WO2015028766A1 - Inhibiteurs de métalloprotéases, leurs procédés de préparation et leurs utilisations thérapeutiques - Google Patents
Inhibiteurs de métalloprotéases, leurs procédés de préparation et leurs utilisations thérapeutiques Download PDFInfo
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- WO2015028766A1 WO2015028766A1 PCT/FR2014/052163 FR2014052163W WO2015028766A1 WO 2015028766 A1 WO2015028766 A1 WO 2015028766A1 FR 2014052163 W FR2014052163 W FR 2014052163W WO 2015028766 A1 WO2015028766 A1 WO 2015028766A1
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- RSIIFTUMTWMFHT-ONEGZZNKSA-N CC(C)OC(/C=C/CN)=O Chemical compound CC(C)OC(/C=C/CN)=O RSIIFTUMTWMFHT-ONEGZZNKSA-N 0.000 description 1
- HXZFHTOLLORIOF-QONNDPFASA-O CCC([C@H](CC(O)=[OH+])NC([C@H]([C@@H](c(cc1OCc(cc2)ccc2OC)n[n]1-c1ccccc1)O)C=C)=O)=C Chemical compound CCC([C@H](CC(O)=[OH+])NC([C@H]([C@@H](c(cc1OCc(cc2)ccc2OC)n[n]1-c1ccccc1)O)C=C)=O)=C HXZFHTOLLORIOF-QONNDPFASA-O 0.000 description 1
- 0 CNC(C(*)NC(C(C(*)O)C=C)=O)=O Chemical compound CNC(C(*)NC(C(C(*)O)C=C)=O)=O 0.000 description 1
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- C07C235/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and unsaturated
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- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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- C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
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- C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
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- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
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Definitions
- the present invention relates to novel selective inhibitors of metalloproteases, and in particular matrix metalloproteases 12 (MMP-12) and / or 9 (MMP-9). It also relates to processes for the preparation of said inhibitors and their therapeutic uses, in particular for preventing and / or treating chronic obstructive pulmonary disease (COPD), in particular emphysema induced by cigarette smoke.
- MMP-12 matrix metalloproteases 12
- MMP-9 matrix metalloproteases 9
- COPD chronic obstructive pulmonary disease
- Matrix metalloproteinases are proteolytic enzymes characterized by the presence of a Zn 2+ ion bound to 3 histidine residues at their catalytic site. These enzymes have roles in the modification of the extracellular matrix. The overexpression of some of these enzymes is involved in many pathological and physiological processes: normal and pathological angiogenesis, embryonic development, scarring, degeneration of connective and articular tissues, invasive and metastatic cancers.
- Zinc metalloproteases have at least thirty members; those whose substrates are known are: collagenases (interstitial MMP-1, MMP-8 neutrophil and collagenase-3 or MMP-13), gelatinases A and B (collagenases MMP-2 and MMP-9), metalloelastase MMP -12, stromelysins (including stromelysin-1 or MMP-3) and activators of gelatinase A (MT-MMP, only MMP with a transmembrane domain).
- collagenases interstitial MMP-1, MMP-8 neutrophil and collagenase-3 or MMP-13
- gelatinases A and B collagenases MMP-2 and MMP-9
- metalloelastase MMP -12 metalloelastase MMP -12
- stromelysins including stromelysin-1 or MMP-3
- activators of gelatinase A MT-MMP, only MMP with a transmembrane
- MMPs are expressed by endothelial cells. Some MMPs increase the release of angiogenic factors, such as VEGF, and play an important role in tumor progression (1). To reversibly block the proteolytic activity of MMPs, it is possible to use synthetic inhibitors that interact directly with the catalytic site of MMPs. These inhibitors will then be therapeutic tools capable of eradicating the evolution of several pathologies.
- MMP-9 is an essential enzyme in many physiological processes, such as inflammation, prostate cancer. This MMP also plays a role in regulating the blood pressure of certain angiotensin converting enzymes and endothelin, but also in the degradation of cartilaginous matrix with aggrecanase (ADAMTS-4 and 5). Its role has been demonstrated in the regulation of coagulation with carboxypeptidase U.
