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2005
Pyrazole derivatives
R 0180
The Development of New Bicyclic Pyrazole-Based Cytokine Synthesis Inhibitors.
The new structural class of cytokine inhibitors consists of vicinal bis-aryl five-mem03- 121 —
bered heterocycles as potential TNF-α inhibitors. The new class is discovered through
functionalization attempts of (Va) to provide bicyclic pyrazoles. However, alkylation
of (Va) with (VIa) yields the bicyclic pyrazole (VIIa). This class is further elaborated
by oxidation of the thiomethylether group in (VIIb) and subsequent displacement of
sulfoxide (VIII) with phenol or amines (IX). Thus, the modestly active lead (VIIa) is
elaborated to the bicyclic pyrazole (Xa), which is a potent inhibitor of TNF-α formation
in an in vitro assay against LPS-stimulated production of TNF-α. In addition, the X-ray
crystal structure of a bicyclic pyrazole, co-crystallized with mutated p38 (mp38) enzyme is presented. — (TOWNES*, J. A.; et al.; Bioorg. Med. Chem. Lett. 14 (2004)
19, 4945-4948; Procter & Gamble Pharm. Health Care Res. Cent., Mason, OH 45040,
USA; Eng.) — H. Hoennerscheid
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