| Autor: |
Brodney MA; Groton Laboratories, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States. michael.a.brodney@pfizer.com, Johnson DE, Sawant-Basak A, Coffman KJ, Drummond EM, Hudson EL, Fisher KE, Noguchi H, Waizumi N, McDowell LL, Papanikolaou A, Pettersen BA, Schmidt AW, Tseng E, Stutzman-Engwall K, Rubitski DM, Vanase-Frawley MA, Grimwood S |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2012 Nov 08; Vol. 55 (21), pp. 9240-54. Date of Electronic Publication: 2012 Oct 05. |
| DOI: |
10.1021/jm300953p |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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