Design and Synthesis of Potent, Orally Bioavailable Dihydroquinazolinone Inhibitors of p38 MAP Kinase.

Stelmach, John E.

doi:10.1002/chin.200319153

Cited by 5 publications

(7 citation statements)

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“…Recently, Stelmach et al . have reported potent, orally bioavailable (in a rat model) dihydroquinazolinone hybrid p38α inhibitors based on a pyridinyl imidazole p38α inhibitor developed by Merck and on VX‐745 159 …”

Section: Ongoing Studies and Clinical Perspectivesmentioning

confidence: 99%

Mitogen‐activated protein kinases in chronic intestinal inflammation — targeting ancient pathways to treat modern diseases

Waetzig

Schreiber

2003

Aliment Pharmacol Ther

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SUMMARYConventional treatment of chronic inflammatory disorders, including inflammatory bowel diseases, employs broad-range anti-inflammatory drugs. In order to reduce the side-effects and increase the efficacy of treatment, several strategies have been developed in the last decade to interfere with intercellular and intracellular inflammatory signalling processes. The highly conserved mitogen-activated protein kinase pathways regulate most cellular processes, particularly defence mechanisms such as stress reactions and inflammation. In this review, we provide an overview of the current knowledge of the specificity and interconnection of mitogen-activated protein kinase pathways, their functions in the gut immune system and published and ongoing studies on the role of mitogen-activated protein kinases in inflammatory bowel disease. The development of mitogen-activated protein kinase inhibitors and their use for the therapy of inflammatory disorders is a paradigm of the successful bridging of the gap between basic research and clinical practice.

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Section: Ongoing Studies and Clinical Perspectivesmentioning

confidence: 99%

Mitogen‐activated protein kinases in chronic intestinal inflammation — targeting ancient pathways to treat modern diseases

Waetzig

Schreiber

2003

Aliment Pharmacol Ther

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“…The subsequent responses that TNF ␣ and IL-1 ␤ transmit through their respective receptors lead to induction of additional proinflammatory proteins involved in the pathogenesis of RA that are also mediated through p38 ␣ , including induction of cyclooxygenase 2 (COX-2), matrix metalloproteases (MMPs) 1, 3 and 9, receptor activator of nuclear factor NF-B ligand (RANKL), inducible nitric oxide synthase (iNOS), and integrin expression [20,[22][23][24][25][26][27][28][29][30] . Selective inhibitors of p38 ␣ block the production and activity of these proteins and have demonstrated marked efficacy in animal models of acute inflammation, arthritis and chronic obstructive pulmonary disease [2,25,[31][32][33][34][35][36] . The ability of p38 ␣ inhibitors to reduce the levels of multiple inflammatory cytokines and mediator proteins suggests that these compounds have the potential for enhanced and/or broader efficacy compared with agents restricted to single-cytokine modulation.…”

Section: Introductionmentioning

confidence: 99%

“…Early p38 ␣ inhibitor patents focused on imidazolebased compounds [39,40] and were followed by patents claiming structures based on pyrroles, thiazoles, and oxazoles [35,41], and others with unrelated structures such as the pyrazole ureas [34,36,42,43] . We report here on the preclinical biological evaluation and phase 1 clinical evaluation of SD0006, a diarylpyrazole (DAP).…”

Section: Introductionmentioning

confidence: 99%

SD0006: A Potent, Selective and Orally Available Inhibitor of p38 Kinase

et al. 2009

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SD0006 is a diarylpyrazole that was prepared as an inhibitor of p38 kinase-α (p38α). In vitro, SD0006 was selective for p38α kinase over 50 other kinases screened (including p38γ and p38δ with modest selectivity over p38β). Crystal structures with p38α show binding at the ATP site with additional residue interactions outside the ATP pocket unique to p38α that can confer advantages over other ATP competitive inhibitors. Direct correlation between inhibition of p38α activity and that of lipopolysaccharide-stimulated TNFα release was established in cellular models and in vivo, including a phase 1 clinical trial. Potency (IC₅₀) for inhibiting tumor necrosis factor-α (TNFα) release, in vitro and in vivo, was <200 nmol/l. In vivo, SD0006 was effective in the rat streptococcal-cell-wall-induced arthritis model, with dramatic protective effects on paw joint integrity and bone density as shown by radiographic analysis. In the murine collagen-induced arthritis model, equivalence was demonstrated to anti-TNFα treatment. SD0006 also demonstrated good oral anti-inflammatory efficacy with excellent cross-species correlation between the rat, cynomolgus monkey, and human. SD0006 suppressed expression of multiple proinflammatory proteins at both the transcriptional and translational levels. These properties suggest SD0006 could provide broader therapeutic efficacy than cytokine-targeted monotherapeutics.

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“…Introduction of the piperizine at C7 increased kinase activity and HWB potency. Stelmach et al has reported the related dihydroquinazolines (35, p38α IC 50 0.2 nM, LPS-TNFα HWB IC 50 10.1 nM) in which the lipophilic aryl group is connected at C5 [48]. Optimal C5 aryl substitution includes methyl, mono or dihalogen, and introduction of the piperidine at C7 imparted better PK properties.…”

Section: Fused 66 and Related P38 Map Kinase Inhibitorsmentioning

confidence: 99%

Small Molecule p38 Inhibitors: Novel Structural Features and Advances from 2002-2005

Hynes¹,

Leftheris²

2005

CTMC

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The discovery and development of selective, efficacious, and safe small molecule p38 mitogen-activated protein kinase inhibitors for the treatment of inflammatory diseases remains the focus of many pharmaceutical research programs. Advances in small molecule p38 inhibitor design in potency and oral efficacy have been accelerated with the large number of available inhibitor-enzyme x-ray structures. These advances have allowed for the discovery of diverse sets of inhibitors with the opportunity to map inhibitor interactions and design selective inhibitors. This review covers recent compound disclosures in the patent and published literature over the last three years. Many disclosures represent new chemotypes as well as creative modifications of known structures.

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Design and Synthesis of Potent, Orally Bioavailable Dihydroquinazolinone Inhibitors of p38 MAP Kinase.

Cited by 5 publications

References 1 publication

Mitogen‐activated protein kinases in chronic intestinal inflammation — targeting ancient pathways to treat modern diseases

Mitogen‐activated protein kinases in chronic intestinal inflammation — targeting ancient pathways to treat modern diseases

SD0006: A Potent, Selective and Orally Available Inhibitor of p38 Kinase

Small Molecule p38 Inhibitors: Novel Structural Features and Advances from 2002-2005

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