Renin inhibition by substituted piperidines: A novel paradigm for the inhibition of monomeric aspartic proteinases?

BackgroundThe aspartic proteinase renin catalyses the first and rate-limiting step in the conversion of angiotensinogen to the hormone angiotensin II, and therefore plays an important physiological role in the regulation of blood pressure. Numerous potent peptidomimetic inhibitors of this important drug target have been developed, but none of these compounds have progressed past clinical phase II trials. Limited oral bioavailability or excessive production costs have prevented these inhibitors from becoming new antihypertensive drugs. We were interested in developing new nonpeptidomimetic renin inhibitors.ResultsHigh-throughput screening of the Roche compound library identified a simple 3,4-disubstituted piperidine lead compound. We determined the crystal structures of recombinant human renin complexed with two representatives of this new class. Binding of these substituted piperidine derivatives is accompanied by major induced-fit adaptations around the enzyme's active site.ConclusionsThe efficient optimisation of the piperidine inhibitors was facilitated by structural analysis of the renin active site in two renin-inhibitor complexes (some of the piperidine derivatives have picomolar affinities for renin). These structural changes provide the basis for a novel paradigm for inhibition of monomeric aspartic proteinases

Observation of amplitude and phase in ridge and photonic crystal waveguides operating at 1.55 μm by use of heterodyne scanning near-field optical microscopy

We apply heterodyne scanning near-field optical microscopy (SNOM) to observe with subwavelength resolution the amplitude and phase of optical fields propagating in several microfabricated waveguide devices operating around the 1.55 mu m wavelength. Good agreement between the SNOM measurements and predicted optical mode propagation characteristics in standard ridge waveguides demonstrates the validity of the method. In situ observation of the subwavelength-scale distribution and propagation of optical fields in straight and 90 degrees bend photonic crystal waveguides facilitates a more detailed understanding of the optical performance characteristics of these devices and illustrates the usefulness of the technique for investigating nanostructured photonic devices

Differential branching fraction and angular analysis of the decay B0→K∗0μ+μ−

The angular distribution and differential branching fraction of the decay B 0→ K ∗0 μ + μ − are studied using a data sample, collected by the LHCb experiment in pp collisions at s√=7 TeV, corresponding to an integrated luminosity of 1.0 fb−1. Several angular observables are measured in bins of the dimuon invariant mass squared, q 2. A first measurement of the zero-crossing point of the forward-backward asymmetry of the dimuon system is also presented. The zero-crossing point is measured to be q20=4.9±0.9GeV2/c4 , where the uncertainty is the sum of statistical and systematic uncertainties. The results are consistent with the Standard Model predictions

Measurements of the branching fractions of B+→ppK+ decays

The branching fractions of the decay B+ → pp̄K+ for different intermediate states are measured using data, corresponding to an integrated luminosity of 1.0 fb-1, collected by the LHCb experiment. The total branching fraction, its charmless component Mpp̄ < 2.85 GeV/c2 and the branching fractions via the resonant cc̄ states η c(1S) and ψ(2S) relative to the decay via a J/ψ intermediate state are [Equation not available: see fulltext.] Upper limits on the B + branching fractions into the η c(2S) meson and into the charmonium-like states X(3872) and X(3915) are also obtained

Observation of associated production of a ZZ boson with a DD meson in the~forward region

A search for associated production of a $Z$ boson with an open charm meson is presented using a data sample, corresponding to an integrated luminosity of $1.0\,\mathrm{fb}^{-`}$ of proton--proton collisions at a centre-of-mass energy of 7\,TeV, collected by the LHCb experiment. %% Seven candidate events for associated production of a $Z$ boson with a $D^0$ meson and four candidate events for a $Z$ boson with a $D^+$ meson are observed with a combined significance of 5.1standard deviations. The production cross-sections in the forward region are measured to be $$\sigma_{Z\rightarrow\mu^+\mu^-\!,D^0} = 2.50\pm1.12\pm0.22pb$$ $$\sigma_{Z\rightarrow\mu^+\mu^-\!,D^+} = 0.44\pm0.23\pm0.03pb,$$ where the first uncertainty is statistical and the second systematic.Comment: 18 pages, 2 figure

