- Preparation method of timolol impurity
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The invention discloses a timolol impurity preparation method, and belongs to the technical field of timolol impurity synthesis. 3-halo-4-morpholinyl-1,2,5-thiadiazole is used as an initial raw material to prepare an intermediate M1 through alkaline hydrolysis and acid treatment, potassium ethyl malonate and tert-butyl amine are subjected to a condensation reaction to prepare an intermediate M2, the intermediate M2 and liquid bromine are subjected to a substitution reaction to prepare an intermediate M3, the intermediate M3 and the intermediate M1 are subjected to a nucleophilic substitution reaction to prepare an intermediate M4, and the intermediate M4 is subjected to a reduction reaction and alkaline hydrolysis to prepare a target product. The method has the characteristics of reasonable synthetic route, easily available raw materials, simple and easy operation, high yield and high purity. The prepared timolol can be used as a reference substance for qualitative and quantitative research of impurities in timolol quality research, the content of related substances in bulk drugs is controlled, and the quality of the bulk drugs is guaranteed.
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Paragraph 0030-0034; 0049-0050
(2021/06/09)
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- Development of a selective activity-based probe for glycosylated LIPA
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Loss of LIPA activity leads to diseases such as Wolman's Disease and Cholesterol Ester Storage Disease. While it is possible to measure defects in LIPA protein levels, it is difficult to directly measure LIPA activity in cells. In order to measure LIPA activity directly we developed a LIPA specific activity based probe. LIPA is heavily glycosylated although it is unclear how glycosylation affects LIPA activity or function. Our probe is specific for a glycosylated form of LIPA in cells, although it labels purified LIPA regardless of glycosylation.
- Schwaid, Adam G.,Ruangsiriluk, Wanida,Reyes, Allan R.,Cabral, Shawn,Rajamohan, Francis,Tu, Meihua,Ward, Jessica,Carpino, Philip A.
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supporting information
p. 1993 - 1996
(2016/04/05)
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- Optimization of 1,2,5-thiadiazole carbamates as potent and selective ABHD6 inhibitors
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At present, inhibitors of α/β-hydrolase domain 6 (ABHD6) are viewed as a promising approach to treat inflammation and metabolic disorders. This article describes the development of 1,2,5-thiadiazole carbamates as ABHD6 inhibitors. Altogether, 34 compounds were synthesized, and their inhibitory activity was tested using lysates of HEK293 cells transiently expressing human ABHD6 (hABHD6). Among the compound series, 4-morpholino-1,2,5-thiadiazol-3-yl cyclooctyl(methyl)carbamate (JZP-430) potently and irreversibly inhibited hABHD6 (IC50 = 44 nM) and showed ～ 230-fold selectivity over fatty acid amide hydrolase (FAAH) and lysosomal acid lipase (LAL), the main off-targets of related compounds. Additionally, activity-based protein profiling indicated that JZP-430 displays good selectivity among the serine hydrolases of the mouse brain membrane proteome. JZP-430 has been identified as a highly selective, irreversible inhibitor of hABHD6, which may provide a novel approach in the treatment of obesity and type II diabetes.
- Patel, Jayendra Z.,Nevalainen, Tapio J.,Savinainen, Juha R.,Adams, Yahaya,Laitinen, Tuomo,Runyon, Robert S.,Vaara, Miia,Ahenkorah, Stephen,Kaczor, Agnieszka A.,Navia-Paldanius, Dina,Gynther, Mikko,Aaltonen, Niina,Joharapurkar, Amit A.,Jain, Mukul R.,Haka, Abigail S.,Maxfield, Frederick R.,Laitinen, Jarmo T.,Parkkari, Teija
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p. 253 - 265
(2015/02/05)
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- A smart library of epoxide hydrolase variants and the top hits for synthesis of (S)-β-blocker precursors
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Microtuning of the enzyme active pocket has led to a smart library of epoxide hydrolase variants with an expanded substrate spectrum covering a series of typical β-blocker precursors. Improved activities of 6- to 430-fold were achieved by redesigning the active site at two predicted hot spots. This study represents a breakthrough in protein engineering of epoxide hydrolases and resulted in enhanced activity toward bulky substrates. Hot pockets: Microtuning of the enzyme active pocket gives a smart library of epoxide hydrolase variants with an expanded substrate spectrum covering a series of typical β-blocker precursors. Improved activities of 6- to 430-fold were achieved by redesigning the active site at two predicted hot spots, and enhanced activity toward bulky substrates was found.
