1,721,248 research outputs found
Matrix Metalloproteinase Inhibitors: New Challenges in the Era of Post Broad-Spectrum Inhibitors
No full textMore than two decades have been spent to develop many families of synthetic matrix metalloproteinases inhibitors (MMPI) as
therapeutical agents for serious pathologies. Unfortunately, clinical trials conducted on broad-spectrum inhibitors have yielded
disappointing results, especially in the cancer pathology area. Despite these outcomes, some small synthetic MMPI are in advanced trials
or launched in clinical ones for cancer, arthritis, periodontal diseases. Today many groups are developing intensive efforts to find new
classes of inhibitors characterized by improved potency and, above all, high selectivity against the specific MMP involved in each
targeted pathology. The new challenges include the development of new MMPI bearing more effective ZBGs and the development of
new allosteric non-zinc binding inhibitors, devoid of ZBGs. An analysis of more recent results in this field reported on journals and
patents will be developed, to consider some of the more interesting new highly selective synthetic MMPI, their SARs, the new theoretical
approaches used for modelling and the results of their biological evaluations
A Medicinal Chemistry Approach to Synthetic Inhibitors of ADAM-10 and ADAM-17
No full textCurrently, two ways are used to develop active ligands for metzincins: 1- targeting their active CDs or Exos
with small molecules; 2- targeting with antibodies their CDs or Exo domains or either. Nowadays
the major efforts in this Medicinal Chemistry field are directed to the inhibitors of active forms of
CD and many families of structurally differentiated ligands have been disclosed. Anyway there are
only few inhibitors that are in clinical trials such as Col-3 or more recently INCB7839, an ADAM-
17 inhibitor (phase II clinical trials for breast cancer, solid tumors and non Hodgkin’s Limphomas).
see file in attac
Aryl-sulphonamidic dimers as metalloproteases inhibitors
No full textThe invention is related to the prepn. of title compds. M-L-M' [M, M' = independently the residues of metalloproteases inhibitors of formula RS(O)nNR1CR2R3G; R = -Ar-X-Ar'; Ar = (un)substituted (hetero)arylene; Ar' = H, (un)substituted (hetero)aryl; X = a single bond, alkylene, O, S, CO, etc.; R1 = H, OH, alk(en)yl, etc.; R2, R3 = independently H, alkyl optionally substituted by OH or C1-4-alkoxy groups or a Zn binding group selected from CO2H, COORb, CONHOH, CONRbOH, P(:O)(OH)2, etc.; Rb = alkyl, (hetero)arylalkyl; or any of R2 or R3 groups is linked to R1 so as to form a 5-7 membered heterocyclyl, optionally substituted by ≥1 oxo groups; G = alkyl, (hetero)aryl, arylalkyl, (CH2)1-6NR4R5; R4 = H, CORc, COORc, SO2Rc, CONHRc, SO2NHRc; Rc = cycloalkyl, alkyl, (hetero)aryl, alkylheterocyclyl, etc.; R5 = H, or NR4R5 = (un)substituted benzocondensed 4-6 membered heterocycle; L = a bond, C1-20-hydrocarbyl optionally interrupted by≥1 groups selected from (hetero)arylene, O, COO, SO2, NH, etc.; with the exclusion of specified compds.], e.g., I, and their pharmaceutically acceptable salts, to their pharmaceutical compns., and to their use as inhibitors of metalloproteases (MMP) useful in the treatment of degenerative disorders. Thus, dimeric hydrxamic acid I was prepd. by a multi-step synthesis using biphenyl-4-sulfonyl chloride, O-benzylhydroxylamine hydrochloride, tert-Bu (2S)-2-hydroxy-4-[[(phenylmethoxy)carbonyl]amino]butanoic acid, and 4-[[3-[[(4-chloro-4-oxobutyl)amino]carbonyl]benzoyl]amino]butanoyl chloride. I inhibited MMP-2, MMP-13 and MMP-14 with IC50 values of 3.7 nM, 2.4 nM and 31 nM, resp. and may be useful for the treatment of degenerative disorders involving those same enzymes
