1.Discovery of triazolopyridine GS-458967, a late sodium current inhibitor (Late INai) of the cardiac NaV 1.5 channel with improved efficacy and potency relative to ranolazine.
Koltun DO1, Parkhill EQ1, Elzein E1, Kobayashi T1, Notte GT1, Kalla R1, Jiang RH1, Li X1, Perry TD1, Avila B1, Wang WQ2, Smith-Maxwell C2, Dhalla AK2, Rajamani S2, Stafford B3, Tang J3, Mollova N3, Belardinelli L2, Zablocki JA1. Bioorg Med Chem Lett. 2016 Mar 30. pii: S0960-894X(16)30331-6. doi: 10.1016/j.bmcl.2016.03.101. [Epub ahead of print]
We started with a medium throughput screen of heterocyclic compounds without basic amine groups to avoid hERG and β-blocker activity and identified [1,2,4]triazolo[4,3-a]pyridine as an early lead. Optimization of substituents for Late INa current inhibition and lack of Peak INa inhibition led to the discovery of 4h (GS-458967) with improved anti-arrhythmic activity relative to ranolazine. Unfortunately, 4h demonstrated use dependent block across the sodium isoforms including the central and peripheral nervous system isoforms that is consistent with its low therapeutic index (approximately 5-fold in rat, 3-fold in dog). Compound 4h represents our initial foray into a 2nd generation Late INa inhibitor program and is an important proof-of-concept compound. We will provide additional reports on addressing the CNS challenge in a follow-up communication.
2.The evolution of substrate specificity-associated residues and Ca2+ -binding motifs in EF-hand-containing type II NAD(P)H dehydrogenases.
Hao MS1, Rasmusson AG1. Physiol Plant. 2016 Apr 15. doi: 10.1111/ppl.12453. [Epub ahead of print]
Most eukaryotic organisms, except some animal clades, have mitochondrial alternative electron transport enzymes that allow respiration to bypass the energy coupling in oxidative phosphorylation. The energy bypass enzymes in plants include the external type II NAD(P)H dehydrogenases of the NDB family, which are characterized by an EF-hand domain for Ca2+ binding. Here we investigate these plant enzymes by combining molecular modelling with evolutionary analysis. Molecular modelling of the Arabidopsis thaliana AtNDB1 with the yeast ScNDI1 as template revealed distinct similarities in the core catalytic parts, and highlighted the interaction between the pyridine nucleotide and residues correlating with NAD(P)H substrate specificity. The EF-hand domain of AtNDB1 has no counterpart in ScNDI1, and was instead modelled with Ca2+ -binding signal transducer proteins. Combined models displayed a proximity of the AtNDB1 EF-hand domain to the substrate entrance side of the catalytic part.
3.Effects of acetylation on the emulsifying properties of Artemisia sphaerocephala Krasch. polysaccharide.
Li J1, Hu X2, Li X1, Ma Z1. Carbohydr Polym. 2016 Jun 25;144:531-40. doi: 10.1016/j.carbpol.2016.02.039. Epub 2016 Feb 26.
In the present study, polysaccharides extracted from Artemisia sphaerocephala Krasch. seeds (ASKP) were acetylated to improve the emulsifying properties of the macromolecules. Several methods were applied for the acetylation purpose, among which the acetic anhydride-pyridine method with formamide as solvent was found to be the most effective one. Acetylated ASKPs with various degree of substitution (DS) were successfully produced and structurally characterized using HPSEC-MALS, FTIR and (1)H NMR techniques in this study. Results showed that acetylation treatment could cause the degradation of ASKP. Moreover, with the increase of DS, both the molecular weight and radius of gyration increased, as well as the molecular conformation trended to be more compact. Low DS (DS: 0.04 and 0.13) conferred acetylated ASKP a lower viscosity than that of ASKP. With the increase of DS, the viscosity of acetylated ASKPs increased and exceeded that of ASKP.
4.Synthesis and characterisation of 5-acyl-6,7-dihydrothieno[3,2-c]pyridine inhibitors of Hedgehog acyltransferase.
Lanyon-Hogg T1, Masumoto N1, Bodakh G1, Konitsiotis AD2, Thinon E1, Rodgers UR2, Owens RJ3, Magee AI2, Tate EW1. Data Brief. 2016 Feb 10;7:257-81. doi: 10.1016/j.dib.2016.02.012. eCollection 2016.
In this data article we describe synthetic and characterisation data for four members of the 5-acyl-6,7-dihydrothieno[3,2-c]pyridine (termed "RU-SKI") class of inhibitors of Hedgehog acyltransferase, including associated NMR spectra for final compounds. RU-SKI compounds were selected for synthesis based on their published high potencies against the enzyme target. RU-SKI 41 (9a), RU-SKI 43 (9b), RU-SKI 101 (9c), and RU-SKI 201 (9d) were profiled for activity in the related article "Click chemistry armed enzyme linked immunosorbent assay to measure palmitoylation by Hedgehog acyltransferase" (Lanyon-Hogg et al., 2015) . (1)H NMR spectral data indicate different amide conformational ratios between the RU-SKI inhibitors, as has been observed in other 5-acyl-6,7-dihydrothieno[3,2-c]pyridines. The synthetic and characterisation data supplied in the current article provide validated access to the class of RU-SKI inhibitors.