Searches for B0(s)→J/ψppˉ and B+→J/ψppˉπ+ decays

The results of searches for B0(s)→J/ψ pp¯ and B + → J/ψ p p¯ π+ decays are reported. The analysis is based on a data sample, corresponding to an integrated luminosity of 1.0 fb−1 of pp collisions, collected with the LHCb detector. An excess with 2.8 σ significance is seen for the decay B0s→J/ψ pp¯ and an upper limit on the branching fraction is set at the 90 % confidence level: B(B0s→J/ψ pp¯) < 4.8 × 10−6, which is the first such limit. No significant signals are seen for B0 → J/ψ pp¯ and B+ → J/ψ pp¯ π + decays, for which the corresponding limits are set: B(B0→J/ψ pp¯) < 5.2 × 10−7, which significantly improves the existing limit; and B(B+→J/ψ pp¯π+) < 5.0 × 10−7, which is the first limit on this branching fraction

Measurement of the relative rate of prompt χc0, χc1 and χc2 production at √s=7TeV

Prompt production of charmonium χc0, χc1 and χc2 mesons is studied using proton-proton collisions at the LHC at a centre-of-mass energy of √s=7TeV. The χc mesons are identified through their decay to J/ψγ, with J/ψ→μ+mu− using photons that converted in the detector. A data sample, corresponding to an integrated luminosity of 1.0fb−1 collected by the LHCb detector, is used to measure the relative prompt production rate of χc1 and χc2 in the rapidity range 2.0<y<4.5 as a function of the J/ψ transverse momentum from 3 to 20 GeV/c. First evidence for χc0 meson production at a hadron collider is also presented

Opposite-side flavour tagging of B mesons at the LHCb experiment

The calibration and performance of the oppositeside flavour tagging algorithms used for the measurements of time-dependent asymmetries at the LHCb experiment are described. The algorithms have been developed using simulated events and optimized and calibrated with B + →J/ψK +, B0 →J/ψK ∗0 and B0 →D ∗− μ + νμ decay modes with 0.37 fb−1 of data collected in pp collisions at √ s = 7 TeV during the 2011 physics run. The oppositeside tagging power is determined in the B + → J/ψK + channel to be (2.10 ± 0.08 ± 0.24) %, where the first uncertainty is statistical and the second is systematic

Measurements of the B+B^+, B0B^0, Bs0B_s^0 meson and Λb0\Lambda_b^0 baryon lifetimes

Measurements of $b$-hadron lifetimes are reported using $pp$ collision data, corresponding to an integrated luminosity of 1.0fb$^{-1}$, collected by the LHCb detector at a centre-of-mass energy of $7$Tev. Using the exclusive decays $B^+\to J/\psi K^+$, $B^0\to J/\psi K^*(892)^0$, $B^0\to J/\psi K^0_{\rm S}$, $\Lambda_b^0\to J/\psi \Lambda$ and $B^0_s\to J/\psi \phi$ the average decay times in these modes are measured to be $\tau_{B^+\to J/\psi K^+}$ = $1.637 \pm$ 0.004 $\pm$ 0.003 ps, $\tau_{B^0\to J/\psi K^*(892)^0}$ = $1.524 \pm$ 0.006 $\pm$ 0.004 ps, $\tau_{B^0\to J/\psi K^0_{\rm S}}$ = $1.499 \pm$ 0.013 $\pm$ 0.005 ps, $\tau_{\Lambda_b^0\to J/\psi \Lambda}$ = $1.415 \pm$ 0.027 $\pm$ 0.006 ps and $\tau_{B^0_s\to J/\psi \phi}$ = $1.480 \pm$ 0.011 $\pm$ 0.005 ps, where the first uncertainty is statistical and the second is systematic. These represent the most precise lifetime measurements in these decay modes. In addition, ratios of these lifetimes, and the ratio of the decay-width difference, $\Delta\Gamma_d$, to the average width, $\Gamma_d$, in the $B^0$ system, $\Delta \Gamma_d/\Gamma_d = -0.044 \pm 0.025 \pm 0.011$, are reported. All quantities are found to be consistent with Standard Model expectations.Comment: 28 pages, 4 figures. Updated reference

Study of DJ meson decays to D+π−, D0π+ and D∗+π− final states in pp collisions

A study of D+π−, D0π+ and D∗+π− final states is performed using pp collision data, corresponding to an integrated luminosity of 1.0 fb−1, collected at a centre-of-mass energy of 7 TeV with the LHCb detector. The D1(2420)0 resonance is observed in the D∗+π− final state and the D∗2(2460) resonance is observed in the D+π−, D0π+ and D∗+π− final states. For both resonances, their properties and spin-parity assignments are obtained. In addition, two natural parity and two unnatural parity resonances are observed in the mass region between 2500 and 2800 MeV. Further structures in the region around 3000 MeV are observed in all the D∗+π−, D+π− and D0π+ final states