- Kong, Xu-Dong,Ma, Qian,Zhou, Jiahai,Zeng, Bu-Bing,Xu, Jian-He
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supporting information
p. 6641 - 6644
(2014/07/08)
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- Thiadiazole carbamates: Potent inhibitors of lysosomal acid lipase and potential niemann-pick type C disease therapeutics
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Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized at the cellular level by abnormal accumulation of cholesterol and other lipids in lysosomal storage organelles. Lysosomal acid lipase (LAL) has been recently identified as a potential therapeutic target for NPC. LAL can be specifically inhibited by a variety of 3,4-disubstituted thiadiazole carbamates. An efficient synthesis of the C(3) oxygenated/C(4) aminated analogues has been developed that furnishes the products in high yields and high degrees of purity. Common intermediates can also be used for the synthesis of the C(3) carbon substituted derivatives. Herein we tested various thiadiazole carbamates, amides, esters, and ketones for inhibition of LAL. In addition, we tested a diverse selection of commercially available non-thiadiazole carbamates. Our studies show that, among the compounds examined herein, only thiadiazole carbamates are effective inhibitors of LAL. We present a mechanism for LAL inhibition by these compounds whereby LAL transiently carbamoylates the enzyme similarly to previously described inhibition of acetylcholinesterase by rivastigmine and other carbamates as well as acylation of various lipases by orlistat.
- Rosenbaum, Anton I.,Cosner, Casey C.,Mariani, Christopher J.,Maxfield, Frederick R.,Wiest, Olaf,Helquist, Paul
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supporting information; experimental part
p. 5281 - 5289
(2010/10/19)
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- Biocatalytic asymmetric synthesis of (S)- and (R)-Timolol
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A new biocatalytic route for the synthesis of both enantiomers of Timolol (1) is described. Starting from 3,4-dichloro-1,2,5-thiadiazole (2), (R)- and (S)-Timolol (87% ee) were obtained in 35% and 30% overall yield, respectively. Asymmetric reduction of the intermediate haloketone 5 with baker's yeast afforded the corresponding halohydrin 6 in the optically active form (87% ee), which gave the R enantiomer (distomer) of Timolol. The S enantiomer (eutomer) was obtained via inversion of configuration of the halohydrin following the Mitsunobu procedure.
- Tosi, Giovanni,Zironi, Federica,Caselli, Emilia,Forni, Arrigo,Prati, Fabio
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p. 1625 - 1628
(2007/10/03)
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- Mass spectrometric study of the photooxidation of the ophthalmic drugs timolol and pindolol
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A mass spectrometric study of the photooxidation products of the ophthalmic drugs pindolol (1-[1H-indol-4-yloxyl]-3-[isopropylamino]-2-propanol) and timolol (S-[-]-1-[t-butylamino]-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxyl]-2-propanol) in water has been performed by LC-MS. Based on these data and the assumption that photooxidation mainly occurs through singlet molecular oxygen attack, a possible reaction mechanism is proposed. The mechanistic pathways involve singlet oxygen attack to the pindolol indole ring and oxidation of the pindolol isopropyl or timolol terbutyl methyl groups.
- Criado,Martire,Allegretti,Furlong, Jorge,Bertolotti,La Falce,Garcia
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p. 551 - 553
(2007/10/03)
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- Novel methods and compounds employed therein
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Preparation of an optically active alkamine in the sinister configuration, or a derivative of said alkamine, which is reacted with an 3-X-4-chloro(or RO-- where R is hydrogen or an alkali metal)-1,2,5-thiadiazole to prepare S-3-X-4-(3-substituted amino-2-hydroxypropoxy)-1,2,5-thiadiazole beta adrenergic blocking agents. Novel 3-morpholino-4-chloro(or RO--)-1,2,5-thiadiazoles and their preparation also are described.
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