The Discovery of VX-745: A Novel and Selective p38α Kinase Inhibitor.

The synthesis of novel, selective, orally active 2,5-disubstituted 6H-pyrimido[1,6-b]pyridazin-6-one p38α inhibitors is described. Application of structural information from enzyme-ligand complexes guided the selection of screening compounds, leading to the identification of a novel class of p38α inhibitors containing a previously unreported bicyclic heterocycle core. Advancing the SAR of this series led to the eventual discovery of 5-(2,6-dichlorophenyl)-2-(2,4-difluorophenylthio)-6H-pyrimido[1,6-b]pyridazin-6-one (VX-745). VX-745 displays excellent enzyme activity and selectivity, has a favorable pharmacokinetic profile, and demonstrates good in vivo activity in models of inflammation.

[1]  P. Emery,et al.  Infliximab for rheumatoid arthritis , 2006, Expert review of clinical immunology.

[2]  R. Fleischmann.  Anakinra in the treatment of rheumatic disease , 2006, Expert review of clinical immunology.

[3]  M. Feldmann,et al.  Role of cytokines in rheumatoid arthritis. , 1996, Annual review of immunology.

[4]  Yong Jiang,et al.  Characterization of the Structure and Function of the Fourth Member of p38 Group Mitogen-activated Protein Kinases, p38δ* , 1997, The Journal of Biological Chemistry.

[5]  J. Boehm,et al.  Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase. , 1997, Bioorganic & medicinal chemistry.

[6]  A. Kavanaugh.  Anakinra (Interleukin-1 Receptor Antagonist) has positive effects on function and quality of life in patients with rheumatoid arthritis , 2006, Advances in therapy.

[7]  E. A. O'neill,et al.  Design and synthesis of potent, selective, and orally bioavailable tetrasubstituted imidazole inhibitors of p38 mitogen-activated protein kinase. , 1999, Journal of Medicinal Chemistry.

[8]  Jerry L. Adams,et al.  A protein kinase involved in the regulation of inflammatory cytokine biosynthesis , 1994, Nature.

[9]  P. Cohen,et al.  Specificity and mechanism of action of some commonly used protein kinase inhibitors , 2000 .

[10]  S. Laufer,et al.  Small molecular anti‐cytokine agents , 2006, Medicinal research reviews.

[11]  Philip R. Cohen,et al.  SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin‐1 , 1995, FEBS letters.

[12]  G. Bemis,et al.  Inhibitors of p38 MAP kinase: therapeutic intervention in cytokine-mediated diseases. , 1999, Current medicinal chemistry.

[13]  John C. Lee,et al.  p38 MAP kinase: molecular target for the inhibition of pro-inflammatory cytokines. , 2001, Progress in medicinal chemistry.

[14]  D E Griswold,et al.  Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function. , 1996, The Journal of pharmacology and experimental therapeutics.

[15]  G. Schieven.  The biology of p38 kinase: a central role in inflammation. , 2005, Current topics in medicinal chemistry.

[16]  K. Wilson,et al.  A single amino acid substitution makes ERK2 susceptible to pyridinyl imidazole inhibitors of p38 MAP kinase , 1998, Protein science : a publication of the Protein Society.

[17]  A. Cuenda,et al.  p38 MAP-kinases pathway regulation, function and role in human diseases. , 2007, Biochimica et biophysica acta.

[18]  R. Maini,et al.  TUMOUR NECROSIS FACTOR AS A THERAPEUTIC TARGET IN RHEUMATOID ARTHRITIS AND OTHER CHRONIC INFLAMMATORY DISEASES: THE CLINICAL EXPERIENCE WITH INFLIXIMAB (REMICADE™) , 2001, International journal of clinical practice.

[19]  D. Zaller,et al.  Structural basis for p38alpha MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity. , 2003 .

[20]  G. Bemis,et al.  The structural basis for the specificity of pyridinylimidazole inhibitors of p38 MAP kinase. , 1997, Chemistry & biology.

[21]  D. Zaller,et al.  Structural basis for p38α MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity , 2003, Nature Structural Biology.

[22]  D E Griswold,et al.  Pyrimidinylimidazole inhibitors of CSBP/p38 kinase demonstrating decreased inhibition of hepatic cytochrome P450 enzymes. , 1998, Bioorganic & medicinal chemistry letters.

[23]  M. Cottone,et al.  Infliximab and ulcerative colitis , 2006, Expert opinion on biological therapy.

[24]  L. Wodicka,et al.  A small molecule–kinase interaction map for clinical kinase inhibitors , 2005, Nature Biotechnology.

[25]  Roger J. Davis,et al.  Differential activation of p38MAPK isoforms by MKK6 and MKK3. , 2010, Cellular signalling.