- Identification of novel imidazole flavonoids as potent and selective inhibitors of protein tyrosine phosphatase
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A series of imidazole flavonoids as new type of protein tyrosine phosphatase inhibitors were synthesized and characterized. Most of them gave potent protein phosphatase 1B (PTP1B) inhibitory activities. Especially, compound 11a could effectively inhibit P
- Zhang, Ling,Ge, Yu,Wang, Qing Ming,Zhou, Cheng-He
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- Discovery of potent & selective inhibitors of activated thrombin-activatable fibrinolysis inhibitor for the treatment of thrombosis
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Thrombin-activatable fibrinolysis inhibitor (TAFI) has emerged as a key link between the coagulation and fibrinolysis cascades and represents a promising new target for the treatment of thrombosis. A novel series of imidazolepropionic acids has been designed that exhibit high potency against activated TAFI (TAFIa) and excellent selectivity over plasma carboxypeptidase N (CPN). Structure activity relationships suggest that the imidazole moiety plays a key role in binding to the catalytic zinc of TAFIa, and this has been supported by crystallographic studies using porcine pancreatic carboxypeptidase B as a surrogate for TAFIa. The SAR program led to the identification of 21 (TAFIa Ki = 10 nM, selectivity TAFIa/CPN > 1000) as a candidate for clinical development. Compound 21 exhibited antithrombotic efficacy in a rabbit model of venous thrombosis, yet had no effect on surgical bleeding in the rabbit. In addition, 21 exhibited an excellent preclinical and clinical pharmacokinetic profile, characterized by paracellular absorption, low clearance, and a low volume of distribution, fully consistent with its physicochemical properties of low molecular weight (MW = 239) and high hydrophilicity (log D = -2.8). These data indicate 21 (UK-396,082) has potential as a novel TAFIa inhibitor for the treatment of thrombosis and other fibrin-dependent diseases in humans.
- Bunnage, Mark E.,Blagg, Julian,Steele, John,Owen, Dafydd R.,Allerton, Charlotte,McElroy, Andrew B.,Miller, Duncan,Ringer, Tracy,Butcher, Ken,Beaumont, Kevin,Evans, Karen,Gray, Andrew J.,Holland, Stephen J.,Feeder, Neil,Moore, Robert S.,Brown, David G.
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p. 6095 - 6103
(2008/09/17)
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- Orally active CCR5 antagonists as anti-HIV-1 agents. Part 3: Synthesis and biological activities of 1-benzazepine derivatives containing a sulfoxide moiety
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In order to develop orally active CCR5 antagonists, 1-propyl- or 1-isobutyl-1-benzazepine derivatives containing a sulfoxide moiety have been designed, synthesized, and evaluated for their biological activities. Sulfoxide compounds containing a 2-pyridyl
- Seto, Masaki,Miyamoto, Naoki,Aikawa, Katsuji,Aramaki, Yoshio,Kanzaki, Naoyuki,Iizawa, Yuji,Baba, Masanori,Shiraishi, Mitsuru
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p. 363 - 386
(2007/10/03)
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- BENZAZEPINE DERIVATIVE, PROCESS FOR PRODUCING THE SAME, AND USE
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The present invention provides a novel benzazepine derivative represented by formula : wherein, R1 is a 5- or 6-membered aromatic ring, R2 is lower alkyl group, etc., Y is an optionally substituted imino group, ring A and ring B are independently an optionally substituted aromatic ring, W is formula -W1-X2-W2- (W1 and W2 are independently S(O)m1 (m1 is 0, 1 or 2), etc., and X2 is an optionally substituted alkylene groupetc. ), a preparation method and use thereof.
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- 3-(Imidazolyl)-2-alkoxypropanoic acids
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Compounds according to formula (I) wherein n is 0-3, R1 is optionally substituted C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, Heterocycle, Aromatic heterocycle, Aryl or hydrogen and R2, R3, R4, R5, R6, R7, R8 and R9 are each independently selected from hydrogen and optionally substituted C1-6 alkyl, or R5 and R8 are an alkylene chain, are novel. They are useful in the treatment of thrombotic conditions and other pathologies associated with fibrin deposition.
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- Pharmaceuticals
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The present invention provides compounds of formula (I) as well as the use of such compounds in pharmaceutical compositions and methods of treatment. The compounds described herein represent a class of TAFIla inhibitors suitable for use in treating condit
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- Bu3SnH mediated oxidative radical cyclisation onto imidazoles and pyrroles
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A new protocol using radical cyclisation has been developed for the synthesis of [1,2-c]-fused imidazoles and [1,2-a]-fused pyrroles. The intermediate nucleophilic N-alkyl radicals, generated using Bu3SnH from N- (ω-bromoalkyl) or N-[ω-(phenylselanyl)alkyl] imidazoles and pyrroles, undergo regio-selective radical cyclisalion onto the azole rings followed by oxidative re-aromatisation.
- Aldabbagh, Fawaz,Russell Bowman,Mann, Emma,Slawin, Alexandra M.Z.
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p. 8111 - 8128
(2007/10/03)
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- Oxidative radical cyclisations onto imidazoles and pyrroles using Bu3SnH
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Oxidative radical cyclisation using Bu3SnH has been used for the synthesis of [1,2-c]-fused imidazoles and [1,2-a]-fused pyrroles from imidazolecarbaldehydes and acylpyrroles respectively. The intermediate nucleophilic N-alkyl radicals cyclise onto imidazole and pyrrole rings followed by oxidative re-aromatisation.
- Aldabbagh, Fawaz,Bowman, W. Russell,Mann, Emma
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p. 7937 - 7940
(2007/10/03)
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