- MMP-12 chronic obstructive pulmonary disease
- COPD chronic obstructive pulmonary disease
- Emphysema induced by cigarette smoke also called pulmonary emphysema
- pulmonary emphysema is a pathophysiology that is the main component of COPD.
- Emphysema is characterized by distention of airspaces and destruction of their walls. Exposure to tobacco smoke is the main etiological factor of the BCPO.
- MMP inhibitors which are, for example, anti-inflammatory antibiotics of the family of macrolides or tetracyclines initially used to treat pulmonary infections. Roxithromycin has been described to reduce the expression of MMP-9 in neutrophils, macrophages and nasal epithelial cells ((3), (4)). Doxycycline may also inhibit the synthesis and / or activity of MMPs (5).
- Another type of MMP inhibitors include peptide inhibitors. These compounds have a pseudo-peptide structure that mimics the cleavage site of the substrate. In competition with this substrate, they bind to the catalytic site by chelation of the zinc atom of the enzyme via their hydrophilic hydroxamate or acid functionality ((6), (7)).
- a third class of non-peptide inhibitors was then developed to overcome the lack of selectivity and low bioavailability of (pseudo) -peptide inhibitors.
- the most important molecules in this category are Prinomastat (AG3340) (Agouron-Pfizer), BAY 12-9566 (Bayer), BMS-275291 (Bristol-Myers Squibb) and CGS-27023 (Novartis) ((11 ), (12)).
- One of the aims of the present invention is therefore to design new selective inhibitors of metalloproteases, and in particular matrix metalloproteases 12 (MMP-12) and / or 9 (MMP-9).
- MMP-12 matrix metalloproteases 12
- MMP-9 matrix metalloproteases 12
- Another object of the invention is to design new compounds active against chronic obstructive pulmonary disease (COPD), and in particular against emphysema induced by cigarette smoke.
- COPD chronic obstructive pulmonary disease
- Another object of the invention is to design a process for the preparation of said active compounds, selective inhibitors of MMP, which is both rapid (limited number of steps), easy to implement, inexpensive and reproducible at a time. industrial scale.
- the subject of the present invention is thus a compound -vinyl carbonyl, characterized in that it presents the formulation
- Ri represents an acyl radical of formula -CO-Rs, in which Rg represents OH, NHR 10 , NRioRn, with R 10 and Ru, which are identical or different, independently of each other, represent hydrogen, alkyl, alkenyl, alkynyl, OH, phenyl (C 6 H 5 ), methoxyphenyl (C 6 H 4 OCH 3 ), phenyloxyphenyl (C 6 H 4 OC 6 H 5 ), biphenyl (C 2 H 9 ), benzyl (CH 2 C 6 H 5 ), cyclohexyl (C 6 Hn), cyclopentyl (C 5 H 9 ),
- R 2 or R 3 which may be identical or different, represent independently of one another:
- n represents an integer from 1 to 6, with R 12 representing OH, phenyl, biphenyl, benzyl, cyclohexyl, cyclopentyl, COOH, COOR 9, SR 9, S (cation), with R 9 representing hydrogen, alkyl, alkenyl, alkynyl,
- a cycloalkyl radical preferably chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 2-isopropyl-5-methylcyclohexyl,
- an aryl radical preferably chosen from phenyl (C 6 H 5 ), methoxyphenyl (C 6 H 4 OCH 3 ), phenyloxyphenyl (C 6 H 4 OC 6 H 5 ), benzyl (C 6 H 5 CH 2 ), phenethyl (C 6 H 5 CH 2 CH 2), tolyl (C 6 H 4 CH 3), xylyl (C 6 H 3 (CH 3) 2), benzylidene (C 6 H 5 CH), benzoyl (C O H S CO ), biphenyl (or diphenyl) (C 12 H 9 ), naphthyl (C 10 H), pyrazole or 5- (4-methoxybenzyloxy) -1-phenyl-pyrazole,
- R 1 and R 2 may also together form a cycloalkyl or aryl radical
- Y represents a nitrogen or oxygen atom
- R 1 represents a hydrogen atom, an alkyl, alkenyl, alkynyl or aryl radical, an electron pair, a - (CH 2 ) n -Ri 2 radical with n and Ri 2 as defined above,
- R5 represents:
- R 6 and R 7 which may be identical or different, independently of one another hydrogen, an alkyl, a pair of electrons, a radical SO 2 R 13 with R 13 representing an alkyl, alkenyl, alkynyl, aryl as defined above, a radical - (CH 2) n -R 12 as defined previously,
- alkyl denotes a hydrocarbon radical, linear or branched, preferably having from 1 to 12 carbon atoms, and preferably from 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, ter butyl, pentyl, neopentyl or n-hexyl.
