Pyrroles and other heterocycles as inhibitors of P38 kinase

doi:10.1016/S0960-894X(98)00495-8

Bioorganic & Medicinal Chemistry Letters

Volume 8, Issue 19, 6 October 1998, Pages 2689-2694

https://doi.org/10.1016/S0960-894X(98)00495-8 Get rights and content

Abstract

Investigation of furans, pyrroles and pyrazolones identified 3-pyridyl-2,5-diaryl-pyrroles as potent, orally bioavailable inhibitors of p38 kinase. 3-(4-pyridyl-2-(4-fluoro-phenyl)-5-(4-methylsulfinylphenyl)-pyrrole (L-167307) reduces secondary paw swelling in the rat adjuvant arthritis model: ID₅₀ = 7.4 mg/kg/b.i.d.

References (20)

M.J. Elliott et al.
Lancet
(1994)
M.J. Elliott et al.
Lancet
(1994)
J.C. Lee et al.
Nature
(1994)
J. Han et al.
Scinece
(1994)
J. Rouse et al.
Cell
(1994)
J.C. Boehm et al.
J. Med. Chem.
(1996)
P.W. Sheldrake
Synth. Commun.
(1993)
C.A. Dinarelo
Curr. Opin. in Immunol.
(1991)
J.C. Lee et al.
Annals New York Academy of Sciences
(1993)
A.M. Badger et al.
J. Pharmacol. Exp. Ther.
(1996)

There are more references available in the full text version of this article.

Cited by (119)

