113266-88-9Relevant academic research and scientific papers
Design, synthesis and in vitro evaluation of novel uni- and bivalent ligands for the cannabinoid receptor type 1 with variation of spacer length and structure
Huang, Guozheng,Pemp, Daniela,Stadtmueller, Patricia,Nimczick, Martin,Heilmann, Joerg,Decker, Michael
, p. 4209 - 4214 (2014)
Using rimonabant, a potent inverse agonist for cannabinoid receptor type 1 (CB1R), as parent ligand, a series of novel univalent and bivalent ligands were designed by variation of spacer length and its chemical structure. The ligands synthesized were evaluated for affinity and selectivity by radioligand displacement and a functional steady-state GTPase assay. The results showed the nature of the spacer influences the biological readout. Albeit all compounds show significantly lower affinities than rimonabant, this fact could be used to demonstrate that affinities and selectivity are influenced by the chemical structure and length of the spacer and might be helpful for designing bivalent probes for other GPCR receptors.
Pyrtriazoles, a Novel Class of Store-Operated Calcium Entry Modulators: Discovery, Biological Profiling, and in Vivo Proof-of-Concept Efficacy in Acute Pancreatitis
Riva, Beatrice,Griglio, Alessia,Serafini, Marta,Cordero-Sanchez, Celia,Aprile, Silvio,Di Paola, Rosanna,Gugliandolo, Enrico,Alansary, Dalia,Biocotino, Isabella,Lim, Dmitry,Grosa, Giorgio,Galli, Ubaldina,Niemeyer, Barbara,Sorba, Giovanni,Canonico, Pier Luigi,Cuzzocrea, Salvatore,Genazzani, Armando A.,Pirali, Tracey
, p. 9756 - 9783 (2018/11/23)
In recent years, channels that mediate store-operated calcium entry (SOCE, i.e., the ability of cells to sense a decrease in endoplasmic reticulum luminal calcium and induce calcium entry across the plasma membrane) have been associated with a number of d
Development of 3,5-dinitrobenzoate-based 5-lipoxygenase inhibitors
Shang, Erchang,Liu, Ying,Wu, Yiran,Zhu, Wei,He, Chong,Lai, Luhua
, p. 2396 - 2402 (2014/05/06)
Human 5-lipoxygenase (5-LOX) is a well-validated target for anti-inflammatory therapy. Development of novel 5-LOX inhibitors with higher activities is highly demanded. In previous study, we have built a model for the active conformation of human 5-LOX, and identified naphthalen-1-yl 3,5-dinitrobenzoate (JMC-4) as a 5-LOX inhibitor by virtual screening. In the present work, 3,5-dinitrobenzoate-based 5-lipoxygenase inhibitors were developed. Twenty aryl 3,5-dinitrobenzoates, N-aryl 3,5-dinitrobenzamides and analogues were designed and synthesized. Several of them were found with significantly increased activities according to cell-free assay and human whole blood assay. The structure-activity relationship study may provide useful insights for designing effective 5-LOX inhibitors.
Identification of vitamin D3-based hedgehog pathway inhibitors that incorporate an aromatic A-ring isostere
Deberardinis, Albert M.,Banerjee, Upasana,Hadden, M. Kyle
, p. 590 - 595 (2013/07/26)
Previous structure-activity relationship studies for vitamin D3 (VD3) inhibition of Hedgehog (Hh) signaling directed the design, synthesis, and evaluation of a series of VD3-based analogues that contain an aromatic A-ring mimic. Characterization of these
Amino acid binding by 2-(guanidiniocarbonyl)pyridines in aqueous solvents: A comparative binding study correlating complex stability with stereoelectronic factors
Schmuck, Carsten,Machon, Uwe
, p. 1109 - 1118 (2007/10/03)
A series of guanidiniocarbonylpyridine receptors has been synthesized, and these compounds bind amino acids (carboxylate forms) in aqueous DMSO with association constants ranging from K = 30 to 460 M-1 as determined by NMR titration experiments. The differences in the complex stabilities can be correlated with steric and electrostatic effects with the aid of calculated complex structures. For example, the electrostatic repulsion between the pyridine nitrogen lone pair and the bound carboxylate makes anion binding less efficient than with the analogous pyrrole receptors previously introduced by us for carboxylate binding in water. Furthermore, steric interactions between the receptor side chain as in 2b and the bound substrate also disfavor complexation.
