The Ras/Raf/MEK/ERK signal transduction, an oncogenic pathway implicated in a variety of human cancers, is a key target in anticancer drug design. A novel series of pyrimidylpyrrole ERK inhibitors has been identified. Discovery of a conformational change for lead compound 2, when bound to ERK2 relative to antitarget GSK3, enabled structure-guided selectivity optimization, which led to the discovery of 11e, a potent, selective, and orally bioavailable inhibitor of ERK.

The Ras/Raf/MEK/ERK signal transduction is a key oncogenic pathway implicated in a variety of human cancers. We have identified a novel series of pyrazolylpyrroles as inhibitors of ERK. Aided by the discovery of two distinct binding modes for the pyrazolylpyrrole scaffold, structure-guided optimization culminated in the discovery of 6p, a potent and selective inhibitor of ERK.

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The photocycloaddition of cyclic enones to C 60 is a general reaction. The addition was initially explored using a crown ether-tagged C 60 molecule which allows convenient monitoring of the reaction course by electrospray ionization mass spectroscopy (ESI-MS) after complexation with metal ions, usually K + . A Hanovia 450-W lamp was used to excite a benzene solution of fullerene and enone, with the latter in large excess. A series of experiments in which the concentration of reagents and reaction time were systematically varied established that adduct formation occurs only upon light absorption by the enones. Thus, excitation at 532 nm or in the UV range using low enone: C 60 ratios did not lead to adduct formation. ESI-MS analysis showed that monoaddition was favored at short irradiation times, and that up to seven enone units could be added to a single fullerene molecule upon longer exposure to light. Competitive experiments using 12 different enones indicated that the best product yields were obtained, in decreasing order, with 3-methyl-2-cyclohexen-1-one, isophorone, 2-cyclohepten-1-one, and 2-cyclohexen-1-one. Products isolated from reactions carried out on a larger scale were subjected to spectroscopic analysis ( 1 H NMR, 13 C NMR, IR, UV). Two monoadducts were formed from 2-cyclohexen-1-one, its 3-methyl analog, and 2-cyclohepten-1-one, which could be separated by HPLC on a Buckyclutcher column. In the first two cases, these products were unambiguously identified as cis-and trans-fused [2 + 2] cycloadducts. In the case of 2-cyclohexen-1-one, the cis-fused C 60 adduct is the major product, while in the case of 3-methyl-2-cyclohexen-1-one the trans isomer predominates. 13 C NMR spectra indicated addition occurred across [6,6] pyracyclene bonds of the fullerene to give ring-closed structures with two sp 3 fullerene carbons. These racemic [2 + 2] adducts could be enantiomerically resolved on a chiral HPLC column. Much larger optical rotations were found for the trans than for the cis isomers. Additional longwavelength bands were also found in the UV absorption and CD spectra of the trans isomers. These chiroptical effects are attributed to an additional chromophore in the trans isomers, which according to MM2 calculations is a C 2 symmetric chiral skewed fullerene moiety. 3 He-NMR analysis of the product mixture from photoaddition of 3-methyl-2-cyclohexen-1-one and 2-cyclohepten-1-one to C 60 containing a 3 He atom ( 3 He@C 60 ) led to the appearance of two new peaks at ca. -9.3 ppm relative to gaseous 3 He, consistent with formation of two monoadduct diastereomers with [6,6]-closed structures. The mechanism of the reaction presumably involves addition of enone triplet excited states to ground state fullerenes, via triplet 1,4-biradical intermediates, as in typical enone-alkene photocycloadditions. The fact that enone triplets are not quenched by triplet energy transfer to the fullerenes, which would be highly favorable energetically, is rationalized by poor coupling of the chromophores and Marcus theory.

The Rho kinases (ROCK1 and ROCK2) are highly homologous serine/threonine kinases that act on substrates associated with cellular motility, morphology, and contraction and are of therapeutic interest in diseases associated with cellular migration and contraction, such as hypertension, glaucoma, and erectile dysfunction. Beginning with compound 4, an inhibitor of ROCK1 identified through high-throughput screening, systematic exploration of SAR, and application of structure-based design, led to potent and selective ROCK inhibitors. Compound 37 represents significant improvements in inhibition potency, kinase selectivity, and CYP inhibition and possesses pharmacokinetics suitable for in vivo experimentation.