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.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Alzheimer Disease / drug therapy*
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Alzheimer Disease / psychology
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Animals
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CHO Cells
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Cognition Disorders / drug therapy*
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Cricetinae
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Cricetulus
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Cyclic AMP / biosynthesis
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Dogs
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Drug Partial Agonism
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HEK293 Cells
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Haplorhini
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Humans
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In Vitro Techniques
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Indoles / chemical synthesis*
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Indoles / pharmacokinetics
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Indoles / pharmacology
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Madin Darby Canine Kidney Cells
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Male
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Microsomes, Liver / metabolism
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Permeability
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Piperidines / chemical synthesis*
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Piperidines / pharmacokinetics
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Piperidines / pharmacology
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Protein Isoforms / metabolism
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Pyrans / chemical synthesis*
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Pyrans / pharmacokinetics
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Pyrans / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptors, Serotonin, 5-HT4 / metabolism
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Serotonin 5-HT4 Receptor Agonists / chemical synthesis*
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Serotonin 5-HT4 Receptor Agonists / pharmacokinetics
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Serotonin 5-HT4 Receptor Agonists / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
Substances
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(4-(4-((R)-(tetrahydrofuran-3-yl)oxy)benzo(d)isoxazol-3-yloxymethyl)piperidin-1-ylmethyl)tetrahydropyran-4-ol
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6-fluoro-3,3-dimethyl-2-oxo-2,3-dihydroindole-1-carboxylic Acid (1-(4-hydroxytetrahydropyran-4-ylmethyl)piperidin-4-ylmethyl)amide
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Indoles
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Piperidines
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Protein Isoforms
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Pyrans
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Serotonin 5-HT4 Receptor Agonists
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Receptors, Serotonin, 5-HT4
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Cyclic AMP