The development of monocyclic pyrazolone based cytokine synthesis inhibitors

Gołębiowski, Adam; Townes, Jennifer A.; Laufersweiler, Matthew J.; Brugel, Todd A.; Clark, Michael P.; Clark, Cynthia M.; Djung, Jane F.; Laughlin, Steven K.; Sabat, Mark; Bookland, Roger G.; VanRens, John C.; De, Biswanath; Hsieh, Lily C.; Janusz, Michael J.; Walter, R.L.; Webster, Mark E.; Mekel, Marlene

doi:10.1016/j.bmcl.2005.03.007

Cited by 27 publications

(20 citation statements)

References 11 publications

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“…Golebiowski and co-workers synthesized some novel monocyclic pyrazolone and investigated their inhibition on the inflammatory cytokines [101]. The outcome showed that compound 142 (Fig.…”

Section: Anti-inflammatory Agentsmentioning

confidence: 99%

Pyrazolone structural motif in medicinal chemistry: Retrospect and prospect

Zhao

Dai

et al. 2020

European Journal of Medicinal Chemistry

139

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a b s t r a c tThe pyrazolone structural motif is a critical element of drugs aimed at different biological end-points. Medicinal chemistry researches have synthesized drug-like pyrazolone candidates with several medicinal features including antimicrobial, antitumor, CNS (central nervous system) effect, anti-inflammatory activities and so on. Meanwhile, SAR (Structure-Activity Relationship) investigations have drawn attentions among medicinal chemists, along with a plenty of analogues have been derived for multiple targets. In this review, we comprehensively summarize the biological activity and SAR for pyrazolone analogues, wishing to give an overall retrospect and prospect on the pyrazolone derivatives.

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“…Golebiowski and co-workers synthesized some novel monocyclic pyrazolone and investigated their inhibition on the inflammatory cytokines [101]. The outcome showed that compound 142 (Fig.…”

Section: Anti-inflammatory Agentsmentioning

confidence: 99%

Pyrazolone structural motif in medicinal chemistry: Retrospect and prospect

Zhao

Dai

et al. 2020

European Journal of Medicinal Chemistry

139

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“…32,48 Starting points for further derivatization primarily were the methylsulfanylimidazoles 5a, 5d, 5i, 7a, and 7b (Scheme 1, Table 1) with a 2-chloro-or a 2-fluoropyridinyl moiety. The functional requirement for the reactivity of the pyridine component was achieved by the above-mentioned syntheses.…”

Section: Chemistrymentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Novel Tri- and Tetrasubstituted Imidazoles as Highly Potent and Specific ATP-Mimetic Inhibitors of p38 MAP Kinase: Focus on Optimized Interactions with the Enzyme’s Surface-Exposed Front Region

et al. 2008

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The synthesis, biological testing, and SAR of novel 2,4,5- and 1,2,4,5-substituted 2-thioimidazoles are described. Amino, oxy, or thioxy substituents at the 2-position of the pyridinyl moiety were evaluated for their contributions to inhibitor potency and selectivity against p38 mitogen activated protein kinase (p38 MAPK) as well as for the ability to minimize cytochrome P450 (CYP450) inhibition. Incorporation of polar substituted (cyclo)aliphatic amino substituents (e.g., tetrahydropyranylamino), which positively interacted with the surface-exposed front region (hydrophobic region II) of the enzyme led to the identification of extremely potent p38 MAPK inhibitors with p38 IC 50 values in the low nanomolar range. Approximately 90 pyridinylimidazole-based compounds with a range of potencies against p38alpha MAP kinase were further investigated for their ability to inhibit the release of tumor necrosis factor-alpha (TNFalpha) and/or interleukin-1beta (IL-1beta) from human whole blood. Some of the most promising drug candidates underwent selectivity profiling against a panel of 17 different kinases besides p38alpha and/or were tested for their interaction potential toward a number of metabolically relevant CYP450 isozymes.

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“…Histidine flip prediction in structure 1ywr[23]. From left to right: Asp150, His148, Asn155, Leu167.…”

Section: Resultsmentioning

confidence: 99%

Fast automated placement of polar hydrogen atoms in protein-ligand complexes

Lippert¹,

Rarey²

2009

J Cheminform

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BackgroundHydrogen bonds play a major role in the stabilization of protein-ligand complexes. The ability of a functional group to form them depends on the position of its hydrogen atoms. An accurate knowledge of the positions of hydrogen atoms in proteins is therefore important to correctly identify hydrogen bonds and their properties. The high mobility of hydrogen atoms introduces several degrees of freedom: Tautomeric states, where a hydrogen atom alters its binding partner, torsional changes where the position of the hydrogen atom is rotated around the last heavy-atom bond in a residue, and protonation states, where the number of hydrogen atoms at a functional group may change. Also, side-chain flips in glutamine and asparagine and histidine residues, which are common crystallographic ambiguities must be identified before structure-based calculations can be conducted.ResultsWe have implemented a method to determine the most probable hydrogen atom positions in a given protein-ligand complex. Optimality of hydrogen bond geometries is determined by an empirical scoring function which is used in molecular docking. This allows to evaluate protein-ligand interactions with an established model. Also, our method allows to resolve common crystallographic ambiguities such as as flipped amide groups and histidine residues. To ensure high speed, we make use of a dynamic programming approach.ConclusionOur results were checked against selected high-resolution structures from an external dataset, for which the positions of the hydrogen atoms have been validated manually. The quality of our results is comparable to that of other programs, with the advantage of being fast enough to be applied on-the-fly for interactive usage or during score evaluation.

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The development of monocyclic pyrazolone based cytokine synthesis inhibitors

Cited by 27 publications

References 11 publications

Pyrazolone structural motif in medicinal chemistry: Retrospect and prospect

Pyrazolone structural motif in medicinal chemistry: Retrospect and prospect

Design, Synthesis, and Biological Evaluation of Novel Tri- and Tetrasubstituted Imidazoles as Highly Potent and Specific ATP-Mimetic Inhibitors of p38 MAP Kinase: Focus on Optimized Interactions with the Enzyme’s Surface-Exposed Front Region

Fast automated placement of polar hydrogen atoms in protein-ligand complexes

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