- A Structure?Activity Relationship Study of Novel Hydroxamic Acid Inhibitors around the S1 Subsite of Human Aminopeptidase N
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Aminopeptidase N (APN/CD13) is a zinc-dependent ubiquitous transmembrane ectoenzyme that is widely present in different types of cells. APN is one of the most extensively studied metalloaminopeptidases as an anti-cancer target due to its significant role in the regulation of metastasis and angiogenesis. Previously, we identified a potent and selective APN inhibitor, N-(2-(Hydroxyamino)-2-oxo-1-(3′,4′,5′-trifluoro-[1,1′-biphenyl]-4-yl)ethyl)-4-(methylsulfonamido)benzamide (3). Herein, we report the further modifications performed to explore SAR around the S1 subsite of APN and to improve the physicochemical properties. A series of hydroxamic acid analogues were synthesised, and the pharmacological activities were evaluated in vitro. N-(1-(3′-Fluoro-[1,1′-biphenyl]-4-yl)-2-(hydroxyamino)-2-oxoethyl)-4-(methylsulfonamido)benzamide (6 f) was found to display an extremely potent inhibitory activity in the sub-nanomolar range.
- Lee, Jisook,Drinkwater, Nyssa,McGowan, Sheena,Scammells, Peter
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- A class of 2 - substituted - (S)- (3 - mercapto -2 - methyl propionyl) - glycine derivatives of preparation and use (by machine translation)
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The invention provides a 2 - substituted - (S)- (3 - mercapto - 2 - methyl propionyl) - glycine derivatives, shown as formula I: . The present invention also provides 2 - substituted - (S)- (3 - mercapto - 2 - methyl propionyl) - glycine derivatives of th
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Paragraph 0023
(2018/06/16)
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- NOVEL AMINOPEPTIDASE INHIBITORS AND METHODS OF USE
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An aminopeptidase inhibitor compound comprising a biaryl, hydroxamic acid based core of formula: wherein X is a 5 or 6-membered ring, and including pharmaceutically acceptable salts and solvates thereof.
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Paragraph 0047
(2017/02/09)
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- Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions
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Malaria remains a global health problem, and though international efforts for treatment and eradication have made some headway, the emergence of drug-resistant parasites threatens this progress. Antimalarial therapeutics acting via novel mechanisms are urgently required. Plasmodium falciparum M1 and M17 are neutral aminopeptidases which are essential for parasite growth and development. Previous work in our group has identified inhibitors capable of dual inhibition of PfA-M1 and PfA-M17, and revealed further regions within the protease S1 pockets that could be exploited in the development of ligands with improved inhibitory activity. Herein, we report the structure-based design and synthesis of novel hydroxamic acid analogues that are capable of potent inhibition of both PfA-M1 and PfA-M17. Furthermore, the developed compounds potently inhibit Pf growth in culture, including the multi-drug resistant strain Dd2. The ongoing development of dual PfA-M1/PfA-M17 inhibitors continues to be an attractive strategy for the design of novel antimalarial therapeutics.
- Drinkwater, Nyssa,Vinh, Natalie B.,Mistry, Shailesh N.,Bamert, Rebecca S.,Ruggeri, Chiara,Holleran, John P.,Loganathan, Sasdekumar,Paiardini, Alessandro,Charman, Susan A.,Powell, Andrew K.,Avery, Vicky M.,McGowan, Sheena,Scammells, Peter J.
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- Rh-catalyzed asymmetric hydrogenation of racemic aldimines via dynamic kinetic resolution
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Catalyzed by a rhodium complex of P-stereogenic diphosphine ligand trichickenfootphos (TCFP), asymmetric hydrogenation of racemic aldimines via dynamic kinetic resolution has been realized for the preparation of chiral arylglycines with good yields and enantioselectivities.
- Fan, Dongyang,Lu, Jian,Liu, Yang,Zhang, Zhenfeng,Liu, Yangang,Zhang, Wanbin
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p. 5541 - 5547
(2016/08/05)
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- OXAZOLIDINONE COMPOUNDS AND DERIVATIVES THEREOF
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Compounds of Formula (I) and Formula (II) are useful inhibitors of tankyrase. Compounds of Formula (I) and Formula (II) have the following structure: where the definitions of the variables are provided herein.
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Paragraph 0251-0252
(2013/09/26)
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- COMBINATIONS OF MEDICAMENTS, CONTAINING PDE4-INHIBITORS AND EP4-RECEPTOR-ANTAGONISTS
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The present invention relates to new medicament combinations which contain in addition to one or more PDE4-inhibitors (1) at least one EP4 receptor antagonist (2), as well as the use thereof for the treatment of preferably respiratory complaints such as particularly COPD, chronic sinusitis and asthma. The invention relates in particular to those medicament combinations which contain, in addition to one or more, preferably one, PDE4 inhibitor of general formula 1 wherein X is SO or SO2, but preferably SO, and wherein R1, R2, R3 and R4 have the meanings given in claim 1, at least one EP4 receptor antagonist (2), the preparation thereof and the use thereof for the treatment of respiratory complaints.
