Design, structure-activity relationships and in vivo characterization of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones: a novel class of receptor tyrosine kinase inhibitors.

The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TKI258), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRbeta with IC(50) values <0.1 microM. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.

Temperature-dependent femtosecond photoinduced desorption in CO/Pd(111).

The desorption of CO from a Pd(111) surface following absorption of 120 fs pulses of 780 nm light occurs on two distinct and well-separated time scales. Two-pulse correlation measurements show a fast subpicosecond decay followed by a slower, approximately 40 ps decay. Simulations based on the two-temperature model of electron and phonon heat baths within the substrate, and an empirical friction model to treat coupling to the adsorbate, support the assignment of the desorption mechanism as an electron-mediated process. The photodesorption yield and overall width of the temporal response exhibit a marked dependence on the initial surface temperature in the 100-375 K range despite the much higher transient electronic temperatures (approximately 7000 K) achieved. The observed temperature dependences can be attributed directly to variations in the initial temperature within the frictional coupling picture. Simulations of this extended data set imply that the activation barrier to photoinduced desorption is equal in magnitude to that derived from thermal desorption experiments for this system within the limits of a one-dimensional Arrhenius desorption model. The simulations also imply that the slower decay is not the result of phonon-driven desorption. Though we cannot unambiguously determine the strength of the adsorbate-phonon coupling, our results suggest that its role is to moderate the degree of the adsorbate excitation.

Adsorption-state-dependent subpicosecond photoinduced desorption dynamics.

Femtosecond laser excitation has been used to initiate desorption of molecular oxygen from the (111) surface of Pd and to study the adsorption-state dependence of the substrate-adsorbate coupling. The relative populations of the two chemical states, peroxo (O2(2-)) and superoxo (O2-), were varied by changing the total coverage. Two-pulse correlation measurements exhibit a dominant 400 fs response and a slower 10 ps decay that are relatively independent of the initial O2 coverage. In contrast, the photodesorption yield and the nonlinearity of the fluence dependence show a systematic coverage dependence. The coverage-independent subpicosecond response indicates that the photoinduced desorption from the two states is driven primarily by the same electron-mediated mechanism, while the coverage dependence of the yield indicates that the desorption efficiency from the superoxo state is greater than that from the peroxo state. These results are discussed in the context of the electron-phonon two-temperature model with an empirical adsorbate-electron frictional coupling that depends on both the electronic temperature and the activation energy for desorption. With a coupling strength that decreases as the activation energy decreases, the trends with varying coverage, absorbed fluence, and time delay can all be reproduced. The model is consistent with a transition from a resonantly enhanced (diabatic) regime to an adiabatic regime as the system relaxes, accounting for the biexponential correlation behavior.

Potent, novel in vitro inhibitors of the Pseudomonas aeruginosa deacetylase LpxC.

Deacetylation of uridyldiphospho-3-O-(R-hydroxydecanoyl)-N-acetylglucosamine by LpxC is the first committed step in the Pseudomonas aeruginosa biosynthetic pathway to lipid A; homologous enzymes are found widely among Gram-negative bacteria. As an essential enzyme for which no inhibitors have yet been reported, the P. aeruginosa LpxC represents a highly attractive target for a novel antibacterial drug. We synthesized several focused small-molecule libraries, each composed of a variable aromatic ring, one of four heterocyclic/spacer moieties, and a hydroxamic acid and evaluated the LpxC inhibition of these compounds against purified P. aeruginosa enzyme. To ensure that the in vitro assay would be as physiologically relevant as possible, we synthesized a tritiated form of the specific P. aeruginosa glycolipid substrate and measured directly the enzymatically released acetate. Several of our novel compounds, predominantly those having fluorinated substituents on the aromatic ring and an oxazoline as the heterocyclic moiety, demonstrated in vitro IC(50) values less than 1 microM. We now report the synthesis and in vitro evaluation of these P. aeruginosa LpxC inhibitors.