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.

Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment

“…3). This profile is in accordance with our objective, because prolonged exposure of G protein-coupled receptors to an agonist can result in receptor desensitization, which is often dependent on the degree of intrinsic activity (30). However, the selectivity of donecopride toward 5-HT 4 R is quite good, because among a panel of 42 common neurotransmitter receptors and transporters, only 5-HT 2B R and σ 2 R are more sensitive than 5-HT 4 R ( Table 2).…”

Intriguing possibilities and beneficial aspects of transporter-conscious drug design

“…Representative brain-penetrant compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) [56][57][58][59][60][61][62][63][64][65][66][67][68][69] are shown in Figure 16 with the exception of nucleic acid mimics. Although these Ncontaining groups were not transporter-consciously incorporated into the molecule of designed compounds in order to control ADMET, they, especially N-alkyl groups, might eventually act as transporter recognition unit from the result of their BBB permeability.…”

Novel tetracyclic benzo[b]carbazolones as highly potent and orally bioavailable ALK inhibitors: Design, synthesis, and structure—activity relationship study

“…Meanwhile, treating 7e with 1,6-dioxaspiro [2.5]octane in the presence of DIPEA followed by palladium-catalyzed hydrogenation generated compound 15c in 37% overall yield (two steps) [46]. yields [47].…”