학술논문
Identification of Multiple 5-HT4Partial Agonist Clinical Candidates for the Treatmentof Alzheimer’s Disease.
Document Type
Article
Author
Brodney, Michael A.; Johnson, David E.; Sawant-Basak, Aarti; Coffman, KarenJ.; Drummond, Elena M.; Hudson, Emily L.; Fisher, Katherine E.; Noguchi, Hirohide; Waizumi, Nobuaki; McDowell, Laura L.; Papanikolaou, Alexandros; Pettersen, Betty A.; Schmidt, Anne W.; Tseng, Elaine; Stutzman-Engwall, Kim; Rubitski, David M.; Vanase-Frawley, Michelle A.; Grimwood, Sarah
Source
Subject
*ALZHEIMER'S disease treatment
*CHOLINERGIC receptors
*CHOLINERGIC mechanisms
*NEURON analysis
*SEROTONIN receptors
*COGNITION disorders
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Language
ISSN
0022-2623
Abstract
The cognitive impairments observed in Alzheimer’sdisease (AD) are in part a consequence of reduced acetylcholine (ACh)levels resulting from a loss of cholinergic neurons. Preclinically,serotonin 4 receptor (5-HT4) agonists are reported to modulatecholinergic function and therefore may provide a new mechanistic approachfor treating cognitive deficits associated with AD. Herein we communicatethe design and synthesis of potent, selective, and brain penetrant5-HT4agonists. The overall goal of the medicinal chemistrystrategy was identification of structurally diverse clinical candidateswith varying intrinsic activities. The exposure–response relationshipsbetween binding affinity, intrinsic activity, receptor occupancy,drug exposure, and pharmacodynamic activity in relevant preclinicalmodels of AD were utilized as key selection criteria for advancingcompounds. On the basis of their excellent balance of pharmacokineticattributes and safety, two lead 5-HT4partial agonist candidates 2dand 3were chosen for clinical development. [ABSTRACT FROM AUTHOR]