N-Heterocyclic Carbene-Catalyzed Condensation/ Oxidation/ Cyclization/ Aromatization Cascade for the Synthesis of Tri- and Tetra-Substituted Imidazoles
2023, Asian Journal of Organic Chemistry
In this study, a novel and efficient one‐pot tandem synthesis of 2,4,5‐tri‐ and 1,2,4,5‐tetra‐substituted imidazoles is described. In the first step of the sequence, benzil is formed via benzoin condensation catalyzed by N‐heterocyclic carbene, followed by in situ aerobic oxidation. Next, it is reacted with another aldehyde and ammonium acetate (or amine) to produce the polysubstituted imidazole. The reaction proceeds smoothly in high yield and short reaction time in ethanol as a green solvent. The current strategy shows high functional group tolerance with respect to aldehydes and avoids the need for ligands and reducing agents. This method allows the synthesis of complex molecules in a one‐pot procedure without isolating intermediates.
Paal–Knorr synthesis: An old reaction, new perspectives
2022, Advances in Heterocyclic Chemistry
Citation Excerpt :
This strategy nowadays, has been employed in synthesis of differently substituted pyrroles.33 3-Pyridyl-2,5-diaryl-pyrroles, found to be orally bioavailable inhibitors of p38 kinase, were synthesized via P–K reaction, exemplifying the prominence of this methodology.33 Similarly, several 1-[2-(substituted pyrrol-1-yl)ethyl]-2-methyl-5-nitroimidazoles derived from metronidazole were obtained and their antibacterial and antifungal potencies were positively examined.34
Paal–Knorr (P–K) synthesis is an old name reaction in organic chemistry that generates either furans, pyrroles, or thiophenes, starting from 1,4-dicarbonyl compounds in acidic media. It is one of the most significant methodologies for the preparation of these five membered aromatic heterocycles. P–K synthesis has found several applications in the total synthesis of natural products. In this chapter, we update our previous chapter published in Advances in Heterocyclic Chemistry in 2014. It covers the advances made in the applications of P–K reaction in the synthesis of pyrroles, furans and thiophenes from 2015 till date. It also underscores the applications of P–K reaction in the total synthesis of natural products.
Conjugated pyrrole/aminoenone and pyrrole/aminoacrylonitrile ensembles: new motives in heterocyclic chemistry
2021, Mendeleev Communications
Methods for the preparation of two highly flexible synthetic building blocks, namely pyrrole/aminoenone and pyrrole/aminoacrylonitrile ensembles, on the basis of available starting materials such as 2-acylethynylpyrroles or pyrrole-2-carbodithioates, are summarized. The presence of several reactive centers in their molecules (pyrrole ring, enamine and carbonyl or nitrile moieties) ensures their multiple reactivity and application as versatile intermediates in the synthesis of heterocyclic ensembles such as pyrrolyl pyridines, bipyrroles, pyrrolyl-isoxazoles and condensed compounds, such as pyrrolo[3,2-a]pyrazines, pyrrolizines, which have high potential for use in medical chemistry and materials science.
Slack sodium-activated potassium channel membrane expression requires p38 mitogen-activated protein kinase phosphorylation
2016, Neuropharmacology
Citation Excerpt :
Anisomycin was purchased from Life Technologies. The p38 MAPK Inhibitor (C₂₀H₁₃ClFN₃O) was purchased from Millipore (de Laszlo et al. 1998). Since the cloning of the Slack channel in 1998, studies attempting to elucidate the structure of the channel have revealed that the KNa channels are set apart from the larger super-family of potassium channels by an extensive intracellular C-terminus (Joiner et al. 1998).
p38 MAPK has long been understood as an inducible kinase under conditions of cellular stress, but there is now increasing evidence to support its role in the regulation of neuronal function. Several phosphorylation targets have been identified, an appreciable number of which are ion channels, implicating the possible involvement of p38 MAPK in neuronal excitability. The K_Na channel Slack is an important protein to be studied as it is highly and ubiquitously expressed in DRG neurons and is important in the maintenance of their firing accommodation. We sought to examine if the Slack channel could be a substrate of p38 MAPK activity. First, we found that the Slack C-terminus contains two putative p38 MAPK phosphorylation sites that are highly conserved across species. Second, we show via electrophysiology experiments that K_Na currents and further, Slack currents, are subject to tonic modulation by p38 MAPK. Third, biochemical approaches revealed that Slack channel regulation by p38 MAPK occurs through direct phosphorylation at the two putative sites of interaction, and mutating both sites prevented surface expression of Slack channels. Based on these results, we conclude that p38 MAPK is an obligate regulator of Slack channel function via the trafficking of channels into the membrane. The present study identifies Slack K_Na channels as p38 MAPK substrates.
Anti-arthritic agents: Progress and potential
2015, Bioorganic and Medicinal Chemistry
Osteoarthritis and rheumatoid arthritis are the two most common types of arthritis. Cartilage breakdown is a key feature of both diseases which contributes to the pain and joint deformity experienced by patients. Therefore, anti-arthritis drugs are of great importance. The aim of this review is to present recent progress in studies of various agents against osteoarthritis and rheumatoid arthritis. The structures and activities of anti-arthritic agents, which used in medical practice or are in development, are presented and discussed. The effects and mechanisms of action of opioids, glucocorticoids, non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, natural products derived from plants, nutraceuticals, and a number of new and perspective agents are considered. Various perspective targets for the treatment of osteoarthritis and rheumatoid arthritis are also discussed. Trials of good quality are needed to draw solid conclusions regarding efficacy of many of the studied agents. Unfortunately, to date, there is no pharmacologic agent proven to prevent the progression of both diseases, and there is an urgent need for further development of better anti-arthritic agents.
Comparison of (bio-)transformation methods for the generation of metabolite-like compound libraries of p38α MAP kinase inhibitors using high-resolution screening
2014, Journal of Pharmaceutical and Biomedical Analysis
Four hydrophobic p38α mitogen-activated protein kinase inhibitors were refluxed with 7.5% hydrogen peroxide at 80 °C and irradiated with visible light in order to generate more hydrophilic conversion products. The resulting mixtures were analyzed in a high-resolution screening (HRS) platform, featuring liquid chromatographic separation coupled in parallel with a fluorescence enhancement based continuous-flow affinity bioassay towards the p38α mitogen-activated protein kinase and with high-resolution (tandem) mass spectrometry on an ion-trap-time-of-flight hybrid instrument. The results were compared with similar data where chemical diversity was achieved by means of electrochemical conversion or incubation with either human liver microsomes or cytochrome P450s from Bacillus megaterium (BM3s). In total, more than 50 conversion products were identified. The metabolite-like compound libraries studied are discussed in terms of the reactions enabled, the retention of affinity, and the change in hydrophilicity by modification, in summary the ability to generate bioactive, more hydrophilic potential lead compounds. In this context, HRS is demonstrated to be an effective tool as it reduces the effort directed towards laborious synthesis and purification schemes.

View all citing articles on Scopus

¹: Present address: Amgen, Boulder, CO.

View full text

Pyrroles and other heterocycles as inhibitors of P38 kinase

Abstract

Lancet

Lancet

Nature

Scinece

Cell

J. Med. Chem.

Synth. Commun.

Curr. Opin. in Immunol.

Annals New York Academy of Sciences

J. Pharmacol. Exp. Ther.