors

Introduction

Neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS), are among the most challenging conditions for the healthcare system. These diseases progressively damage nerve cells in the brain and spinal cord, leading to cognitive decline, motor function loss, and, ultimately, death. Current treatments offer only symptomatic relief and fail to address the underlying causes of these conditions. With the aging global population, the need for new, targeted therapeutic strategies has never been greater. Our patented small-molecule inhibitors of neutral sphingomyelinase 2 (nSMase2) provide an innovative approach to treating neurodegenerative diseases by targeting a key enzyme involved in neuroinflammation and cell death.

Limitations of Existing Treatments

Current therapies for neurodegenerative diseases primarily focus on symptom management, offering minimal impact on disease progression. These treatments often involve addressing secondary symptoms such as tremors or memory loss, without halting the disease itself. Additionally, many neurodegenerative diseases, like ALS and Alzheimer’s, still have no cure, and treatment options remain limited in their ability to slow down or reverse neurological damage. The healthcare sector is in dire need of a therapeutic approach that addresses the root causes of these diseases, providing real hope for long-term disease management and improved quality of life for patients.

A Novel Approach with nSMase2 Inhibitors

Our patented technology offers a breakthrough by targeting the enzyme neutral sphingomyelinase 2 (nSMase2), which is known to play a critical role in the progression of neurodegenerative diseases. By inhibiting nSMase2 activity, these small-molecule inhibitors reduce the production of ceramide, a lipid molecule involved in neuroinflammation and neuronal death. This approach aims to slow down or stop the neurodegenerative process, directly addressing the cellular mechanisms behind these diseases.

This therapy offers the potential for disease-modifying effects, giving patients more than just temporary relief from symptoms. Instead, it targets the biological pathways that contribute to neurodegeneration, offering hope for slowing disease progression and possibly preventing further neuronal damage.

Advantages of Licensing This Technology

Targeted Mechanism: The inhibition of nSMase2 addresses the cellular processes leading to neurodegeneration, potentially slowing disease progression.
Broader Therapeutic Applications: While initially focused on Alzheimer’s, Parkinson’s, and ALS, this approach could have broader applications for other neurodegenerative conditions.
Disease-Modifying Potential: Unlike current treatments that only manage symptoms, this technology offers the possibility of slowing or halting the disease process at its core.
Reduced Inflammation: By targeting neuroinflammation, these inhibitors could improve overall brain health and long-term patient outcomes.

A Pivotal Opportunity in Neurodegenerative Disease Treatment

Licensing this small-molecule inhibitor technology positions your company to be at the forefront of neurotherapeutic innovation. As the demand for effective neurodegenerative treatments continues to rise, this patent offers a pathway to providing patients and healthcare providers with new hope for managing and potentially altering the course of these devastating diseases.

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Abstract
Claims

Small molecule inhibitors of neutral sphingomyelinase 2 (nSMase2) and their use for treating neurodegenerative diseases, such as, neurodegenerative diseases associated with high levels of ceramide, including, but not limited to Alzheimer’s disease (AD), HIV-associated neurocognitive disorder (HAND), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), and, in other aspects, for treating cancer, are provided.

That which is claimed:

1. A compound of formula (I):

R₃is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, substituted or unsubstituted thioalkyl, substituted or unsubstituted aryl, and halogen;

R₄is selected from the group consisting of H, substituted or unsubstituted alkyl, and substituted or unsubstituted aryl;

R₅is selected from the group consisting of H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and a substituted or unsubstituted multicyclic aryl or multicyclic heteroaryl ring;

R₆is selected from the group consisting of H or substituted or unsubstituted C_1-6alkyl; and

R₇is selected from the group consisting of —C(═O)—(CR_yR_z)_m—R₈, —C(═O)—(CR_yR_z)_m—O—R₈, —C(═O)—O—(CR_yR_z)_m—R₈, and —S(═O)₂—R₉, wherein each m is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6, R_yand R_zare each independently H, alkoxyl, or halogen, R₈and R₉are each independently selected from the group consisting of substituted or unsubstituted alkyl, —CF₃, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloheteroaryl, substituted or unsubstituted multicyclic aryl or heteroaryl ring, and NR₁₀R₁₁, wherein R₁₀and R₁₁are each independently selected from the group consisting of H, substituted or unsubstituted C_1-6alkyl, and substituted or unsubstituted aryl; and

pharmaceutically acceptable salts thereof.