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Paragraph 0290; 0291
(2013/09/12)
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- DRUG COMBINATIONS CONTAINING PDE4 INHIBITORS AND NSAIDS
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The present invention relates to new drug combinations which contain in addition to one or more PDE4-inhibitors at least one NSAID (=non-steroidal anti-inflammatory drug) (2), processes for preparing them and their use in treating in particular respiratory complaints such as for example COPD, chronic sinusitis and asthma. The invention particularly relates to those drug combinations which contain, in addition to one or more, preferably one PDE4 inhibitor of general formula 1 wherein X is SO or SO2, but preferably SO, and wherein R1, R2, R3 and R4 have the meanings given in claim 1, at least one NSAID (2), the preparation thereof and the use thereof for the treatment of respiratory complaints.
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- CGRP RECEPTOR ANTAGONISTS
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Compounds of Formula I: (where variables R1, R2, R3, R7, G, J, Q, T, W, X and Y are as defined herein) useful as antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved, such as headache, migraine and cluster headache, and pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
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Page/Page column 50
(2008/06/13)
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- Substituted pteridines for the treatment of inflammatory diseases
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The invention relates to new pteridines which are suitable for the treatment of respiratory or gastrointestinal complaints or diseases, inflammatory diseases of the joints, skin or eyes, diseases of the peripheral or central nervous system or cancers, as
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Page/Page column 9
(2010/11/08)
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- Sulfonamide compounds for the treatment of neurodegenerative disorders
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The present invention relates to compounds of the Formula I wherein R1, R2, R3, m, and n are as defined. Compounds of the Formula I have activity inhibiting production of Aβ-peptide. The invention also relates to pharmaceu
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Page/Page column 16
(2008/06/13)
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- Rapid access to N-Boc phenylglycine derivatives via benzylic lithiation reactions
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We report a novel and efficient method for the enantioselective synthesis of N-Boc protected phenylglycines. Yields and enantiomeric ratios vary widely depending on the nature of the solvent, the substrate and on the method of forming the chiral complex. Results show that the major reaction pathway is an enantioselective deprotonation/substitution process. The enantioselectivity appears to be limited by the chiral discrimination ability of the s-BuLi-(-)-sparteine complex. The synthetic method described is one of the shortest route to useful enantioenriched N-Boc phenylglycine derivatives.
- Barberis, Claude,Voyer, Normand,Roby, Johanne,Chénard, Sylvain,Tremblay, Martin,Labrie, Philippe
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p. 2965 - 2972
(2007/10/03)
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- Polymorphic form of a tachykinin receptor antagonist
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This invention is concerned with a novel polymorphic form of the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)-ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine which is a tachykinin receptor antagonist useful in the treatment or prevention of disorders of the central nervous system, inflammatory diseases, pain or migraine, asthma, and emesis. The instant polymorphic form has advantages over the other known forms of 2-(R)-(1-(R)-(3,5-bis(trifluoro-methyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine in terms of thermodynamic stability and suitability for inclusion in pharmaceutical formulations.
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- MORPHOLINE AND THIOMORPHOLINE TACHYKININ RECEPTOR ANTAGONISTS
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Substituted heterocycles of the general structural formula: STR1 are tachykinin receptor antagonists useful in the treatment of inflammatory diseases, pain or migraine, asthma and emesis, and calcium channel blockers useful in the treatment of cardiovascular conditions such as angina, hypertension or ischemia.
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- MORPHOLINE AND THIOMORPHOLINE TACHYKININ RECEPTOR ANTAGONISTS
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Substituted heterocycles of the general structural formula: STR1 are tachykinin receptor antagonists useful in the treatment of inflammatory diseases, pain or migraine, asthma and emesis, and calcium channel blockers useful in the treatment of cardiovascular conditions such as angina, hypertension or ischemia.
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- MORPHOLINE COMPOUNDS ARE PRODRUGS USEFUL AS TACHYKININ RECEPTOR ANTAGONISTS
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Substituted heterocycles of the general structural formula: STR1 are tachykinin receptor antagonists useful in the treatment of inflammatory diseases, pain or migraine, asthma, and emesis.
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- Crystallisation induced resolution of 4-fluorophenylglycine
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4-Fluorophenylglycine 1 is resolved to 99.0% e.e. and 65% overall yield via its methyl ester 2 using a crystallisation induced resolution.
- Moseley, Jonathan D.,Williams, Brian J.,Owen, Simon N.,Verrier, Hugh M.
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p. 3351 - 3352
(2007/10/03)
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