- alkenyl denotes a hydrocarbon radical, linear or branched, comprising one or more carbon-carbon double bonds, advantageously having 2 to 12 carbon atoms, and preferably 2 to 6 carbon atoms with one or two double bonds.
- alkynyl denotes a hydrocarbon radical, linear or branched, comprising one or more carbon-carbon triple bonds, advantageously having 2 to 12 carbon atoms, and preferably 2 to 6 carbon atoms with one or two triple bonds.
- cycloalkyl denotes a cyclic hydrocarbon system, which may advantageously comprise from 3 to 8 carbon atoms, preferably from 3 to 6, and may be mono- or poly-cyclic.
- aryl refers to a mono-, bi- or tricyclic aromatic hydrocarbon system having from 6 to 18 carbon atoms, and which may be substituted or unsubstituted.
- alkyls, alkenyls, alkynyls and cycloalkyls as defined above can also be substituted.
- Halogen is fluorine, chlorine, bromine or iodine.
- R 13 when they represent for example a methoxyphenyl (C 6 H 4 OCH 3 ) then the methoxy group may be substituted in the ortho, meta or para position with respect to the phenyl . It is the same phényloxyphényle of (C 6 H 4 OC 6 H 5) for which the OC H O S group may be substituted in the ortho, meta or para to the phenyl.
- S denotes a negatively charged sulfur and “Cation” denotes a positively charged cation, said cation possibly denoting an organic or metallic cation.
- the cation of an organic cation may be an ammonium, trialkylammonium or pyridinium cation, an example of a metal cation that may be a sodium (Na + ), lithium (Li + ) or potassium (K + ) cation.
- the compounds of the invention are more particularly represented by the following formula (I):
- R 1; R 2 , R 4, R 5, R 3 and Y are as defined above.
- Y represents a nitrogen atom and R 4 represents a hydrogen atom
- R5 represents a radical XR 6 R 7 in which X represents an oxygen atom, R 6 represents a hydrogen and R 7 represents an electron pair,
- Ri represents an acyl radical -CO-Rs, in which Rg represents OH or NHRio with Rio as defined previously,
- R 2 represents a radical - (CH 2 ) n -Ri 2 , a radical - (CH 2 ) n -N- (R 9 ) 2 or an aryl radical as defined above,
- R 3 represents an alkyl or aryl radical as defined above.
- Y represents an oxygen atom and R 4 represents a pair of electrons
- R 5 represents a radical XR 6 R 7 in which X represents an oxygen atom, R 6 represents a hydrogen and R 7 represents a pair of electrons,
- R 1 and R 2 together form a cycloalkyl or aryl radical.
- the present invention also relates to a process for the preparation of the compounds of formula (I), in which Y represents a nitrogen atom, said process being characterized in that it comprises the following steps:
- Y represents a nitrogen atom
- R 1; R 2 , R 3 and R 4 are as defined in formula (I)
- Y represents a nitrogen and R 5 represents a radical XR 6 R 7 in which X represents an oxygen, R 6 a hydrogen and R 7 an electron pair, that is, R 5 represents an OH radical.
- reaction step of the compound (II) in the presence of the compound ( ⁇ ) is carried out by a substitution reaction, according to conventional conditions of organic synthesis, of the primary or secondary amine function with said compound ( ⁇ ).
