title: Identification of multiple 5-HT₄ partial agonist clinical candidates for the treatment of Alzheimer's disease.
abstract: 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-HT(4)) 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-HT(4) 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-HT(4) partial agonist candidates 2d and 3 were chosen for clinical development.
authors.affiliation: Groton Laboratories, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States. michael.a.brodney@pfizer.com
authors.forename: Michael A
authors.initials: MA
authors.lastname: Brodney
authors.forename: David E
authors.initials: DE
authors.lastname: Johnson
authors.forename: Aarti
authors.initials: A
authors.lastname: Sawant-Basak
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Coffman
authors.forename: Elena M
authors.initials: EM
authors.lastname: Drummond
authors.forename: Emily L
authors.initials: EL
authors.lastname: Hudson
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Fisher
authors.forename: Hirohide
authors.initials: H
authors.lastname: Noguchi
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Waizumi
authors.forename: Laura L
authors.initials: LL
authors.lastname: McDowell
authors.forename: Alexandros
authors.initials: A
authors.lastname: Papanikolaou
authors.forename: Betty A
authors.initials: BA
authors.lastname: Pettersen
authors.forename: Anne W
authors.initials: AW
authors.lastname: Schmidt
authors.forename: Elaine
authors.initials: E
authors.lastname: Tseng
authors.forename: Kim
authors.initials: K
authors.lastname: Stutzman-Engwall
authors.forename: David M
authors.initials: DM
authors.lastname: Rubitski
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Vanase-Frawley
authors.forename: Sarah
authors.initials: S
authors.lastname: Grimwood
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000523:psychology; D000818:Animals; D016466:CHO Cells; D003072:Cognition Disorders / Q000188:drug therapy*; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D004285:Dogs; D054333:Drug Partial Agonism; D057809:HEK293 Cells; D000882:Haplorhini; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010539:Permeability; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D020033:Protein Isoforms / Q000378:metabolism; D011714:Pyrans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism; D058828:Serotonin 5-HT4 Receptor Agonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C578489:(4-(4-((R)-(tetrahydrofuran-3-yl)oxy)benzo(d)isoxazol-3-yloxymethyl)piperidin-1-ylmethyl)tetrahydropyran-4-ol; C578488:6-fluoro-3,3-dimethyl-2-oxo-2,3-dihydroindole-1-carboxylic Acid (1-(4-hydroxytetrahydropyran-4-ylmethyl)piperidin-4-ylmethyl)amide; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007211:Indoles; D010880:Piperidines; D020033:Protein Isoforms; D011714:Pyrans; D058828:Serotonin 5-HT4 Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4; D000242:Cyclic AMP