The discovery of N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZD6703), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases.

@article{Brown2012TheDO,
  title={The discovery of N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZD6703), a clinical p38$\alpha$ MAP kinase inhibitor for the treatment of inflammatory diseases.},
  author={Dearg Sutherland Brown and John G. Cumming and Paul A. Bethel and Jonathan E Finlayson and Stefan Gerhardt and Ian Alun Nash and Richard A. Pauptit and Kurt G. Pike and A. C. Reid and Wendy L. Snelson and Steven Swallow and Caroline Thompson},
  journal={Bioorganic \& medicinal chemistry letters},
  year={2012},
  volume={22 12},
  pages={
          3879-83
        }
}
The Discovery of N‐Cyclopropyl‐4‐methyl‐3‐ [6‐(4‐methylpiperazin‐1‐yl)‐4‐oxoquinazolin‐3(4H)‐yl]benzamide (AZD6703, a Clinical p38α MAP Kinase Inhibitor for the Treatment of Inflammatory Diseases.
Sequential conversion of two embedded aniline functionalities in the bisamide series to a quinazolinone and an N-cyclopropyl reverse amide provide a potent, selective, and orally available series of
Structure–property relationship studies of 3-acyl-substituted furans: the serendipitous identification and characterization of a new non-classical hydrogen bond donor moiety
TLDR
The 3-acyl-substituted furan moiety can be rationally explored as a hydrogen bond donor moiety in drug design projects, according to the strength of this interaction with intermolecular models.
Discovery and characterization of MAPK-activated protein kinase-2 prevention of activation inhibitors.
TLDR
Two structurally distinct series of novel, MAPK-activated kinase-2 prevention of activation inhibitors have been discovered by high throughput screening and are suitable for further investigation for their potential to treat chronic inflammatory diseases with improved tolerability over previously studied p38α inhibitors.
Substituted quinazolinones as kinase inhibitors endowed with anti-fibrotic properties.
Anti-Inflammation of N-Benzyl-4-Bromobenzamide in Lipopolysaccharide-Induced Human Gingival Fibroblasts
TLDR
NBBA exhibited an inhibitory effect on the production of IL-6 and PGE2 in LPS-induced HGFs, suggesting it could serve as a compound with inhibiting inflammatory activity in periodontal disease.
PSD-95 protects the pancreas against pathological damage through p38 MAPK signaling pathway in acute pancreatitis
TLDR
The findings showed that PSD-95 is expressed in the pancreatic tissues of humans, C57BL/6 mice, and AR42J cells, primarily in the cytoplasm, and affects the phosphorylation of p38 MAPK.

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TLDR
Inhibitor 7k is slightly less active than 1a in the p38α enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model.
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NPY5RA-972 (4o) is a highly potent Y5 antagonist in vivo but does not block neuropeptide Y-induced feeding nor does it reduce feeding in rats, suggesting that the Y5 receptor alone has no significant role in feeding in these models.
Discovery of orally efficacious melanin-concentrating hormone receptor-1 antagonists as antiobesity agents. Synthesis, SAR, and biological evaluation of bicyclo[3.1.0]hexyl ureas.
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Research is document in a bicyclo[3.1.0]hexyl urea series with particular emphasis on structure-activity relationships and optimization of receptor occupancy, measured both in vitro and via an ex vivo binding assay following an oral dosing regimen.
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This paper describes how a series of novel p38alpha/beta inhibitors are optimized using crystal structures of their inhibitors bound to p38 alpha, classical medicinal chemistry, and modeling of virtual libraries to derive a molecule suitable for progression into clinical development.
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A structure-activity investigation identified several compounds possessing excellent potency in both enzyme and human whole blood assays and among them, compound 31 exhibited good pharmacokinetic properties and showed excellent selectivity against other related kinases.
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Although greater selectivity has been achieved with these newly disclosed series, their safety profile after chronic treatment remains a question to be answered in human clinical trials.
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TLDR
It is demonstrated that selectivity pocket compounds prevent MKK6-dependent activation of p38alpha in addition to inhibiting catalysis by activated p38 Alpha, a potential approach for the treatment of inflammatory disorders.
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TLDR
A new allosteric binding site for a diaryl urea class of highly potent and selective inhibitors against human p38 MAP kinase is reported, requiring a large conformational change not observed previously for any of the protein Ser/Thr kinases.
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