150986-83-7Relevant articles and documents
Discovery of Selective Phosphodiesterase 1 Inhibitors with Memory Enhancing Properties
Dyck, Brian,Branstetter, Bryan,Gharbaoui, Tawfik,Hudson, Andrew R.,Breitenbucher, J. Guy,Gomez, Laurent,Botrous, Iriny,Marrone, Tami,Barido, Richard,Allerston, Charles K.,Cedervall, E. Peder,Xu, Rui,Sridhar, Vandana,Barker, Ryan,Aertgeerts, Kathleen,Schmelzer, Kara,Neul, David,Lee, Dong,Massari, Mark Eben,Andersen, Carsten B.,Sebring, Kristen,Zhou, Xianbo,Petroski, Robert,Limberis, James,Augustin, Martin,Chun, Lawrence E.,Edwards, Thomas E.,Peters, Marco,Tabatabaei, Ali
, p. 3472 - 3483 (2017)
A series of potent thienotriazolopyrimidinone-based PDE1 inhibitors was discovered. X-ray crystal structures of example compounds from this series in complex with the catalytic domain of PDE1B and PDE10A were determined, allowing optimization of PDE1B potency and PDE selectivity. Reduction of hERG affinity led to greater than a 3000-fold selectivity for PDE1B over hERG. 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one was identified as an orally bioavailable and brain penetrating PDE1B enzyme inhibitor with potent memory-enhancing effects in a rat model of object recognition memory.
Discovery and biological evaluation of tetrahydrothieno[2,3-c]pyridine derivatives as selective metabotropic glutamate receptor 1 antagonists for the potential treatment of neuropathic pain
Nam, Mina,Kim, TaeHun,Kwak, Jinsook,Seo, Seon Hee,Ko, Min Kyung,Lim, Eun Jeong,Min, Sun-Joon,Cho, Yong Seo,Keum, Gyochang,Baek, Du-Jong,Lee, Jiyoun,Pae, Ae Nim
, p. 245 - 258 (2015)
Abstract Metabotropic glutamate receptor 1 (mGluR1) has been a prime target for drug discovery due to its heavy involvement in various brain disorders. Recent studies suggested that mGluR1 is associated with chronic pain and can serve as a promising targe
N-(3-Cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amides as potent, selective, inhibitors of JNK2 and JNK3
Angell, Richard M.,Atkinson, Francis L.,Brown, Murray J.,Chuang, Tsu Tshen,Christopher, John A.,Cichy-Knight, Maria,Dunn, Allison K.,Hightower, Kendra E.,Malkakorpi, Susanna,Musgrave, James R.,Neu, Margarete,Rowland, Paul,Shea, Robyn L.,Smith, Jeffery L.,Somers, Donald O.,Thomas, Sonia A.,Thompson, Gladstone,Wang, Ruolan
, p. 1296 - 1301 (2007)
The identification and exploration of a novel, potent and selective series of N-(3-cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amide inhibitors of JNK2 and JNK3 kinases is described. Compounds 5a and 11a were identified as potent inhibitors of JNK3 (pIC50 6.7 and 6.6, respectively), with essentially equal potency against JNK2 (pIC50 6.5). Selectivity within the mitogen-activated protein kinase (MAPK) family, against JNK1, p38α and ERK2, was observed for the series. X-ray crystallography of 5e and 8a in JNK3 revealed a unique binding mode, with the 3-cyano substituent forming an H-bond acceptor interaction with the hinge region of the ATP-binding site.
Preparation and application of 2, 4-dimethoxybenzylurea compound
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Paragraph 0018, (2021/07/31)
The invention relates to the field of medicinal chemistry, in particular to a 2, 4-dimethoxy benzylurea compound capable of inhibiting activity of alpha-glucosidase, the structural general formula of the 2, 4-dimethoxy benzylurea compound is shown in the specification, and a preliminary activity test proves that the compound has remarkable inhibitory activity on alpha-glucosidase and shows a relatively strong anti-diabetic effect. The compound provided by the invention is simple to prepare and strong in alpha-glucosidase activity inhibition capability, and provides guidance for research and development of novel anti-diabetic drugs.
