Identification of Multiple 5‑HT4 Partial Agonist Clinical Candidates for the Treatment of Alzheimer’s Disease

• Published in: Journal of medicinal chemistry Vol. 55; no. 21; pp. 9240 - 9254
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.11.2012; Amer Chemical Soc
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - psychology; Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Chemistry, Medicinal; CHO Cells; Cognition Disorders - drug therapy; Cricetinae; Cricetulus; Cyclic AMP - biosynthesis; Dogs; Drug Partial Agonism; Haplorhini; HEK293 Cells; Humans; In Vitro Techniques; Indoles - chemical synthesis; Indoles - pharmacokinetics; Indoles - pharmacology; Life Sciences & Biomedicine; Madin Darby Canine Kidney Cells; Male; Microsomes, Liver - metabolism; Permeability; Pharmacology & Pharmacy; Piperidines - chemical synthesis; Piperidines - pharmacokinetics; Piperidines - pharmacology; Protein Isoforms - metabolism; Pyrans - chemical synthesis; Pyrans - pharmacokinetics; Pyrans - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT4 - metabolism; Science & Technology; Serotonin 5-HT4 Receptor Agonists - chemical synthesis; Serotonin 5-HT4 Receptor Agonists - pharmacokinetics; Serotonin 5-HT4 Receptor Agonists - pharmacology; Stereoisomerism; Structure-Activity Relationship; CHOLINERGIC HYPOTHESIS; LIGANDS; MEMORY; ACETYLCHOLINE; RECEPTOR AGONISTS; PRUCALOPRIDE; DRUGS; BINDING
• DOI: 10.1021/jm300953p
• ISSN: 0022-2623

The cognitive impairments observed in Alzheimer’s 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.