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A novel chemical class of potent chemoattractant receptor-homologous expressed on Th2 lymphocytes (CRTH2 or DP2) antagonists is reported. An initial and moderately potent spiro-indolinone compound ( 5) was found during a high-throughput screening campaign. Structure-activity relationship (SAR) investigation around the carboxylic acid group revealed that changes in this part of the molecule could lead to a reversal of functional activity, yielding weakly potent agonists. SAR investigation of the succinimide functional group led to the discovery of several single-digit nanomolar antagonists. The potency of these compounds was confirmed in a human eosinophil chemotaxis assay. Moreover, compounds ( R)- 58 and ( R)- 71 were shown to possess pharmacokinetic properties suitable for development as an orally bioavailable drug.

We have measured the longitudinal and transverse l70 NMR relaxation rates and chemical shifts in solutions of Cu2+ in DMF as a function of temperature, pressure, and magnetic field. The temperature and magnetic field dependence of the transverse relaxation rates and chemical shifts yields the following kinetic parameters for DMF exchange on [Cu(DMF)(,]2+: k«298 = (9.1 ± 2.4) x 108 s-1 [lifetime rm298 = (1.1 ± 0.4) x 10-9 s] with activation parameters AH* = 24.3 ± 1.2 kJ mol-1 and AS* = 8.1 ± 4.6 J K.-1 mol-1. The pressure dependence of the transverse relaxation rates yielded the activation volume, AV* = +8.4 ± 0.4 cm3 mol-1, which indicates a dissociative activation mode for solvent exchange. The unusually large magnetic field dispersion of the longitudinal relaxation rates at high temperatures is similar to that observed in aqueous Cu2+ solutions and is consistent with a model of relaxation due to a scalar interaction modulated by a dynamic Jahn-Teller distortion. We estimate the characteristic lifetime for inversion of the distortion axis to be rr98 = (6.0 ± 2.5) x 10-12 s, i.e., the process is very much faster than either solvent exchange or rotation of the solvated ion. We have also measured the pressure dependence of the transverse l70 NMR relaxation rates in aqueous Cu2+ solutions. This study complements our earlier variable-temperature and magnetic field study of the same system and yields the activation volume, AV* = +2.0 ± 1.5 cm3 mol-1, consistent with a dissociative activation mode for water exchange. We compare all these results with kinetic data for solvent exchange on other divalent first-row transition metal ions. We conclude that solvent exchange on hexasolvento Cu2+ occurs via the dissociatively activated loss of a solvent molecule from an axial position in the tetragonally elongated complex: the high lability of this relatively distant axial site is conferred to all the bound solvent molecules by the rapid inversion of the distortion axis.

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