New Inhibitors of Metalo-enzymes with Potential Clinical Application: 1-hydroxy-piperazino-2,6-dione as a new Zinc-binding group
No full textThe present invention pertains to new compds. having increased capacity for inhibiting metalloproteinases contg. zinc at
the active center. The inhibitors here disclosed possess a new type of chelating group for the zinc(II) ion at the enzymic
catalytic center: a heterocycle with a 6-member ring, 1-hydroxypiperazino-2,6-dione. These compds. can be derived
from an iminodiacetic acid or other amino acids contg. or not chiral centers with one or more C atoms in the ring and
possessing adequate lipophilic 4-N-substituents. These new compds. exhibit increased stability and inhibitory activity (of
nanomolar order) and selectivity for certain matrix metalloproteinases and thus may have applications in pharmacol
Compounds having aryl-sulphonamidic structure useful as metalloproteases inhibitors
No full textThe invention relates to arylsulfonamide derivs. of formula I, which endowed with inhibitory activity against
metalloproteases (MMP). The invention also refers to the process for their prepn., to pharmaceutical compns.
comprising them and to their use as therapeutic agents, particularly in the treatment of degenerative disorders. Compds.
of formula I wherein R is -Ar-X-Ar1; Ar is (un)substituted arylene and (un)substituted aryl; Ar1 is H, (un)substituted
arylene and (un)substituted aryl; X is a single bond, (un)branched C1-4 alkylene, O, S, SO2, CO, NH and derivs., NHCO
and derivs. and CONH and derivs.; R1 is OH and derivs.; R2 and R3 are independently H and (un)substituted
(un)branched C1-4 alkyl; R4 is H, CORc, COORc, SO2Rc, CONHRc and SO2NHRc; Rc is C3-6 cycloalkyl, (un)branched
alkyl, aryl, arylalkyl, alkylaryl, 5- to 6-membered heterocyclyl, etc.; R5 is H; R4R5 may taken together with nitrogen atom
attached to form (un)substituted benzo(un)condensed 4- to 6-membered heterocyclyl; n is 1-2; A is (CH2)m; m is 1-6;
provided that R is biphenyl-4-yl, R1 is iso-Pr, one of R2 and R3 is CONHOH and the other one of R2 and R3 is H, R5 is
H, m and n are both 2, then R4 is not H and benzyloxycarbonyl; and their pharmaceutically acceptable salts thereof, are
claimed. Example compd. II was prepd. by a multi-step procedure (procedure given). All the invention compds. were
evaluated for their metalloproteases inhibitory activity. From the assay, it was detd. that II exhibited IC50 value of
0.13±0.03 nM against MMP-2
Synthesis and inhibitory activity towards human neutrophil elastase of some oximic and hydroxylaminic derivatives
No full textProtein Data Bank 6TJN (pdb) Human transthyretin (TTR) complexed with (E)-3-(((4-hydroxybenzylidene)amino)oxy)propanoic acid
No full textpdb 6TJ
Synthesis and aldose reductase inhibitory activity of some N-(aroyl)-N-(arylalkyloxy)-glycines and -beta-alanines
No full textSome N-(aroyl)-N-(phenylethyloxy)glycines (C) and N-(aroyl)-N-(arylmethyloxy)beta-alanines (D) were synthesised and tested as aldose reductase inhibitors (ARIs). Compounds C and D differ from the previously reported ARIs of type A in the presence of a further CH2 spacer between the aryl moiety and the oxyamidic oxygen and between the oxyamidic nitrogen and the carboxyl group. Compounds C revealed a certain loss of inhibitory activity with respect to the corresponding type A derivatives. Compounds D were found to be devoid of any appreciable inhibitory activity
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