- the invention also relates to a process for preparing the compounds of formula (I) as defined above, in which Y represents an oxygen atom, said process being characterized in that it comprises the following steps:
- R 5 represents a radical XR 6 R 7 in which X represents an oxygen, R 6 a hydrogen and R 7 a pair of electrons, namely, R5 represents an OH radical.
- the reaction step of the compound (V) in the presence of the compound ( ⁇ ) is carried out by a substitution reaction, according to conventional conditions of organic synthesis, of the secondary alcohol function with said compound ( ⁇ ).
- the subject of the invention is also a compound of formula (I) for use as a medicament, and more particularly for its use in the prevention and / or treatment of chronic obstructive pulmonary disease (COPD), in particular emphysema induced by cigarette smoke.
- COPD chronic obstructive pulmonary disease
- the invention relates to a compound of formula (I) for selectively inhibiting at least one metalloprotease chosen from matrix metalloprotease 12 (MMP-12) or 9 (MMP-9).
- MMP-12 matrix metalloprotease 12
- MMP-9 matrix metalloprotease 9
- the subject of the invention is also a composition comprising at least one compound of formula (I) and optionally at least one pharmaceutically acceptable excipient.
- the invention relates to the composition as defined above for use as a medicament.
- the invention relates to a composition as defined above, for its use in the prevention and / or treatment of chronic obstructive pulmonary disease (COPD), in particular the emphysema induced by tobacco smoke. cigarettes.
- COPD chronic obstructive pulmonary disease
- compositions for example, their route of administration, their dosage and their dosage naturally depend on the severity of the pathology, its stage of evolution, the age, the sex, the weight of the subject to be treated, etc. Those skilled in the art will therefore be careful to adapt the dosages according to the patient to be treated.
- compositions according to the invention can be formulated for topical, oral, systemic, parenteral, intravenous, intramuscular, subcutaneous, or other administration.
- the composition according to the invention may be in any suitable galenic form.
- the compounds (I) of the present invention are particularly advantageous since they have been shown to be metalloprotease inhibitors which do not require chelation due to the presence of the hydroxamic acid function, unlike most metalloprotease inhibitors, such as example the Marimastat, the Batimastat.
- the compounds of the invention are therefore useful for the treatment of certain cancers, rheumatic diseases such as osteoarthritis and rheumatoid arthritis, Alzheimer's disease as well as pulmonary emphysema (the main component of COPD).
- the subject of the invention is also the use of a compound of formula (I) for the manufacture of a medicament, in particular a medicinal product intended for the treatment of chronic obstructive pulmonary disease (COPD), and more particularly the induced emphysema by the smoke of cigarettes.
- COPD chronic obstructive pulmonary disease
- Another subject of the invention also relates to methods of treating a subject suffering from COPD, including cigarette smoke-induced emphysema, comprising the step of administering to said subject a therapeutically effective amount of at least one compound (I) or a composition of the invention.
- terapéuticaally effective amount is meant an amount sufficient to treat and / or stop said COPD.
- FIG. 1 illustrates the synthesis scheme of the compounds of formula (I) in which Y represents a nitrogen atom
- FIG. 2 illustrates the synthesis scheme of the compounds of formula (I) in which Y represents an atom of oxygen and R 4 a doublet of electrons.
- Figure 3 illustrates respectively the interactions between the compound 1 of the invention with the inhibitor MMP-12 (figure on the left) and with the inhibitor MMP-9 (figure on the right).
- Figure 4 illustrates respectively the interactions between the compound 3 of the invention with the inhibitor MMP-12 (figure on the left) and with the inhibitor MMP-9 (figure on the right).
- Figure 5 illustrates respectively the interactions between the compound 2 of the invention with the inhibitor MMP-12 (figure on the left) and with the inhibitor MMP-9 (figure on the right).
- Figure 6 relates to specific examples of compounds of the invention having formula (I).
- Y represents a nitrogen and R 4 represents a hydrogen atom
- - P 5 represents a radical XR 6 R 7 in which X represents an oxygen atom, R 6 represents a hydrogen and R 7 represents an electron pair.
- R 3 alkyl radical, namely a methyl (CH).
- R 3 aryl radical, namely a biphenyl.
