1,721,140 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
Arylsulfonamide derivatives, especially dimeric hydroxamic acid-containing amino acids, metalloproteases inhibitors and their preparation, pharmaceutical compositions and use in the treatment of degenerative disorders
No full textThe invention relates to dimeric aryl-sulphonamido compounds endowed with inhibitory activity against metalloproteases MMP, having formula (I) below (M)-L-(M') (I) wherein M and M', the same or different from each other, represent the residues of the mctalloprotcascs inhibitors of formula (II) wherein R, R 1 , R 2 , R 3 , G and n have the meanings reported in the specification; the invention also refers to the process for their preparation, to pharmaceutical compositions comprising them and to their use as therapeutic agents, particularly in the treatment of degenerative disorders
Inibitori di ADAM17 atti a modulare il rilascio di ALCAM (CD166) solubile in cellule tumorali e loro uso nel trattamento terapeutico del carcinoma ovarico epiteliale (EOC)
No full textCompounds 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
New arylsulfonamido-based MMP inhibitors with improved water solubility
No full textAbstract non disponibil
INHIBITORS OF ZINC PROTEASES THIOARYL SUBSTITUTED AND THEIR USE
No full textTitle compds. I [X1 = S(O)q; R1 and R2 independently = H, (un)substituted alkyl, aryl, etc., or R1 and R2 are linked to
form carbocyclic or heterocyclic ring; X = O or S, or divalent group selected from disulfide, disulfoxide, sulfone, amino,
etc.; E = alkyl, alkenyl, alkynyl or (un)substituted carbocyclic or heterocyclic ring, optionally benzocondensed; Z =
chelating moiety; m = 0 or 1; n = 0 or 1; q = 0-2], and their pharmaceutically acceptable salts thereof, are prepd. and
disclosed as inhibitors of zinc metalloproteinases. Thus, e.g., II was prepd. by substitution of o-iodobenzoic acid with 4-
methoxythiophenol. Data for inhibition activity of representative compds. towards select proteases were provided, e.g.,
2-(2-biphenyl-4-ylthio)phenylacetic acid possessed IC50 values of 334±5.7, 0.33±0.026, and 6.7±0.3 (mM) toward MMP-
1, MMP-2, and MMP-9, resp
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
Targeting ADAM17 Sheddase Activity in Cancer
Full text linkA disintegrin and metalloprotease (ADAM)17 is a sheddase, capable of releasing the ectodomains of membrane proteins such as growth factors (e.g. Epidermal Growth Factor Receptor ligands), cytokines and their receptors, adhesion and signaling molecules. These activities regulate several physiological and pathological processes including inflammation, tumor growth and metastatic progression. In this review, we will summarize ADAM17 biology and focus on its role in cancer and the possible usage of ADAM17 inhibitors in cancer therapy. Recent achievements in this area include the development of small molecule metalloprotease inhibitors with enhanced specificity for ADAM17, monoclonal antibodies, and synthetic short RNA molecules for gene silencing. These approaches successfully inhibited cancer cell growth and invasiveness or sensitized them to cytotoxic drugs, ionizing radiations or targeted therapies, in preclinical studies. These findings suggest the repositioning of ADAM17 inhibitors, which have yet proven unsuccessful as anti-inflammatory agents, for the development of new anti-cancer therapies, particularly in EGFR ligand-dependent cancers. Future studies should address ADAM17 inhibitors as short-term treatments in combination with different anti-cancer therapies
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