Novel tetrahydrobenzo[b]thiophen-2-yl)urea derivatives as novel α-glucosidase inhibitors: Synthesis, kinetics study, molecular docking, and in vivo anti-hyperglycemic evaluation
Xie, Hong-Xu,Zhang, Juan,Li, Yue,Zhang, Jin-He,Liu, Shan-Kui,Zhang, Jie,Zheng, Hua,Hao, Gui-Zhou,Zhu, Kong-Kai,Jiang, Cheng-Shi
, (2021/08/19)
α-Glucosidase inhibitors, which can inhibit the digestion of carbohydrates into glucose, are one of important groups of anti-type 2 diabetic drugs. In the present study, we report our effort on the discovery and optimization of α-glucosidase inhibitors with tetrahydrobenzo[b]thiophen-2-yl)urea core. Screening of an in-house library revealed a moderated α-glucosidase inhibitors, 5a, and then the following structural optimization was performed to obtain more efficient derivatives. Most of these derivatives showed increased inhibitory activity against α-glucosidase than the parental compound 5a (IC50 of 26.71 ± 1.80 μM) and the positive control acarbose (IC50 of 258.53 ± 1.27 μM). Among them, compounds 8r (IC50 = 0.59 ± 0.02 μM) and 8s (IC50 = 0.65 ± 0.03 μM) were the most potent inhibitors, and showed selectivity over α-amylase. The direct binding of both compounds with α-glucosidase was confirmed by fluorescence quenching experiments. Kinetics study revealed that these compounds were non-competitive inhibitors, which was consistent with the molecular docking results that compounds 8r and 8s showed high preference to bind to the allosteric site instead of the active site of α-glucosidase. In addition, compounds 8r and 8s were not toxic (IC50 > 100 μM) towards LO2 and HepG2 cells. Finally, the in vivo anti-hyperglycaemic activity assay results indicated that compounds 8r could significantly decrease the level of plasma glucose and improve glucose tolerance in SD rats treated with sucrose. The present study provided the tetrahydrobenzo[b]thiophen-2-yl)urea chemotype for developing novel α-glucosidase inhibitors against type 2 diabetes.
N-SUBSTITUTED TETRAHYDROTHIENOPYRIDINE DERIVATIVES AND USES THEREOF
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Paragraph 00224, (2020/01/11)
A compound of Formula (I) is provided that has been shown to be useful for treating a disease caused by a viral infection: (I) wherein R1, R2, R3, A, L, m, n, p and q are as defined herein.
Design, synthesis and molecular modeling study of certain VEGFR-2 inhibitors based on thienopyrimidne scaffold as cancer targeting agents
Ghith, Amna,Youssef, Khairia M.,Ismail, Nasser S.M.,Abouzid, Khaled A.M.
, p. 111 - 128 (2018/10/24)
Different series of novel thieno [2,3-d]pyrimidine derivative (9a-d,10a-f,l,m and 15a-m) were designed, synthesized and evaluated for their ability to in vitro inhibit VEGFR-2 enzyme. Also, the cytotoxicity of the final compounds was tested against a panel of 60 different human cancer cell lines by NCI. The VEGFR-2 enzyme inhibitory results revealed that compounds 10d, 15d and 15 g are among the most active inhibitors with IC50 values of 2.5, 5.48 and 2.27 μM respectively, while compound 10a remarkably showed the highest cell growth inhibition with mean growth inhibition (GI) percent of 31.57%. It exhibited broad spectrum anti-proliferative activity against several NCI cell lines specifically on human breast cancer (T7-47D) and renal cancer (A498) cell lines of 85.5% and 77.65% inhibition respectively. To investigate the mechanistic aspects underlying the activity, further biological studies like flow cytometry cell cycle together with caspase-3 colorimetric assays were carried on compound 10a. Flow cytometric analysis on both MCV-7 and PC-3 cancer cells revealed that it induced cell-cycle arrest in the G0-G1phase and reinforced apoptosis via activation of caspase-3. Furthermore, molecular modeling studies have been carried out to gain further understanding of the binding mode in the active site of VEGFR-2 enzyme and predict pharmacokinetic properties of all the synthesized inhibitors.
