Pyrazole Urea-Based Inhibitors of p38 MAP Kinase:  From Lead Compound to Clinical Candidate

• Published in: Journal of medicinal chemistry Vol. 45; no. 14; pp. 2994 - 3008
• Main Authors: Regan, John, Breitfelder, Steffen, Cirillo, Pier, Gilmore, Thomas, Graham, Anne G, Hickey, Eugene, Klaus, Bernhard, Madwed, Jeffrey, Moriak, Monica, Moss, Neil, Pargellis, Chris, Pav, Sue, Proto, Alfred, Swinamer, Alan, Tong, Liang, Torcellini, Carol
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 04.07.2002; Amer Chemical Soc
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Binding, Competitive; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cell Line; Chemistry, Medicinal; Chromatography, High Pressure Liquid; Crystallography, X-Ray; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Female; Fluorescence; Humans; Life Sciences & Biomedicine; Lipopolysaccharides - pharmacology; Medical sciences; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Models, Molecular; Naphthalenes - chemical synthesis; Naphthalenes - chemistry; Naphthalenes - pharmacology; p38 Mitogen-Activated Protein Kinases; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protein Binding; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Science & Technology; Structure-Activity Relationship; Tumor Necrosis Factor-alpha - biosynthesis; Urea - analogs & derivatives; Urea - chemical synthesis; Urea - chemistry; Urea - pharmacology; RHEUMATOID-ARTHRITIS; PYRIMIDINYLIMIDAZOLE INHIBITORS; NECROSIS-FACTOR; POTENT; CYTOKINES; ACTIVATED PROTEIN-KINASE; CROHNS-DISEASE; HETEROCYCLES; BIOSYNTHESIS; INFLIXIMAB; Intravenous administration; Nitrogen heterocycle; Monkey; Selectivity; Morpholine derivatives; Modeling; Structure activity relation; Molecular model; Primates; Pyrazole derivatives; Inhibition; Tumor necrosis factor α; Human; Ether; Enzyme; Transferases; Rodentia; Antiinflammatory agent; Cytokine; Oral administration; Enzyme inhibitor; Mitogen-activated protein kinase; Aminoether; Inhibitor enzyme complex; Bioavailability; X ray diffraction; In vitro; Naphthalene derivatives; In vivo; Vertebrata; Mammalia; Cell line; Mouse; Protein kinase; Animal; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm020057r

We report on a series of N-pyrazole, N‘-aryl ureas and their mode of binding to p38 mitogen activated protein kinase. Importantly, a key binding domain that is distinct from the adenosine 5‘-triphoshate (ATP) binding site is exposed when the conserved activation loop, consisting in part of Asp168-Phe169-Gly170, adopts a conformation permitting lipophilic and hydrogen bonding interactions between this class of inhibitors and the protein. We describe the correlation of the structure−activity relationships and crystallographic structures of these inhibitors with p38. In addition, we incorporated another binding pharmacophore that forms a hydrogen bond at the ATP binding site. This modification affords significant improvements in binding, cellular, and in vivo potencies resulting in the selection of 45 (BIRB 796) as a clinical candidate for the treatment of inflammatory diseases.