2. The compound of claim 1, wherein the compound of formula (I) is:

wherein:

p is an integer selected from the group consisting of 0, 1, 2, 3, 4, and 5;

each R₁₂is independently selected from the group consisting of substituted or unsubstituted alkyl, hydroxyl, alkoxyl, halogen, cyano, amino, —CF₃, —O—CF₃, substituted or unsubstituted cycloheteroalkyl, —NR₁₃(C═O)R₁₄, —S(═O)₂—R₁₅, —S(═O)₂—NR₁₅R₁₆, —C(═O)—R₁₇, —C(═O)—O—R₁₈, and —C(═O)—NR₁₉R₂₀, wherein R₁₃is selected from the group consisting of H or substituted or unsubstituted C_1-6alkyl, R₁₄is substituted or unsubstituted C_1-6alkyl or —O—R₂₁, and R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁are each independently H or substituted or unsubstituted C_1-6alkyl.

3. The compound of claim 2, wherein R₆is H and R₇is —C(═O)—(CR_yR_z)_m—R₈, wherein m is 0 and R₈is C_1-6alkyl.

4. The compound of claim 3, wherein the compound of formula (I) is selected from the group consisting of:

5. The compound of claim 2, wherein R₆is H and R₇is selected from the group consisting of —C(═O)—(CR_yR_z)_m—R₈, —C(═O)—(CR_yR_z)_m—O—R₈, —C(═O)—O—(CR_yR_z)_m—R₈, wherein each m is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6, R_yand R_zare each independently H, alkoxyl, or halogen, R₈is selected from the group consisting of substituted or unsubstituted alkyl, —CF₃, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloheteroaryl, substituted or unsubstituted multicyclic aryl or heteroaryl ring, and NR₁₀R₁₁, wherein R₁₀and R₁₁are each independently selected from the group consisting of H, substituted or unsubstituted C_1-6alkyl, and substituted or unsubstituted aryl.

6. The compound of claim 5, wherein the compound of formula (I) is selected from the group consisting of:

7. The compound of claim 2, wherein R₆is H and R₇is —S(═O)₂—R₉.

8. The compound of claim 5, wherein the compound of formula (I) is selected from the group consisting of:

9. The compound of claim 1, wherein R₅is selected from the group consisting of H, halogen, and substituted or unsubstituted alkyl.

10. The compound of claim 9, wherein the compound of formula (I) is selected from the group consisting of:

11. The compound of claim 1, wherein R₅is a substituted or unsubstituted multicyclic aryl or multicyclic heteroaryl ring.

12. The compound of claim 11, wherein the compound of formula (I) is selected from the group consisting of:

13. The compound of claim 1, wherein R₅is a substituted or unsubstituted heteroaryl.

14. The compound of claim 13, wherein the compound of formula (I) is selected from the group consisting of:

15. A method for treating a subject afflicted with Alzheimer’s disease, the method comprising administering to a subject in need of treatment thereof an effective amount of compound of claim 1.

16. The method of claim 15, wherein the administration of an effective amount of a compound of formula (I) to the subject decreases a neutral sphingomyelinase 2 (nSMase2) activity or expression or decreases a level of ceramide in the subject.

17. A method for inhibiting neutral sphingomyelinase 2 (nSMase2), the method comprising administering to a subject, cell, or tissue an amount of a compound of claim 1.

Title

Small molecule inhibitors of neutral sphingomyelinase 2 (nSMase2) for the treatment of neurodegenerative diseases

Inventor(s)

Barbara Slusher, Camilo Rojas, Ajit G. Thomas, Radim Nencka, Michal Sala, Hubert Hrebabecky, Norman Haughey

Assignee(s)

Johns Hopkins University, Institute of Organic Chemistry and Biochemistry of ASCR vvi

Patent #

11427590

Patent Date

August 30, 2022