65678-11-7Relevant academic research and scientific papers
Bisphosphonate esters interact with HMG-CoA reductase membrane domain to induce its degradation
Hashimoto, Yuichi,Ohgane, Kenji,Sagimori, Ikuya,Toyota, Yosuke,Yoshioka, Hiromasa
, (2020/06/18)
HMG-CoA reductase (HMGCR) is a rate-limiting enzyme in the cholesterol biosynthetic pathway, and its catalytic domain is the well-known target of cholesterol-lowering drugs, statins. HMGCR is subject to layers of negative feedback loops; excess cholesterol inhibits transcription of the gene, and lanosterols and oxysterols accelerate degradation of HMGCR. A class of synthetic small molecules, bisphosphonate esters exemplified by SR12813, has been known to induce accelerated degradation of HMGCR and reduce the serum cholesterol level. Although genetic and biochemical studies revealed that the accelerated degradation requires the membrane domain of HMGCR and Insig, an oxysterol sensor on the endoplasmic reticulum membrane, the direct target of the bisphosphonate esters remains unclear. In this study, we developed a potent photoaffinity probe of the bisphosphonate esters through preliminary structure–activity relationship study and demonstrated binding of the bisphosphonate esters to the HMGCR membrane domain. These results provide an important clue to understand the elusive mechanism of the SR12813-mediated HMGCR degradation and serve as a basis to develop more potent HMGCR degraders that target the non-catalytic, membrane domain of the enzyme.
HYDANTOIN DERIVATIVES USEFUL AS KV3 INHIBITORS
-
Paragraph 1396-1398, (2013/10/22)
The invention provides compounds of formula (I): Said compounds being inhibitors of Kv3 channels and of use in the prophylaxis or treatment of related disorders.
HYDANTOIN DERIVATIVES USEFUL AS KV3 INHIBITORS
-
Page/Page column 226, (2012/06/30)
The invention provides compounds of formula (I): Said compounds being inhibitors of Kv3 channels and of use in the prophylaxis or treatment of related disorders.
IMIDAZOLIDINEDIONE DERIVATIVES
-
Page/Page column 82, (2011/06/26)
The invention provides a compound of formula (Ia), and pharmaceutically acceptable salts thereof. The invention also provides use of the compounds or salts as modulators of Kv3.1 and/or Kv3.2, and in the treatment of diseases or disorders where a modulator of Kv3.1 and/or Kv3.2 is required, such as depression and mood disorders, hearing disorders, schizopherenea, substance abuse disorders, sleep disorders or epilepsy.
Understanding the cardioprotective effects of flavonols: Discovery of relaxant flavonols without antioxidant activity
Cheng, Xue Qin,Chen, Xingqiang,Hughes, Richard A.,Williams, Spencer J.,Woodman, Owen L.
, p. 1874 - 1884 (2008/12/21)
3′,4′-Dihydroxyflavonol (DiOHF) is a cardioprotective flavonol that can reduce injury after myocardial ischemia and reperfusion and thus is a promising small molecule for the treatment of cardiovascular disease. Like all vasoactive flavonols reported to date, DiOHF is both relaxant and antioxidant, hindering investigation of the relative contribution of each activity for the prevention of reperfusion injury. This study investigates structure-activity relationships of variations at the 3′ and 4′ positions of the B ring of DiOHF and vasorelaxant and antioxidant activities. Relaxation of rat isolated aortic rings precontracted with KCl revealed that the most active flavonols were those with a 4′-hydroxyl group, with the opening of potassium channels as a possible contributing mechanism. For the antioxidant activity, with the exception of DiOHF, none of the flavonols investigated were able to significantly scavenge superoxide radical, and none of the three most potent vasorelaxant flavonols could prevent oxidant-induced endothelial dysfunction. The discovery of single-acting vasorelaxant flavonols without antioxidant activity, in particular 4′-hydroxy-3′-methoxyflavonol, will assist in investigating the mechanism of flavonol-induced cardioprotection.
Galactose oxidase models: Creation and modification of proton transfer coupled to copper(II) coordination processes in pro-phenoxyl ligands
Michel, Fabien,Thomas, Fabrice,Hamman, Sylvain,Philouze, Christian,Saint-Aman, Eric,Pierre, Jean-Louis
, p. 3684 - 3696 (2007/10/03)
Two tripodal ligands containing two pyridyl and one 4-(benzimidazol-2-yl)- 2-tert-butylphenol (HLH) and one 2-tert-butyl-4-(N- methylbenzimidazol-2-yl)phenol (HLMe) unit have been synthesized. They possess a N3O donor set that is known to stabilize phenoxyl radicals more efficiently than the corresponding N2O2 donor unit. Reaction of one molar equiv. of Cu(ClO4) 2·6H2O with HLH or HLMe affords the zwitterionic benzimidazolium phenolate complexes [Cu IIHLH)]2+ and [CuII(HL Me)]2+ via a proton transfer reaction coupled to copper(II) coordination. Addition of HClO4 to [Cu II(HLH)]2+ and [CuII(HL Me)]2+ results in the formation of the benzimidazolium phenol complexes [CuII(H2LH)]3+ and [CuII(H2LMe)]2+, while addition of NEt3 affords the benzimidazol-phenolate complexes [Cu II(LH)]2+ and [CuII(L Me)]2+, respectively. The phenol's pKa is remarkably low due to the strong withdrawing effect of the benzimidazolium substituent. X-ray crystallographic analysis of the copper(II) complexes shows that deprotonation of the axial phenol forces the metal to move out of the square plane towards the oxygen atom, and one (or two) Cu-Npyridine equatorial bond length increases. The copper(II) phenoxyl species [Cu II(HLH)].3+ and [CuII(HL Me)].3+ were prepared electrochemically, or by addition of two molar equiv. of copper(II) to HLH or HLMe. Under these conditions, radical formation has never been observed for tripodal ligands containing two pyridyl and one 2,4-di-tert-butylphenol group. This difference is explained in terms of the proton transfer mechanism and redox potentials. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.
AMIDE COMPOUND AND USE OF THE SAME
-
Page/Page column 63, (2010/02/14)
PROBLEM TO BE SOLVED: To provide a compound having an excellent controlling effect against plant pests. SOLUTION: This amide compound expressed by formula (1) [wherein, R1 is H, a halogen atom, a 1-4C alkyl or the like; R2 is a 1-4C alkyl, a 1-4C haloalkyl or the like; R3 is H or a 1-3C alkyl; R4 is a halogen, a 1-4C alkylthio, a 2-5C alkylcarbonyloxy or the like; R5 is a 3-4C alkynyl; and X is O or S] has the excellent controlling effect against the plant pests. COPYRIGHT: (C)2006,JPOandNCIPI
Method for treating multiple sclerosis
-
, (2008/06/13)
Provided is a method of treating multiple sclerosis employing certain aryl-substituted rhodanines.
