Synthesis of GR 125487, a selective 5-HT₄ receptor antagonist

<p>The 5-HT₄ receptor (5-HT₄R) agonists are important in treating gastrointestinal motility disorders. Their role is currently being evaluated for the treatment of cognitive and mood disorders. A selective 5-HT₄R antagonist GR 125487 is used in many biological assays to cross confirm the 5-HT₄R agonist’s activity. A practical synthesis of GR 125487 is developed so as to have it in desired quantities. The synthesis consists of seven steps starting from commercially available methyl 5-fluoroindole 3-carboxylate. The GR 125487 thus synthesized was used in blocking the activity of 5-HT₄R agonist compound in animal models of cognition.</p

Practical synthesis of 5-amino-6-chlorochroman-8-carboxylic acid – a key intermediate for several potent 5-HT₄ receptor agonists

<div><p>Synthetic routes for 5-amino-6-chlorochroman-8-carboxylic acid 1 a key intermediate for several potent 5-HT₄ agonists have been explored. An efficient, high yielding, and a concise synthetic route has been established with significant modifications to the earlier reported synthetic protocols, where we have avoided the use of toxic and corrosive reagents and reduced the reaction temperature from reflux to room temperature wherever is possible. We have also reduced the number of steps to reach the target compound and avoided the use of silica gel column purifications.</p></div

Synthesis, Structure–Activity Relationships, and Preclinical Evaluation of Heteroaromatic Amides and 1,3,4-Oxadiazole Derivatives as 5‑HT₄ Receptor Partial Agonists

Alzheimer’s disease (AD) is a neurodegenerative disorder that has a higher prevalence and incidence in people older than 60 years. The need for improved AD therapies is unmet as the current therapies are symptomatic with modest efficacy. Partial agonists of the 5-HT₄ receptor (5-HT₄R) offer both symptomatic and disease-modifying treatments as they shift amyloid-precursor-protein (APP) processing from the amyloidogenic pathway to the nonamyloidogenic pathway by activating the α-secretase enzyme. In addition, they also offer symptomatic treatment by increasing levels of the neurotransmitter acetylcholine in the brain. Because of this fascinating dual mechanism of action, several chemical scaffolds having 5-HT₄R pharmacophores were designed and evaluated. Most of the synthesized compounds showed potent in vitro affinities and in vivo efficacies. Upon analysis of focused structure–activity relationships, compound <b>4o</b> was identified as a potent 5-HT₄R partial agonist with favorable ADME properties and good in vivo efficacy. GR-125487, a selective 5-HT₄R antagonist, attenuated the activity of compound <b>4o</b> in the novel-object-recognition-test cognition model

Synthesis, Structure–Activity Relationships, and Preclinical Evaluation of Heteroaromatic Amides and 1,3,4-Oxadiazole Derivatives as 5‑HT₄ Receptor Partial Agonists

Alzheimer’s disease (AD) is a neurodegenerative disorder that has a higher prevalence and incidence in people older than 60 years. The need for improved AD therapies is unmet as the current therapies are symptomatic with modest efficacy. Partial agonists of the 5-HT₄ receptor (5-HT₄R) offer both symptomatic and disease-modifying treatments as they shift amyloid-precursor-protein (APP) processing from the amyloidogenic pathway to the nonamyloidogenic pathway by activating the α-secretase enzyme. In addition, they also offer symptomatic treatment by increasing levels of the neurotransmitter acetylcholine in the brain. Because of this fascinating dual mechanism of action, several chemical scaffolds having 5-HT₄R pharmacophores were designed and evaluated. Most of the synthesized compounds showed potent in vitro affinities and in vivo efficacies. Upon analysis of focused structure–activity relationships, compound <b>4o</b> was identified as a potent 5-HT₄R partial agonist with favorable ADME properties and good in vivo efficacy. GR-125487, a selective 5-HT₄R antagonist, attenuated the activity of compound <b>4o</b> in the novel-object-recognition-test cognition model