- Benzamide nitriles
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Compounds of the formula (I) wherein m, n, A, R1, R2, R3, R4, R5 and R6 are as described herein, together with methods for making the compounds and using the compounds for treatment of diseases or conditions mediated by Cathepsin K.
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- A structure-Permeability study of small drug-like molecules
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A systematic structure-permeability relationship study on a set of small drug-like molecules with log D values in the range -2.5 to 3 and carrying a diverse array of functionality reveals that the compounds with log D>0 and 3 are highly permeable. Surprisingly, several tetrazole derivatives were found to be substrates for efflux pump(s).
- Fichert, Thomas,Yazdanian, Mehran,Proudfoot, John R.
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p. 719 - 722
(2007/10/03)
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- Aromatic hydrazides as specific inhibitors of bovine serum amine oxidase
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New hydrazides were synthesized in search for specific inhibitors of bovine serum amine oxidase: a series of benzoic and phenylacetic acid hydrazides containing the 1H-imidazol-1-yl or the 1H-imidazol-1-ylmethyl group as (o,m,p)-substituent in the phenyl ring; an analogous series of p-substituted phenylhydrazides with 5 or 6-membered heterocyclic ring as substituent, and a series of similar phenylpropionic hydrazides. The longer and more flexible phenylacetic hydrazides, and to a somewhat lesser extent the phenylpropionic ones, were better specific inhibitors of bovine serum amine oxidase than the benzoic hydrazides, which were also bound by the enzyme with high affinity, but at a slow rate. Derivatives with p- and m-substituents were more reactive than the o-substituted ones. The chemical nature of the substituent was less important than its position in the phenyl ring and the presence of methylene spacers. These data point to the presence of a hydrophobic site at short distance from the protein carbonyl cofactor, so that simultaneous interaction of the 2 ends of the inhibitor molecule can occur at the 2 sites. The presence of the hydrophobic site was confirmed by the capability of some molecule deprived of the hydrazidic group to act as mild inhibitors. All hydrazides were less reactive by 2-3 orders of magnitude towards pig kidney diamine oxidase and FAD-dependent monoamine oxidase from rat brain mitochondria, while the other compounds showed similar inhibition power against all proteins. The specificity for the bovine enzyme seems therefore to be related to the concerted action of the 2 moieties of the inhibitor molecule.
- Artico,Silvestri,Stefancich,Avigliano,Di Giulio,Maccarrone,Agostinelli,Mondovi,Morpurgo
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p. 219 - 228
(2007/10/02)
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- Cardiotonic Agents. 2. (Imidazolyl)aroylimidazolones, Highly Potent and Selective Positive Inotropic Agents
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A series of 4-alkyl-1,3-dihydro-5--2H-imidazol-2-ones 9 was synthesized and evaluated in vitro for positive inotropic and cyclic AMP phosphodiesterase inhibitory activity.A wide range of inotropic and enzyme-inhibitory potencies wa
- Hagedorn, Alfred A.,Erhardt, Paul W.,Lumma, William C.,Wohl, Ronald, A.,Cantor, Elinor,et al.
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p. 1342 - 1347
(2007/10/02)
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