- Stages A and B similar to stages A and B of compound 1.
- R 3 aryl radical, namely 5- (4-methoxybenzyloxy) -1-phenyl-pyrazole.
- Stages A and B similar to stages A and B of compound 1.
- R 2 has the same meaning as for compound 1,
- R 3 has the same meaning as for compound 3.
- R 2 has the same meaning as for compound 1,
- R 3 has the same meaning as for compound 3.
- Stages A, B, C, D similar to Steps A, B, C and D of Compound 4.
- R 3 has the same meaning as for compound 3.
- EXAMPLE 2 Process for preparing a compound 8 corresponding to the general formula (I) in which Y represents an oxygen atom and R4 a pair of electrons.
- Y represents oxygen and R 4 a pair of electrons, R 1 and R 2 together form a cycloalkyl radical substituted with 2 alkyls, namely 2-isopropyl-5-methylcyclohexyl,
- R 3 represents an alkyl radical, namely methyl
- R 5 represents a radical XR 6 R 7 in which X represents an oxygen atom, R 6 represents a hydrogen and R 7 represents an electron pair.
- the inhibition selectivity of the compounds synthesized 1 to 7 was tested with respect to MMP-9 and MMP-12.
- the duality between the hydrophobic part (pocket S 'and the hydrophilic part (zinc atom) of an MMP inhibitor plays an important role in the degree of inhibition and therefore can also play a determining role for the inhibition selectivity with respect to a single MMP.
- the inventors have in particular studied the interactions between the hydrophobic part which occupies the pocket S 'i of the MPP inhibitor with the compounds of the invention. More particularly, the various possible orientations and the different possibilities of introduction of the hydrophobic group, in particular for the Ri group of the compounds of the invention, have been studied. Protocol of enzymatic inhibition tests of MMP-9 and MM-P12.
- the enzymatic screening assays for compounds 1 to 7 were carried out in solution on two purified human enzymes: gelatinase MMP-9 (Anaspec, USA) and metalloelastase MMP-12 (Anaspec, USA).
- the activity is revealed by a colorimetric method adapted to a 96-well plate format.
- the principle is based on the cleavage by the MMP-9 or MMP-12 enzymes of a chromogenic substrate: the thiopeptide (Ac-Pro-Leu-Gly- [2-mercapto-4-methylpentanoyl] -Leu-Gly-OC 2 Hs) (Enzo Life Sciences, USA).
- TLB 2-nitro-5-thiobenzoic acid
- the tests are carried out in the buffer "50 mM Hepes, 10 mM CaCl 2 ,, 05% Brij35, 1 mM DTNB, pH 7.0" containing the purified MMP-9 and MMP-12 enzymes diluted to the final concentration of 0, 8 ⁇ g / ml.
- the cleavage reactions are initiated by adding 150 ⁇ (final concentration) of substrate in a total final volume of 100 ⁇ (96-well plate format).
- the plates containing the reactions are read in a microplate reader (Multiskan Ascent, ThermoElectron, France) to measure continuous absorbance and record values every 3 min for 3 h. Each condition is performed in triplicate.
- the concentration inhibiting 50% of the reaction (IC 50 ) is determined from curves representing absorbance (optical density) of the final reaction product (TNB) as a function of the doses tested. Each experiment is performed at least twice.
- the compounds 1 to 7 of the invention have IC 50 between 5 and 330 ⁇ and Kj (inhibition constant) between 2.5 and 160 ⁇ for the enzymes MMP-9 and MMP -12 (see Table 1 below).
- the 7 compounds tested can be divided into two categories, namely on the one hand the compounds 1, 3 and 5 and on the other hand the compounds 2, 4, 6 and 7 .
- the first category corresponds to the compounds having close inhibition values on the two MMPs tested.
- Compounds 1 and 3 have binding modes (binding modes) that are very original and different from MMP-12 and MMP-9.
- Compound 5 has the same mode of binding with respect to the two MMPs.
- compound 1 is very interesting because of its low number of atoms and its good biological activity. It has an identical Kj towards the two enzymes MMP-12 and MMP-9, but its mode of binding is very different with these two enzymes.
