83902-02-7Relevant articles and documents
Discovery, synthesis and anti-atherosclerotic activities of a novel selective sphingomyelin synthase 2 inhibitor
Li, Yali,Huang, Taomin,Lou, Bin,Ye, Deyong,Qi, Xiangyu,Li, Xiaoxia,Hu, Shuang,Ding, Tingbo,Chen, Yan,Cao, Yang,Mo, Mingguang,Dong, Jibin,Wei, Min,Chu, Yong,Li, Huiti,Jiang, Xian-Cheng,Cheng, Nengneng,Zhou, Lu
, p. 864 - 882 (2019/01/04)
The sphingomyelin synthase 2 (SMS2) is a potential target for pharmacological intervention in atherosclerosis. However, so far, few selective SMS2 inhibitors and their pharmacological activities were reported. In this study, a class of 2-benzyloxybenzamides were discovered as novel SMS2 inhibitors through scaffold hopping and structural optimization. Among them, Ly93 as one of the most potent inhibitors exhibited IC50 values of 91 nM and 133.9 μM against purified SMS2 and SMS1 respectively. The selectivity ratio of Ly93 was more than 1400-fold for purified SMS2 over SMS1. The in vitro studies indicated that Ly93 not only dose-dependently diminished apoB secretion from Huh7 cells, but also significantly reduced the SMS activity and increased cholesterol efflux from macrophages. Meanwhile, Ly93 inhibited the secretion of LPS-mediated pro-inflammatory cytokine and chemokine in macrophages. The pharmacokinetic profiles of Ly93 performed on C57BL/6J mice demonstrated that Ly93 was orally efficacious. As a potent selective SMS2 inhibitor, Ly93 significantly decreased the plasma SM levels of C57BL/6J mice. Furthermore, Ly93 was capable of dose-dependently attenuating the atherosclerotic lesions in the root and the entire aorta as well as macrophage content in lesions, in apolipoprotein E gene knockout mice treated with Ly93. In conclusion, we discovered a novel selective SMS2 inhibitor Ly93 and demonstrated its anti-atherosclerotic activities in vivo. The preliminary molecular mechanism-of-action studies revealed its function in lipid homeostasis and inflammation process, which indicated that the selective inhibition of SMS2 would be a promising treatment for atherosclerosis.
APELIN RECEPTOR AGONISTS AND METHODS OF USE THEREOF
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, (2019/02/25)
Provided herein are agonists of the apelin receptor for the treatment of disease. The compounds disclosed herein are useful for the treatment of a range of cardiovascular, renal and metabolic conditions.
Synthesis and Insecticidal Activity of Spinosyns with C9- O -Benzyl Bioisosteres in Place of the 2′,3′,4′-Tri- O -methyl Rhamnose
Oliver, M. Paige,Crouse, Gary D.,Demeter, David A.,Sparks, Thomas C.
, p. 5571 - 5577 (2015/06/25)
The spinosyns are fermentation-derived natural products active against a wide range of insect pests. They are structurally complex, consisting of two sugars (forosamine and rhamnose) coupled to a macrocyclic tetracycle. Removal of the rhamnose sugar results in a >100-fold reduction in insecticidal activity. C9-O-benzyl analogues of spinosyn D were synthesized to determine if the 2′,3′,4′-tri-O-methyl rhamnose moiety could be replaced with a simpler, synthetic bioisostere. Insecticidal activity was evaluated against larvae of Spodoptera exigua (beet armyworm) and Helicoverpa zea (corn earworm). Whereas most analogues were far less active than spinosyn D, a few of the C9-O-benzyl analogues, such as 4-CN, 4-Cl, 2-isopropyl, and 3,5-diOMe, were within 3-15 times the activity of spinosyn D for larvae of S. exigua and H. zea. Thus, although not yet quite as effective, synthetic bioisosteres can substitute for the naturally occurring 2′,3′,4′-tri-O-methyl rhamnose moiety.
SN2 substitution reactions at the amide nitrogen in the anomeric mutagens, N-acyloxy-N-alkoxyamides
Cavanagh, Katie L.,Glover, Stephen A.,Price, Helen L.,Schumacher, Rhiannon R.
experimental part, p. 700 - 710 (2010/02/16)
N-Acyloxy-N-alkoxyamides 1a are unusual anomeric amides that are pyramidal at the nitrogen because of bis oxyl substitution. Through this configuration, they lose most of their amide character and resemble -haloketones in reactivity. They are susceptible to SN2 reactions at nitrogen, a process that is responsible for their mutagenic behaviour. Kinetic studies have been carried out with the nucleophile N-methylaniline that show that, like SN2 reactions at carbon centres, the rate constant for SN2 displacement of carboxylate is lowered by branching to the nitrogen centre, or bulky groups on the alkoxyl side chain. Branching or bulky groups on the carboxylate leaving group, however, do not impact on the rate of substitution, which is mostly controlled by the pKA of the departing carboxylate group. These results are in line with computed properties for the model reaction of ammonia with N-acetoxy-N-methoxyacetamide but are in contrast to the role of steric effects on their mutagenicity. CSIRO 2009.
