Discovery and Preclinical Characterization of Usmarapride (SUVN-D4010): A Potent, Selective 5-HT4 Receptor Partial Agonist for the Treatment of Cognitive Deficits Associated with Alzheimer's Disease.

Abstract

A series of oxadiazole derivatives were synthesized and evaluated as 5-hydroxytryptamine-4 receptor (5-HT4R) partial agonists for the treatment of cognitive deficits associated with Alzheimer's disease. Starting from a reported 5-HT4R antagonist, a systematic structure-activity relationship was conducted, which led to the discovery of potent and selective 5-HT4R partial agonist 1-isopropyl-3-{5-[1-(3-methoxypropyl) piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate (Usmarapride, 12l). It showed balanced physicochemical-pharmacokinetic properties with robust nonclinical efficacy in cognition models. It also showed disease-modifying potential, as it increased neuroprotective soluble amyloid precursor protein alpha levels, and dose-dependent target engagement and correlation of efficacy with oral exposures. Phase 1 clinical studies have been completed and projected efficacious concentration was achieved without any major safety concerns. Phase 2 enabling long-term safety studies have been completed with no concerns for further development.

• Authors: Ramakrishna Nirogi, Abdul Rasheed Mohammed, Anil Karbhari Shinde, Shankar Reddy Gagginapally, Durga Malleshwari Kancharla, Srinivasa Rao Ravella, Narsimha Bogaraju, Vanaja Reddy Middekadi, Ramkumar Subramanian, Raghava Choudary Palacharla, Vijay Benade, Nageswararao Muddana, Renny Abraham, Rajesh Babu Medapati, Jagadeesh Babu Thentu, Venkat Reddy Mekala, Surendra Petlu, Bujji Babu Lingavarapu, Sivasekhar Yarra, Narendra Kagita, Vinod Kumar Goyal, Santosh Kumar Pandey, Venkat Jasti
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 15 Pg. 10641-10665 (08 12 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 34251799 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Neuroprotective Agents
• Serotonin 5-HT4 Receptor Agonists
• Receptors, Serotonin, 5-HT4

Topics

• Alzheimer Disease (drug therapy, metabolism)
• Cognition Disorders (drug therapy, metabolism)
• Dose-Response Relationship, Drug
• Drug Discovery
• Humans
• Molecular Structure
• Neuroprotective Agents (chemical synthesis, chemistry, pharmacology)
• Receptors, Serotonin, 5-HT4 (metabolism)
• Serotonin 5-HT4 Receptor Agonists (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship