Case 8 p38

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Dumas et al.31 at Bayer Research Center reported the automated parallel solution-phase synthesis of biaryl ureas as p38 kinase inhibitors. Mitogen-activated protein (MAP) kinases are involved in the transduction of extracellular signals received by cell-surface receptors. These signals then target a diverse set of downstream targets, resulting in a cellular response. The p38 MAP kinase is a 38-kDa enzyme that consists of four known isozymes: p38a, p380, p38y, and p385. It was been determined that p38 plays a key role in the cyctokine signaling network, which is implicated in chronic inflammatory conditions such as rheumatoid arthritis. Consequently, inhibition of p38 could offer a way for the therapeutic treatment of cytokine-regulated afflictions such as rheumatoid arthritis.

From a previous combinatorial chemistry effort, the authors discovered urea 317 as a potent p38 inhibitor (IC50 = 53 nM). At the time of this discovery, ureas were not known to act as kinase inhibitors, and thus efforts were invested in the optimization of this hit.

Toward this goal, the authors developed an automated parallel solution-phase synthetic approach for the synthesis of a 1000-member library. For this, a Gilson 215 robotic liquid handler was used in conjunction with a 100-vessel dry-block heater with an orbital shaker from J-KEM Scientific.

The synthesis involved the reaction of amines (319) with isocyanates (320) in DMF at 80 to 95°C for 18 hr. Unreacted isocyanates were quenched by the addition of MeOH and the solvents removed using a Savant SpeedVac evaporator.

The first efforts centered on the SAR elucidation around the pyrazole unit of the main scaffold 318, for which the 2,3-dichlorophenyl group and the ieri-butyl group on the 5-member ring were kept constant. It was determined that replacing the pyrazole unit with an isoxazole was well tolerated, observing that the two possible isoxazole regioisomers exhibited similar activity in the enzyme-inhibition assay (321, 322: IC50 = 58 and 36 nM, respectively) as well as in the singlepoint SW1353 (human chondrosarcoma) cell-based assay (321, 322: % Inh at 0.5 ^M = 88 and 93, respectively). Replacing the pyrazole with either thiophene or thiadiazole resulted in loss of activity (greater than threefold).

The second optimization round focused on isoxazole 322, where substitution effects on the isox-azole ring were explored. Substitution of the teri-butyl group by smaller alkyl (e.g., Me, ¿-Pr, n-Bu) and bulkier groups (e.g., cyclobutyl, adamantyl) resulted in loss of p38 inhibition potency.

Central Scaffold

Solution-phase synthesis

Central Scaffold

Solution-phase synthesis

First optimization round: Hits

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