139277-58-0Relevant articles and documents
Synthesis and structure-activity relationships of 3,4,5-trisubstituted-1,2,4-triazoles: High affinity and selective somatostatin receptor-4 agonists for Alzheimer's disease treatment
Crider, A. Michael,Farr, Susan A.,Frare, Rafael,Hospital, Audrey,Kontoyianni, Maria,Kukielski, Stephen G.,Minaeian, Mahsa,Mobayen, Shirin,Neumann, William L.,Niehoff, Michael L.,Sandoval, Karin E.,Slater, Olivia,Srabony, Khush N.,Witt, Ken A.
, p. 1352 - 1365 (2021/11/09)
Somatostatin receptor-4 (SST4) is highly expressed in brain regions affiliated with learning and memory. SST4 agonist treatment may act to mitigate Alzheimer's disease (AD) pathology. An integrated approach to SST4 agonist lead optimization is presented herein. High affinity and selective agonists with biological efficacy were identified through iterative cycles of a structure-based design strategy encompassing computational methods, chemistry, and preclinical pharmacology. 1,2,4-Triazole derivatives of our previously reported hit (4) showed enhanced SST4 binding affinity, activity, and selectivity. Thirty-five compounds showed low nanomolar range SST4 binding affinity, 12 having a Ki 500-fold affinity for SST4 as compared to SST2A. SST4 activities were consistent with the respective SST4 binding affinities (EC50 600-fold selectivity over SST2A) display a favorable physiochemical profile, and was advanced to learning and memory behavior evaluations in the senescence accelerated mouse-prone 8 model of AD-related cognitive decline. Chronic administration enhanced learning with i.p. dosing (1 mg kg-1) compared to vehicle. Chronic administration enhanced memory with both i.p. (0.01, 0.1, 1 mg kg-1) and oral (0.01, 10 mg kg-1) dosing compared to vehicle. This study identified a novel series of SST4 agonists with high affinity, selectivity, and biological activity that may be useful in the treatment of AD. This journal is
Studies and synthesis of substituted 4-biphenyl acetamide derivatives
Khullar, Anju
, p. 510 - 514 (2019/02/06)
A new series of substituted 4-biphenylamides have been synthesized by condensation of 4-biphenyl acetic acid with different primary amines (aromatic and aliphatic). 4-Biphenyl acetic acid was first treated with thionyl chloride in dry benzene to prepare substituted 4-biphenyl acetyl chloride, which is then treated with different aliphatic or aromatic amines to synthesize various substituted 4-biphenyl acid-amide derivatives. The structure of newly synthesized compounds has been established by analytical and spectral methods. These synthesized compounds have shown antifungal properties against Fusarium udum and Curvularia lunata.
3,4,5-TRISUBSTITUTED-1,2,4-TRIAZOLES AND 3,4,5-TRISUBSTITUTED-3-THIO-1,2,4-TRIAZOLES AND USES THEREOF
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Paragraph 0158; 0193; 0206, (2018/12/02)
The present disclosure describes novel compounds that are somatostatin receptor type 4 agonists.
Aggrecanase-2 inhibitors based on the acylthiosemicarbazide zinc-binding group
Maingot, Lucie,Elbakali, Jamal,Dumont, Julie,Bosc, Damien,Cousaert, Nicolas,Urban, Agathe,Deglane, Gaelle,Villoutreix, Bruno,Nagase, Hideaki,Sperandio, Olivier,Leroux, Florence,Deprez, Benoit,Deprez-Poulain, Rebecca
, p. 244 - 261 (2013/10/01)
Osteoarthritis is a disabling disease characterized by the articular cartilage breakdown. Aggrecanases are potential therapeutic targets for the treatment of this pathology. At the starting point of this project, an acylthiosemicarbazide was discovered to inhibit aggrecanase-2. The acylthiosemicarbazide Zn binding group is also a convenient linker for library synthesis. A focused library of 920 analogs was thus prepared and screened to establish structure-activity relationships. The modification of the acylthiosemicarbazide was also explored. This strategy combining library design and discrete compounds synthesis yielded inhibitor 35, that is highly selective for aggrecanases over a panel of metalloproteases and inhibits the degradation of native fully glycosylated aggrecan. A docking study generated binding conformations explaining the structure-activity relationships.
Aromatic hydrazides as specific inhibitors of bovine serum amine oxidase
Artico,Silvestri,Stefancich,Avigliano,Di Giulio,Maccarrone,Agostinelli,Mondovi,Morpurgo
, p. 219 - 228 (2007/10/02)
New hydrazides were synthesized in search for specific inhibitors of bovine serum amine oxidase: a series of benzoic and phenylacetic acid hydrazides containing the 1H-imidazol-1-yl or the 1H-imidazol-1-ylmethyl group as (o,m,p)-substituent in the phenyl ring; an analogous series of p-substituted phenylhydrazides with 5 or 6-membered heterocyclic ring as substituent, and a series of similar phenylpropionic hydrazides. The longer and more flexible phenylacetic hydrazides, and to a somewhat lesser extent the phenylpropionic ones, were better specific inhibitors of bovine serum amine oxidase than the benzoic hydrazides, which were also bound by the enzyme with high affinity, but at a slow rate. Derivatives with p- and m-substituents were more reactive than the o-substituted ones. The chemical nature of the substituent was less important than its position in the phenyl ring and the presence of methylene spacers. These data point to the presence of a hydrophobic site at short distance from the protein carbonyl cofactor, so that simultaneous interaction of the 2 ends of the inhibitor molecule can occur at the 2 sites. The presence of the hydrophobic site was confirmed by the capability of some molecule deprived of the hydrazidic group to act as mild inhibitors. All hydrazides were less reactive by 2-3 orders of magnitude towards pig kidney diamine oxidase and FAD-dependent monoamine oxidase from rat brain mitochondria, while the other compounds showed similar inhibition power against all proteins. The specificity for the bovine enzyme seems therefore to be related to the concerted action of the 2 moieties of the inhibitor molecule.
