- Aclidinium bromide, a new, long-acting, inhaled muscarinic antagonist: In vitro plasma inactivation and pharmacological activity of its main metabolites
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Aclidinium bromide is a novel, long-acting inhaled muscarinic antagonist drug in Phase III clinical trials for chronic obstructive pulmonary disease (COPD). The aims of this study were to evaluate the in vitro stability of the ester drug aclidinium in plasma from various species, and the in vitro and in vivo pharmacological activity of its hydrolysis metabolites. Following incubation of aclidinium in pooled samples of human, rat, guinea pig or dog plasma, the rate of hydrolysis was quantified by reversed phase ultra performance liquid chromatography and mass spectrometry. Tiotropium and ipratropium were used as comparators. The in vitro biochemical profile of the hydrolysis metabolites of aclidinium was assessed in human M1 to M5 muscarinic receptors and in a standard selectivity panel (85 G protein-coupled receptors [GPCRs], ion channels and enzymes). The bronchodilator activity of the metabolites of aclidinium bromide was studied in guinea pigs after acetylcholine-induced bronchoconstriction. Aclidinium was rapidly hydrolysed into carboxylic acid and alcohol derivatives in guinea pig, rat, human and dog plasma with half-lives of 38, 11.7, 2.4 and 1.8 min, respectively. In contrast, ≥70% of tiotropium and ipratropium remained unchanged in the plasma after 60 min of incubation. The carboxylic acid and alcohol metabolites had no significant affinity for any of the muscarinic receptors, other GPCRs, ion channels or enzymes studied and showed no relevant antibronchoconstrictory activity in vivo. These results suggest that aclidinium may have a reduced systemic exposure and therefore less propensity for class-related systemic side effects in the clinical setting.
- Sentellas, Sonia,Ramos, Israel,Albertí, Joan,Salvà, Miquel,Antón, Francisca,Miralpeix, Montserrat,Beleta, Jorge,Gavaldà, Amadeu
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- Identification of the human enzymes responsible for the enzymatic hydrolysis of aclidinium bromide
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Aclidinium bromide [LAS34273, 3R-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1- (3-phenoxy-propyl)1-azonia bicycle-[2.2.2]-octane bromide], a novel, long-acting, inhaled muscarinic antagonist for the treatment of chronic obstructive pulmonary disease, has shown rapid hydrolysis in human and animal plasma. This process occurred both nonenzymatically (kh, 0.0075 min-1) and enzymatically. The purpose of the current study was to investigate the in vitro enzymatic hydrolysis of aclidinium in humans. Human butyrylcholinesterase was identified as the most important esterase responsible for the enzymatic hydrolysis of aclidinium from inhibition studies in human plasma with selective paraoxonase, arylesterase, carboxylesterase, acetylcholinesterase, and butyrylcholinesterase chemical inhibitors, as well as from incubations with pure human cholinesterases. Furthermore, neither human cytochrome P450 nor human serum albumin participated in the enzymatic ester cleavage of aclidinium. Butyrylcholinesterase activity in the human lung was lower than that observed in human plasma. Aclidinium was shown to inhibit competitively both human butyrylcholinesterase (Ki, 2.7 μM) and acetylcholinesterase (6.3 μM) but did not have any effect on the activity of other human esterases, as well as its hydrolysis metabolites. These results suggest that the potential for clinical interactions involving human cholinesterases is remote at clinically relevant plasma, which are less than 1 nM. Copyright
- Alberti, Joan,Martinet, Audrey,Sentellas, Sonia,Salva, Miquel
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- Preparation method of tiotropium bromide intermediate
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The invention belongs to the technical field of drug synthesis, and provides a preparation method of a tiotropium bromide important intermediate bis (2-dithienyl) glycolic acid ester, which comprises the following steps: reacting bis (2-thiophene) ketone as a starting material with sodium ethynyl under the catalysis of indium bromide to obtain 1, 1-bis (2-thienyl) propyl-2-alkyn-1-ol, oxidizing by acidic potassium permanganate to generate di (2-dithienyl) glycolic acid, and finally, carrying out esterification on the di (2-dithienyl) glycolic acid and methyl iodide to obtain di (2-dithienyl) methyl glycolate. Reaction conditions are milder, starting materials are cheap and easy to obtain, generation of heterogeneous impurities can be avoided, the product quality is more stable, and the method is suitable for industrial production.
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- Influence of different copolymer sequences in low band gap polymers on their performance in organic solar cells
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The chemical design of a polymer can be tailored by a random or a block sequence of the comonomers in order to influence the properties of the final material. In this work, two sequences, PCPDTBT and F8BT (F8), were polymerized to form a block or a random copolymer. Differences between the various polymers were examined by exploring the surface topography and charge carrier mobility. A distinct surface texture and a higher charge carrier mobility was found for the block copolymer with respect to the other materials. Solar cells were prepared with polymer:PC71BM blend active layers and the best performance of up to 2% was found for the block copolymer, which was a direct result of the fill factor. Overall, the sequences of different copolymers for solar cell applications were varied and a positive impact on efficiency was found when the block copolymer structure was utilized.
- Lange, Alexander,Krueger, Hartmut,Ecker, Bernhard,Tunc, Ali Veysel,Von Hauff, Elizabeth,Morana, Mauro
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experimental part
p. 1622 - 1635
(2012/06/01)
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- A Study of Some Thiophene Analogues of Glycolic Acid
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Reaction of phenyl(3-thienyl)glycolic acid (1) with AlCl3 in benzene solution leads to the formation of 4H-indenothiophene-4-carboxylic acid (2) whereas analogous reaction of phenyl(2-thienyl)glycolic acid (4) produces no indenothiophene but only a mixture of 5 and 6.In the case of di-(2-thienyl)glycolic acid (14b) and di-(3-thienyl)glycolic acid (16b) analogous results are obtained, with the former leading to the formation of 15 and the latter producing 17.In the case of the (benzothienyl)phenylglycolic analogues of 1 and 4 the acids were unstable to heat so that the esters, ethyl (2-benzothienyl)phenylglycolate (21) and ethyl (3-benzothienyl)phenylglycolate (20), upon treatment with AlCl3 in benzene led to cyclized products only.The former gave 23 which was saponified and decarboxylated to yield 25 and compared with an authentic sample obtained by synthesis.Ester 20 similarly gave 22 which was similarly converted to the known 24.A mechanistic explanation of these findings is proposed.
- Jeffries, Alfred T.,Moore, Kenneth C.,Ondeyka, Debra M.,Springsteen, Arthur W.,MacDowell, Denis W.H.
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p. 2885 - 2889
(2007/10/02)
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