Novel Tetrahydrothieno[2,3-c]pyridine derivatives as mGluR1 and/or mGluR5 antagonists
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Paragraph 0139-0141, (2018/03/13)
The present invention relates to a tetrahydrothieno [2,3-c]pyridine derivative showing activity for a metabolic glutamate receptor 1 and/or a glutamate receptor 5 as an antagonist; a producing method of the compound; and a drug composition comprising the
Structure-activity relationships of new cyanothiophene inhibitors of the essential peptidoglycan biosynthesis enzyme MurF
Hrast, Martina,Turk, Samo,Sosi?, Izidor,Knez, Damijan,Randall, Christopher P.,Barreteau, Hélène,Contreras-Martel, Carlos,Dessen, Andréa,O'Neill, Alex J.,Mengin-Lecreulx, Dominique,Blanot, Didier,Gobec, Stanislav
, p. 32 - 45 (2013/10/01)
Peptidoglycan is an essential component of the bacterial cell wall, and enzymes involved in its biosynthesis represent validated targets for antibacterial drug discovery. MurF catalyzes the final intracellular peptidoglycan biosynthesis step: the addition of D-Ala-D-Ala to the nucleotide precursor UDP-MurNAc-L-Ala-γ-D-Glu-meso-DAP (or L-Lys). As MurF has no human counterpart, it represents an attractive target for the development of new antibacterial drugs. Using recently published cyanothiophene inhibitors of MurF from Streptococcus pneumoniae as a starting point, we designed and synthesized a series of structurally related derivatives and investigated their inhibition of MurF enzymes from different bacterial species. Systematic structural modifications of the parent compounds resulted in a series of nanomolar inhibitors of MurF from S. pneumoniae and micromolar inhibitors of MurF from Escherichia coli and Staphylococcus aureus. Some of the inhibitors also show antibacterial activity against S. pneumoniae R6. These findings, together with two new co-crystal structures, represent an excellent starting point for further optimization toward effective novel antibacterials.
Synthesis, biological evaluation, and structure-activity relationships of a novel class of apurinic/apyrimidinic endonuclease 1 inhibitors
Rai, Ganesha,Vyjayanti, Vaddadi N.,Dorjsuren, Dorjbal,Simeonov, Anton,Jadhav, Ajit,Wilson, David M.,Maloney, David J.
supporting information; experimental part, p. 3101 - 3112 (2012/06/01)
APE1 is an essential protein that operates in the base excision repair (BER) pathway and is responsible for a‰￥ 95% of the total apurinic/apyrimidinic (AP) endonuclease activity in human cells. BER is a major pathway that copes with DNA damage induced by several anticancer agents, including ionizing radiation and temozolomide. Overexpression of APE1 and enhanced AP endonuclease activity have been linked to increased resistance of tumor cells to treatment with monofunctional alkylators, implicating inhibition of APE1 as a valid strategy for cancer therapy. We report herein the results of a focused medicinal chemistry effort around a novel APE1 inhibitor, N-(3-(benzo[d]thiazol-2-yl)-6-isopropyl-4,5,6,7-tetrahydrothieno[2,3-c] pyridin-2-yl)acetamide (3). Compound 3 and related analogues exhibit single-digit micromolar activity against the purified APE1 enzyme and comparable activity in HeLa whole cell extract assays and potentiate the cytotoxicity of the alkylating agents methylmethane sulfonate and temozolomide. Moreover, this class of compounds possesses a generally favorable in vitro ADME profile, along with good exposure levels in plasma and brain following intraperitoneal dosing (30 mg/kg body weight) in mice. This article not subject to U.S. Copyright. Published 2012 by the American Chemical Society.
