- Focal adhesion kinase inhibitor and use
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The invention belongs to the field of medicines, relates to a focal adhesion kinase inhibitor and use, in particular relates to a novel focal adhesion kinase inhibitor compound, or stereoisomers, geometric isomers, tautomers, oxynitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, further relates to the use of the compound and pharmaceutical compositions as medicines, in particular the use of the compound and pharmaceutical compositions in manufacture of medicines for treatment or prevention of cancer, pulmonary hypertension, and pathological angiogenesis-related diseases.
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- The discovery of UK-369003, a novel PDE5 inhibitor with the potential for oral bioavailability and dose-proportional pharmacokinetics
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This paper describes our recent efforts to design and synthesise potent and selective PDE5 inhibitors and the use of in vitro predictors of clearance, absorption and permeability to maximise the potential for dose-proportional pharmacokinetics and good oral bioavailability in man. Optimisation of the preclinical profile resulted in the identification of UK-369003 (19a) and its nomination as a clinical candidate. The clinical pharmacokinetic and safety profile has enabled us to progress the compound to test its efficacy in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and a paper describing its efficacy has recently been published.2,3.
- Rawson, David J.,Ballard, Stephen,Barber, Christopher,Barker, Laura,Beaumont, Kevin,Bunnage, Mark,Cole, Susan,Corless, Martin,Denton, Stephen,Ellis, David,Floc'H, Marion,Foster, Laura,Gosset, James,Holmwood, Frances,Lane, Charlotte,Leahy, David,Mathias, John,Maw, Graham,Million, William,Poinsard, Cedric,Price, Jenny,Russel, Rachel,Street, Stephen,Watson, Lesa
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experimental part
p. 498 - 509
(2012/03/08)
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- Identification of fused bicyclic heterocycles as potent and selective 5-HT2A receptor antagonists for the treatment of insomnia
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A series of fused bicyclic heterocycles was identified as potent and selective 5-HT2A receptor antagonists. Optimization of the series resulted in compounds that had improved PK properties, favorable CNS partitioning, good pharmacokinetic properties, and significant improvements on deep sleep (delta power) and sleep consolidation.
- Xiong, Yifeng,Ullman, Brett,Choi, Jin-Sun Karoline,Cherrier, Martin,Strah-Pleynet, Sonja,Decaire, Marc,Feichtinger, Konrad,Frazer, John M.,Yoon, Woo H.,Whelan, Kevin,Sanabria, Erin K.,Grottick, Andrew J.,Al-Shamma, Hussien,Semple, Graeme
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p. 1870 - 1873
(2012/04/17)
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- 2H-PYRAZOLO [4,3-D]PYRIMIDIN-5-AMINE DERIVATIVES AS H4 HISTAMINE RECEPTOR ANTAGONISTS FOR THE TREATMENT OF ALLERGIC, IMMUNOLOGICAL AND INFLAMMATORY DISEASES
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Pyrazolopyrimidine derivatives of formula (I), wherein the meaning of the different substituents are those indicated in the description. These compounds are useful as histamine H4 receptor antagonists.
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Page/Page column 101-102
(2010/04/30)
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- Bicyclic 6-alkylidene-penems as class-D beta-lactamases inhibitors
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This invention relates to certain bicyclic 6-alkylidene penems which act as a inhibitor of class-D enzymes. β-Lactamases hydrolyze β-lactam antibiotics, and as such serve as the primary cause of bacterial resistance. The compounds of the present invention when combined with β-lactam antibiotics will provide an effective treatment against life threatening bacterial infections. In accordance with the present invention there are provided compounds of general formula I or a pharmaceutically acceptable salt or in vivo hydrolyzable ester R5 thereof: wherein: One of A and B denotes hydrogen and the other an optionally substituted fused bicyclic heteroaryl group; and X═O or S.
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Page/Page column 19
(2010/11/25)
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- Structure-activity relationship of 6-methylidene penems bearing 6,5 bicyclic heterocycles as broad-spectrum β-lactamase inhibitors: Evidence for 1,4-thiazepine intermediates with C7 R stereochemistry by computational methods
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The design and synthesis of a series of 6-methylidene penems containing [6,5]-fused bicycles (thiophene, imidazole, or pyrazle-fused system) as novel class A, B, and C β-lactamase inhibitors is described. These penems proved to be potent inhibitors of the TEM-1 (class A) and AmpC (class C) β-lactamases and less so against the class B metallo-β-lactamase CcrA. Their in vitro and in vivo activities in combination with piperacillin are discussed. On the basis of the crystallographic structures of a serine-bound reaction intermediate of 2 with SHV-1 (class A) and GC1 (class C) enzymes, compounds 14a-1 were designed and synthesized. Penems are proposed to form a seven-membered 1,4 thiazepine ring in both class A and C β-lactamases. The interaction energy calculation for the enzyme-bound intermediates favor the formation of the C7 R enantiomer over the S enantiomer of the 1,4-thiazepine in both β-lactamases, which is consistent with those obtained from the crystal structure of 2 with SHV-1 and GC1.
- Venkatesan, Aranapakam M.,Agarwal, Atul,Abe, Takao,Ushirogochi, Hideki,Yamamura, Itsuka,Ado, Mihira,Tsuyoshi, Takasaki,Dos Santos, Osvaldo,Gu, Yansong,Sum, Fuk-Wah,Li, Zhong,Francisco, Gerry,Lin, Yang-I.,Petersen, Peter J.,Yang, Youjun,Kumagai, Toshio,Weiss, William J.,Shlaes, David M.,Knox, James R.,Mansour, Tarek S.
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p. 4623 - 4637
(2007/10/03)
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- Process for preparing 6-alkylidene penem derivatives
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The present invention provides a process of making compounds of formula I, which are useful for the treatment of bacterial infection or disease.
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- PROCESS FOR PREPARING 6-ALKYLIDENE PENEM DERIVATIVES
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The present invention provides a process of making compounds of Formula (I), which are useful for the treatment of bacterial infection or disease.
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Page/Page column 98
(2010/02/07)
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- BICYCLIC 6-ALKYLIDENE-PENEMS AS ?-LACTAMASES INHIBITORS
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The present invention provides a compound of Formula (I), pharmaceutical compositions and the use thereof for the treatment of bacterial infection or disease in a patient in need thereof.
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Page/Page column 69-70
(2008/06/13)
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- Pyrazolopyrimidine derivatives
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The present invention provides a compound of formula (I): where Q is a group of formula: These compounds inhibit cyclic guanosine 3',5'-monophosphate phosphodiesterases (cGMP PDEs). More notably, the compounds are potent and selective inhibitors of the type 5 cyclic guanosine 3',5'-monophosphate phosphodiesterases and have utility therefore in a variety of therapeutic areas. In particular, the present compounds are of value for the curative or prophylactic treatment of mammalian sexual disorders.
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