Synthesis, biological evaluation, and molecular modeling investigation of chiral 2-(4-chloro-phenoxy)-3-phenyl-propanoic acid derivatives with PPARα and PPARγ agonist activity
Fracchiolla, Giuseppe,Lavecchia, Antonio,Laghezza, Antonio,Piemontese, Luca,Trisolini, Raffaella,Carbonara, Giuseppe,Tortorella, Paolo,Novellino, Ettore,Loiodice, Fulvio
experimental part, p. 9498 - 9510 (2009/04/05)
PPARs are ligand-activated transcription factors that govern lipid and glucose homeostasis and play a central role in cardiovascular disease, obesity, and diabetes. Herein, we present screening results for a series of chiral 2-(4-chloro-phenoxy)-3-phenyl-propanoic acid derivatives, some of which are potent PPARγ agonists as well as PPARα agonists. To investigate the binding modes of the most interesting derivatives into the PPARα and PPARγ binding clefts and evaluate their agonist activity, docking experiments, molecular dynamics simulations, and MM-PBSA analysis were performed.
NOVEL SULFONAMIDE DERIVATIVE
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, (2010/11/25)
A compound of the formula (1): wherein m, n and p is independently an integer of 0 to 4 with the proviso that 3 a?| m + n a?| 8; X is the formula: NR4, etc.; R1, R3 and R4 are a substituted or unsubstituted aryl group, etc.; R2 is a hydrogen atom, etc.; a, b, c, d, e and f are a hydrogen atom or a substituted or unsubstituted alkyl group, etc.; Y is the formula: -SO2-, etc.; and Z is an oxygen atom, etc.; or a prodrug thereof or a pharmaceutically acceptable salt of the same has an activity of potentiating an expression of a low density lipoprotein receptor and thus is useful as an agent for treating hyperlipidemia or arteriosclerosis.
Large-scale asymmetric synthesis of novel sterically constrained 2′,6′-dimethyl- and α,2′,6′-trimethyltyrosine and -phenylalanine derivatives via alkylation of chiral equivalents of nucleophilic glycine and alanine
Soloshonok, Vadim A,Tang, Xuejun,Hruby, Victor J
, p. 6375 - 6382 (2007/10/03)
Asymmetric synthesis of (S)-2′,6′-dimethyltyrosine (DMT), (S)-2′,6′-dimethylphenylalanine (DMP), (S)-α,2′,6′-trimethyltyrosine (α-TMT) and (S)-α,2′,6′-trimethylphenylalanine (α-TMP) via reactions of 4′-benzyloxy-2′,6′-dimethylbenzyl bromide or 2′,6′-dimet
Tachykinin NK-1 receptor probed with constrained analogues of substance P
Sagan, Sandrine,Josien, Hubert,Karoyan, Philippe,Brunissen, Alie,Chassaing, Gerard,Lavielle, Solange
, p. 2167 - 2178 (2007/10/03)
The action of rotameric probes introduced either in position 7 or 8 in the sequence of substance P (SP) was investigated, i.e. L-tetrahydroisoquinoleic acid (Tic) L-fluorenylglycine (Flg), L-diphenylalanine (Dip), the diastereoisomers of L-1-indanylglycine (Ing) and L-benz[f]indanylglycine (Bfi), the Z- and E-isomers of dehydrophenylalanine and dehydronaphthylananine (Δ(Z)Phe, Δ(E)Phe, Δ(Z)Nal, Δ(E)Nal) and L-o,o'-dimethylphenylalanine (Dmp). The aim of this study was the topographical characterization of the binding subsites of human NK-1 receptor expressed in CHO cells, especially the S7 and 8, subsites, corresponding to residues Phe7 and Phe8 of substance P. According to the binding potencies of these substituted-SP analogues, the S7 binding subsite is smaller than the S8 subsite: the S7 subsite accepts only one aromatic nucleus, while the S8 can accommodate three coplanar nuclei altogether. These findings are compatible with the idea that the S8 binding subsite may reside in the extracellular loops of the hNK-1 receptor. NK-1 agonists bind to human NK-1 receptor and activate the production of both inositol phosphates and cyclic AMP. As already quoted for septide, [pGlu6, Pro9]]SP(6-11), discrepancies are observed between affinity (K(i)) and activity (EC50) values for IPs production. While a weak correlation between K(i) and EC50 values for IPs production could be found (r=0.70), an excellent correlation could be demonstrated between their affinities (K(i)) and their potencies (EC50) for cAMP production (r=0.97). The high potency (EC50) observed for 'septide-like' molecules on PI hydrolysis, compared to their affinity is not an artefact related to the high level of NK-1 receptors expressed on CHO cells since a good correlation was found between EC50 values obtained for PI hydrolysis and those measured for spasmogenic activity in guinea pig ileum bioassay (r=0.94).
Solvolysis of 2-substituted-9-(ortho-substituted) phenylmethyl)fluoren-9-yltrimethylammonium ions in various solvents
Smith, Peter James,Pradhan, Jyotsna
, p. 1060 - 1071 (2007/10/02)
The solvolytic reaction of several 9-(ortho-substituted phenylmethyl)fluoren-9-yltrimethylammonium salts has been investigated in several different solvents.Substitution and elimination products were found for the reactions in all solvents studied, with the exceptions that rection in both tert-butyl alcohol and chloroform led exclusively to the alkene product.The observed rate constants for alkene formation and the percent alkene were measured and it was found that the di-ortho compounds reacted at a faster rate but produced less alkene than the reaction of the corresponding mono-ortho salts.Hydrogen-deuterium isotope effects were also determined for the various reactions.The results are discussed in terms of the reaction proceeding by way of the E1 mechanism, where steric acceleration promotes the loss of the bulky ammonium leaving group to give the carbocation intermediate.
