907607-49-2Relevant academic research and scientific papers
Identification of multiple 5-HT4 partial agonist clinical candidates for the treatment of alzheimers disease
Brodney, Michael A.,Johnson, David E.,Sawant-Basak, Aarti,Coffman, Karen J.,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
, p. 9240 - 9254 (2013/01/15)
The cognitive impairments observed in Alzheimers disease (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 modulate cholinergic function and therefore may provide a new mechanistic approach for treating cognitive deficits associated with AD. Herein we communicate the design and synthesis of potent, selective, and brain penetrant 5-HT4 agonists. The overall goal of the medicinal chemistry strategy was identification of structurally diverse clinical candidates with varying intrinsic activities. The exposure-response relationships between binding affinity, intrinsic activity, receptor occupancy, drug exposure, and pharmacodynamic activity in relevant preclinical models of AD were utilized as key selection criteria for advancing compounds. On the basis of their excellent balance of pharmacokinetic attributes and safety, two lead 5-HT4 partial agonist candidates 2d and 3 were chosen for clinical development.
BENZISOXAZOLE DERIVATIVES
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Page/Page column 46, (2008/06/13)
This invention relates to compounds of the formula (I): wherein A, B, R1, R4, m, and n are each as described herein or a pharmaceutically acceptable salt thereof, and compositions containing such compounds and the use of such compounds in the treatment of a condition mediated by 5-HT4 receptor activity such as, but not limited to, gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central 10 nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders such as cardiac failure and heart arrhythmia, diabetes and apnea syndrome.