- Compound 1 behaves vis-à-vis MMP-9 as a pseudo-peptide inhibitor with the formation of two hydrogen bonds with backbone backbone residues of the protein substrate.
- the benzyl part of the compound 1 ie the substituent R 2
- the cyclohexylcarboxamide moiety i.e., the substituent R of the compound 1 is found in the MMP-12 pocket S and the hydroxy acid moiety interacts with the protein substrate groove by forming two hydrogen bonds.
- the interaction with the zinc atom is carried out via the benzyl radical (substituent R 2 ) of compound 1 by forming ⁇ -cation type interactions (see Figure 3, left) . This interaction is entirely original. in the inhibition of matrix metalloproteinase.
- Compound 3 also has the same Ki value for both enzymes. However, two binding modes are highlighted with respect to MMP-12 and MMP-9.
- the pyrazole portion of compound 3 interacts with the S-pocket with its ⁇ -methoxybenzyloxy radical and again forms an ⁇ -cation-type interaction with its phenyl radical and the zinc atom (FIG. 4, left ).
- Compound 3 is also very interesting because of its particular binding mode in which the pyrrazole part interacts with the pocket S and forms an interaction again. ⁇ -cation type with the zinc atom. The chirality of the amino acid part does not seem to be important for the activity.
- the second category of compounds (compounds 2, 4, 6 and 7) has different inhibition values on both MMPs with a factor increasing 2 to 13-fold in favor of MMP-12. interesting.
- Compound 2 is therefore particularly promising and has good selectivity with respect to MMP-12.
- the compounds of the invention stand out for their biological activities (selectivity with respect to MMP-12 and / or MMP-9) and their binding modes.
- Binding Indeed, they generate very original and selective modes of binding (binding) according to the target MMP ( ⁇ -cation interaction).
- the binding modes of the compounds of the invention with the matrix metalloproteinases MMP are very different from those of the prior art compounds known to be MMP inhibitors, such as Marimastat, which still binds with the zinc part MMPs through its hydroxamic acid part, which is not the case of the compounds of the invention.
- the compounds of the invention have made it possible to determine the duality between the hydrophobic binding mode (pouch S 'and hydrophilic (Zinc atom) of the MMP inhibitor.
- the compounds of the invention are selective inhibitors of the metalloproteases, and in particular matrix metalloproteases 12 (MMP-12) and 9 (MMP-9), and more particularly MMP-12.
- MMP-12 matrix metalloproteases 12
- MMP-9 matrix metalloproteases 12
- the compounds of the invention are also interesting because of their particularly advantageous method of preparation: low number of steps (3-4) to synthesize said compounds, "modulability" of the process at each stage of the synthesis (diversity of structures for better inhibition selectivity).
- the parameter "QplogPo / w" corresponds to the water / octanol partition coefficient commonly called "P log”.
- the optimal values of this parameter are between 3 and 5 ( ⁇ 3 for apolar compounds targeting the central nervous system).
- the "QplogHERG” parameter corresponds to the log of the ICso of the test compound vis-à-vis cardiac channels with a large potassium ion. Thus, if this value is less than -5, the compound can induce cardiac toxicity.
- the chirality of the amino acid part is "D" for the compounds 24 to 33 described above.
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US14/915,807 US9682929B2 (en) | 2013-09-02 | 2014-09-02 | Metalloprotease inhibitors, methods for producing same, and therapeutics uses thereof |
JP2016537369A JP2016529276A (ja) | 2013-09-02 | 2014-09-02 | メタロプロテアーゼ阻害剤、それを産生する方法、およびその治療的使用 |
EP14777685.0A EP3041817A1 (fr) | 2013-09-02 | 2014-09-02 | Inhibiteurs de métalloprotéases, leurs procédés de préparation et leurs utilisations thérapeutiques |
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US20160200676A1 (en) | 2016-07-14 |
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FR3010076B1 (fr) | 2016-12-23 |
US9682929B2 (en) | 2017-06-20 |
JP2016529276A (ja) | 2016-09-23 |
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