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

  • J Med Chem. 2021 Aug 12;64(15):10641-10665. doi: 10.1021/acs.jmedchem.1c00703.
Ramakrishna Nirogi  1 ,  Abdul Rasheed Mohammed  1 ,  Anil Karbhari Shinde  1 ,  Shankar Reddy Gagginapally  1 ,  Durga Malleshwari Kancharla  1 ,  Srinivasa Rao Ravella  1 ,  Narsimha Bogaraju  1 ,  Vanaja Reddy Middekadi  1 ,  Ramkumar Subramanian  1 ,  Raghava Choudary Palacharla  1 ,  Vijay Benade  1 ,  Nageswararao Muddana  1 ,  Renny Abraham  1 ,  Rajesh Babu Medapati  1 ,  Jagadeesh Babu Thentu  1 ,  Venkat Reddy Mekala  1 ,  Surendra Petlu  1 ,  Bujji Babu Lingavarapu  1 ,  Sivasekhar Yarra  1 ,  Narendra Kagita  1 ,  Vinod Kumar Goyal  1 ,  Santosh Kumar Pandey  1 ,  Venkat Jasti  1
Affiliations
  • 1. Suven Life Sciences Limited, Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034, India.
PMID: 34251799 DOI: 10.1021/acs.jmedchem.1c00703
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.

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