IMIDAZO(1,2-a)PYRIDINE DERIVATIVE
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Page 112, (2010/02/09)
A compound reprsented by the following formula (I), its salts or nsolvates thereof capable of specifically or selectively expressig an antifungal activity in a broad spectrum based on the novel mechanism thereof of 1,6-β-glucan synthesis inhibition, and an antifungal agent containing any of them.
Design, synthesis, and proposed active site binding analysis of monocyclic 2-azetidinone inhibitors of prostate specific antigen
Adlington,Baldwin,Becker,Chen,Cheng,Cooper,Hermann,Howe,McCoull,McNulty,Neubauer,Pritchard
, p. 1491 - 1508 (2007/10/03)
A homology derived molecular model of prostate specific antigen (PSA) was created and refined. The active site region was investigated for specific interacting functionality and a binding model postulated for the novel 2-azetidinone acyl enzyme inhibitor 1 (IC50 = 8.98 ± 0.90 μM) which was used as a lead compound in this study. A single low energy conformation structure II (Figure 2) was adopted as most likely to represent binding after minimization and dynamics calculations. Systematic analysis of the binding importance of all three side chains appended to the 2-azetidinone was conducted by the synthesis of several analogues. A proposed salt bridge to Lys-145 with 4 (IC50 = 5.84 ± 0.92 μM) gave improved inhibition, but generally the binding of the N-1 side chain in a specific secondary aromatic binding site did not tolerate much structural alteration. A hydrophobic interaction of the C-4 side chain afforded inhibitor 6 (IC50 = 1.43 ± 0.19 μM), and polar functionality could also be added in a proposed interaction with Gln-166 in 5 (IC50 = 1.34 ± 0.05 μM). Reversal of the C-4 ester connectivity furnished inhibitors 7 (IC50 = 1.59 ± 0.15 μM), 11 IC50 = 3.08 ± 0.41 μM) and 13 (IC50 = 2.19 ± 0.36 Mμ) which were perceived to bind to PSA by a rotation of 180° relative to the C-4 ester of normal connectivity. Incorporation of hydroxyl functionality into the C-3 side chain provided 16 IC50 = 348 ± 50 nM) with the greatest increase in PSA inhibition by a single modification. Multiple copy simultaneous search (MCSS) analysis of the PSA active site further supported our model and suggested that 18 would bind strongly. Asymmetric synthesis yielded 18 (IC50 = 226 ± 10 nM) as the most potent inhibitor of PSA reported to date. It is concluded that our design approach has been successful in developing PSA inhibitors and could also be applied to the inhibition of other enzymes, especially in the absence of crystallographic information.
AN EFFICIENT SUBSTITUTE FOR THE α-AMINODIPOYL MOIETY OF δ-(L-α-AMINOADIPOYL)-L-CYSTEINYL-D-VALINE IN THE ENZYMATIC SYNTHESIS OF PENICILLINS
Baldwin, Jack E.,Adlington, Robert M.,Crabbe, M. James C.,Nomoto, Takashi,Schofield, Christopher J.
, p. 4217 - 4220 (2007/10/02)
meta-Carboxyphenylacetyl-L-cysteinyl-D-valine was shown to be a highly efficient substrate for Isopenicillin N Synthetase, with similar Michaelis constant and maximum velocity parameters to the natural substrate δ-(L-α-aminoadipoyl)-L-cysteinyl-D-valine.
1,1-Alkanediol dicarboxylate linked antibacterial agents
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, (2008/06/13)
Useful antibacterial agents in which a penicillin and/or a beta-lactamase inhibitor are linked via 1,1-alkanediol dicarboxylates are of the formula STR1 where A is the residue of certain dicarboxyic acids, R3 is H or (C1 -C3), n is zero or 1 such that when n is zero R is P or B and R1 is the residue of certain esters, H or a salt thereof; and when n is 1, one of R and R1 is P and the other is B, and P is STR2 where R2 is H or certain acyl groups, and B is the residue of a beta-lactamase inhibiting carboxylic acid; a method for their use, pharmaceutical compositions thereof and intermediates useful in their production.
