N-Substituted pyrrolidines and tetrahydrofurans as novel AMPAR positive modulators

Thewlis, Kevin M.; Aldegheri, Laura; Harries, Mark H; Mookherjee, Claudette; Oliosi, Beatrice; Ward, Simon E.

doi:10.1016/j.bmcl.2010.09.062

Cited by 12 publications

(5 citation statements)

References 12 publications

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“…Additional analyses of these virtual compounds by superimposing their structures onto the crystal structure of 5 indicated the cis-isomers were optimal to match the bioactive conformations. Consistent with prior findings, 29 further consideration of the physicochemical properties of these molecules allowed additional refinement and selection of the cis-tetrahydrofuran (THF) ether analogues as the primary series (Figure 4B, A = O).…”

Section: ■ Results and Discussionsupporting

confidence: 77%

The Discovery and Characterization of the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Potentiator N-{(3S,4S)-4-[4-(5-Cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242)

et al. 2015

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A unique tetrahydrofuran ether class of highly potent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators has been identified using rational and structure-based drug design. An acyclic lead compound, containing an ether-linked isopropylsulfonamide and biphenyl group, was pharmacologically augmented by converting it to a conformationally constrained tetrahydrofuran to improve key interactions with the human GluA2 ligand-binding domain. Subsequent replacement of the distal phenyl motif with 2-cyanothiophene to enhance its potency, selectivity, and metabolic stability afforded N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242, 3), whose preclinical characterization suggests an adequate therapeutic index, aided by low projected human oral pharmacokinetic variability, for clinical studies exploring its ability to attenuate cognitive deficits in patients with schizophrenia.

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Section: ■ Results and Discussionsupporting

confidence: 77%

The Discovery and Characterization of the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Potentiator N-{(3S,4S)-4-[4-(5-Cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242)

et al. 2015

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“…In addition to these chemical classes, there are other important compounds under development, such as N‐substituted pyrrolidines and tetrahydrofurans presented by GlaxoSmithKline . Among these are compound 65 (Figure ) with an N ‐methylpyrrolidine group and compound 66 (Figure ) with a cyano group.…”

Section: Ampa Receptorsmentioning

confidence: 99%

“…[230] In addition to thesec hemical classes,t here are other important compounds under development, such as N-substituted pyrrolidines and tetrahydrofurans presented by GlaxoSmithKline. [231] Amongt hese are compound 65 (Figure 7) with an Nmethylpyrrolidine group and compound 66 (Figure 7) with a cyano group. Pfizer researchers also revealed ac lass of compounds known as dihydroisoxazoles (DHI), particularly hit 67 (Figure 7), with apparent favorablep hysicochemical and ADME properties.…”

Section: Ampar Eceptorsmentioning

confidence: 99%

Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

et al. 2019

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Among neurodegenerative disorders, Alzheimer's disease (AD) is the most common type of dementia, and there is an urgent need to discover new and efficacious forms of treatment for it. Pathological patterns of AD include cholinergic dysfunction, increased β‐amyloid (Aβ) peptide concentration, the appearance of neurofibrillary tangles, among others, all of which are strongly associated with specific biological targets. Interactions observed between these targets and potential drug candidates in AD most often occur by competitive mechanisms driven by orthosteric ligands that sometimes result in the production of side effects. In this context, the allosteric mechanism represents a key strategy; this can be regarded as the selective modulation of such targets by allosteric modulators in an advantageous manner, as this may decrease the likelihood of side effects. The purpose of this review is to present an overview of compounds that act as allosteric modulators of the main biological targets related to AD.

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“…Between 2005 and 2010, GSK have filed a large number of patent applications for novel AMPAR modulators, indicating a strong interest of the company in this area of neuro-science [84][85][86][87][88][89][90][91][92][93][94][95]. In the period covered by this review, they published three scientific articles, each focusing on a different chemotype [82,83,96]. Table 1.…”

Section: Two Novel Templates From Gskmentioning

confidence: 99%

“…In a short communication, [96] they reported the discovery of a series of N-substituted pyrrolidines and tetrahydrofurans, related to the phenethyl sulfonamide modulators de-scribed by Lilly. We can assume that this exploratory work, based on existing literature, was conducted when the company first started to develop an interest in this area and can be considered as GSK's initial attempt to identify AMPAR positive modulators.…”

Section: Fig (1) Representative Chemotypes Of Ampar Positive Allostmentioning

confidence: 99%

AMPA Receptor Positive Allosteric Modulators: Potential for the Treatment of Neuropsychiatric and Neurological Disorders

Reuillon

Ward²,

Beswick³

2016

CTMC

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The neurotransmitter glutamate and its receptors have long been of interest to scientists involved in pharmaceutical research since dysfunction of the glutamatergic signalling pathway has been associated with the pathophysiology of several psychiatric and neurological disorders. The research on AMPAR positive allosteric modulators offers opportunities to modulate fast excitatory synaptic transmission and identify new potential therapeutic agents for a range of neurodiseases. The field of AMPAR modulators continues to be a dynamic area of drug discovery with a pronounced diversification of the chemotypes explored in recent years. This article reviews literature published in this area in the last 6 years, focusing on the new core templates, some derived from high-throughput screens, with an emphasis on structure-activity relationships, drug metabolism and pharmacokinetics properties, and pharmacological profiles of these series.

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N-Substituted pyrrolidines and tetrahydrofurans as novel AMPAR positive modulators

Cited by 12 publications

References 12 publications

The Discovery and Characterization of the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Potentiator N-{(3S,4S)-4-[4-(5-Cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242)

The Discovery and Characterization of the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Potentiator N-{(3S,4S)-4-[4-(5-Cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242)

Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

AMPA Receptor Positive Allosteric Modulators: Potential for the Treatment of Neuropsychiatric and Neurological Disorders

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