Maximizing lipophilic efficiency: the use of Free-Wilson analysis in the design of inhibitors of acetyl-CoA carboxylase.

This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues.

Discovery of 2-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-5-(5-fluoropyrimidin-2-yl)benzamide as a potent and CNS penetrable P2X7 receptor antagonist.

Focused SAR studies were carried out around 5-heteroaryl and 1-amide portions of the 2-chlorobenzamide scaffold, resulting in the discovery of a potent, metabolically stable and centrally penetrable antagonist against P2X(7) receptor.

Curvature wavefront sensing performance evaluation for active correction of the Large Synoptic Survey Telescope (LSST).

The Large Synoptic Survey Telescope (LSST) uses a novel, three-mirror, modified Paul-Baker design, with an 8.4-meter primary mirror, a 3.4-m secondary, and a 5.

Effects of phase shifts on four-beam interference patterns.

An analysis of the effects of relative phase changes on the interference pattern formed by the coherent addition of four plane waves is presented. We focus on the configuration in which four plane waves converge at equal angles along two orthogonal planes, an arrangement that is potentially useful for printing arrays of microstructures in resist. We show that, depending on the set of polarization vectors chosen, the shape of the interference pattern is a strong function of the phase difference between each pair of beams.

General methods for generating phase-shifting interferometry algorithms.

Two completely independent systematic approaches for designing algorithms are presented. One approach uses recursion rules to generate a new algorithm from an old one, only with an insensitivity to more error sources. The other approach uses a least-squares method to optimize the noise performance of an algorithm while constraining it to a desired set of properties.

Controlling the intracellular localization of fluorescent polyamide analogues in cultured cells.

The intracellular distribution of fluorescent-labeled polyamides was examined in live cells. We showed that BODIPY-labeled polyamides accumulate in acidic vesicles, mainly lysosomes, in the cytoplasm of HCT116 colon cancer cells and human rheumatoid synovial fibroblasts (RSF). Verapamil blocked vesicular accumulation and led to nuclear accumulation of the BODIPY-labeled polyamide in RSFs.

Synthesis and biochemical characterization of an analogue of CheY-phosphate, a signal transduction protein in bacterial chemotaxis.

CheY is a signal transduction protein of the bacterial chemotaxis system that acts as a molecular switch to alter the swimming behavior of the bacterium. When CheY becomes phosphorylated at Asp57, CheY-Pi interacts with flagellar motor proteins, including FliM, to increase the likelihood that the flagellar motor will change its sense of rotation, increasing the frequency of tumbling. The structure of CheY in its dephosphorylated (inactive) state has been intensively investigated.

X-ray production ˜ 13 nm from laser-produced plasmas for projection x-ray lithography applications.

X-ray production in the region ˜ 13 nm from laser-produced plasmas has been investigated as a source for projection x-ray lithography. The dependence of x-ray conversion efficiency on target material, intensity, and pulse length has been studied by using a 0.53-µm laser with a maximum of 0.