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

Search for the rare decays Bs -->mumu and Bd -->mumu

A search for the decays Bs-->mumu and Bd-->mumu is performed with about 37 pb^{-1} of pp collisions at sqrt{s} = 7 TeV collected by the LHCb experiment at the Large Hadron Collider at CERN. The observed numbers of events are consistent with the background expectations. The resulting upper limits on the branching ratios are BR(Bs-->mumu) < 5.6 x 10^{-8} and BR(Bd-->mumu) <1.5 x 10^{-8} at 95% confidence level

Measurements of the Branching fractions for B_(s) -> D_(s)πππ and Λ_b^0 -> Λ_c^+πππ

Branching fractions of the decays $H_b\to H_c\pi^-\pi^+\pi^-$ relative to $H_b\to H_c\pi^-$ are presented, where $H_b$ ($H_c$) represents B^0-bar($D^+$), $B^-$ ($D^0$), B_s^0-bar ($D_s^+$) and $\Lambda_b^0$ ($\Lambda_c^+$). The measurements are performed with the LHCb detector using 35${\rm pb^{-1}}$ of data collected at $\sqrt{s}=7$ TeV. The ratios of branching fractions are measured to be B(B^0-bar -> D^+\pi^-\pi^+\pi^-)/ B(B^0-bar -> D^+\pi^-) = 2.38\pm0.11\pm0.21 B(B^- -> D^0\pi^-\pi^+\pi^-) / B(B^- -> D^0\pi^-) = 1.27\pm0.06\pm0.11 B(B_s^0-bar -> D_s^+\pi^-\pi^+\pi^-) / B(B_s^0-bar -> D_s^+\pi^-) = 2.01\pm0.37\pm0.20 B(\Lambda_b^0->\Lambda_c^+\pi^-\pi^+\pi^-) / B(\Lambda_b^0 -> \Lambda_c^+\pi^-) = 1.43\pm0.16\pm0.13. We also report measurements of partial decay rates of these decays to excited charm hadrons. These results are of comparable or higher precision than existing measurements

First observation of Bs -> J/psi f0(980) decays

Using data collected with the LHCb detector in proton-proton collisions at a centre-of-mass energy of 7 TeV, the hadronic decay Bs -> J/psi f0(980) is observed. This CP eigenstate mode could be used to measure mixing-induced CP violation in the B_s system. Using a fit to the pi+ pi- mass spectrum with interfering resonances gives R_{f0/phi} = [Gamma(Bs -> J/psi f0, f0 -> pi+ pi-)]/[Gamma(Bs -> J/psi phi, phi -> K+K-)] = 0.252^{+0.046+0.027}_{-0.032-0.033}, where the uncertainties are statistical and systematic, respectively

Determination of f_s/f_d for 7 TeV pp collisions and a measurement of the branching fraction of the decay Bd->D-K+

The relative abundance of the three decay modes $B_d \to D^- K^+$, $B_d \to D^- \pi^+$ and $B_s \to D_s^- \pi^+$ produced in 7 TeV $pp$ collisions at the LHC is determined from data corresponding to an integrated luminosity of 35 pb$^{-1}$. The branching fraction of $B_d \to D^- K^+$ is found to be $\cal B (B_d \to D^- K^+) = (2.01 \pm 0.18^{\textrm{stat}} \pm 0.14^{\textrm{syst}})\times 10^{-4}$. The ratio of fragmentation fractions \fsfdt is determined through the relative abundance of $B_s \to D_s^- \pi^+$ to $B_d \to D^- K^+$ and $B_d \to D^-\pi^+$, leading to $f_s/f_d = 0.253 \pm 0.017 \pm 0.017 \pm 0.020$, where the uncertainties are statistical, systematic, and theoretical respectively

First observation of Bs -> D_{s2}^{*+} X mu nu decays

Using data collected with the LHCb detector in proton-proton collisions at a centre-of-mass energy of 7 TeV, the semileptonic decays Bs -> Ds+ X mu nu and Bs -> D0 K+ X mu nu are detected. Two structures are observed in the D0 K+ mass spectrum at masses consistent with the known D^+_{s1}(2536) and $D^{*+}_{s2}(2573) mesons. The measured branching fractions relative to the total Bs semileptonic rate are B(Bs -> D_{s2}^{*+} X mu nu)/B(Bs -> X mu nu)= (3.3\pm 1.0\pm 0.4)%, and B(Bs -> D_{s1}^+ X munu)/B(Bs -> X mu nu)= (5.4\pm 1.2\pm 0.5)%, where the first uncertainty is statistical and the second is systematic. This is the first observation of the D_{s2}^{*+} state in Bs decays; we also measure its mass and width