| Abstract
| - We report on the structure−activity relationships (SAR) of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]urea (BIRB 796), an inhibitor of p38α MAPkinase which has advanced into human clinical trials for the treatment of autoimmune diseases.Thermal denaturation was used to establish molecular binding affinities for this class of p38αinhibitors. The tert-butyl group remains a critical binding element by occupying a lipophilicdomain in the kinase which is exposed upon rearrangement of the activation loop. An aromaticring attached to N-2 of the pyrazole nucleus provides important π-CH2 interactions with thekinase. The role of groups attached through an ethoxy group to the 4-position of the naphthaleneand directed into the ATP-binding domain is elucidated. Pharmacophores with good hydrogenbonding potential, such as morpholine, pyridine, and imidazole, shift the melting temperatureof p38α by 16−17 °C translating into Kd values of 50−100 pM. Finally, we describe severalcompounds that potently inhibit TNF-α production when dosed orally in mice.
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