WO2019163945A1 - Il-17a活性阻害剤およびその用途 - Google Patents
Il-17a活性阻害剤およびその用途 Download PDFInfo
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Definitions
- the present invention relates to an IL-17A activity inhibitor, a low molecular weight compound having an action of inhibiting the binding between interleukin 17A (IL-17A) and interleukin 17 receptor A (IL-17RA).
- the present invention also relates to a medicament for treating or preventing symptoms and diseases in intervertebral disc tissues such as intervertebral disc degeneration, and inflammatory skin diseases such as psoriasis, comprising such an IL-17A activity inhibitor as an active ingredient.
- Interleukin 17A is a cytokine produced by one of the T cell subsets, T helper 17 (Th17) cells.
- the produced IL-17A regulates the expression of various genes by binding to interleukin 17 receptor (IL-17R) possessed by various cells and causing JAK-STAT system intracellular signal transduction.
- IL-17R interleukin 17 receptor
- Abnormal production of IL-17 and abnormal signal transduction in the JAK-STAT system are deeply related to tissue inflammatory reactions, autoimmune diseases, tumor formation, and the like.
- IL-17 increases in IL-4, IL-6, IL-12, IFN- ⁇ and the like in nucleus pulposus cells of degenerated or hernia discs.
- IL-17A is a homodimeric (A chain and B chain) protein.
- IL-17R is a protein composed of two subunits, interleukin 17 receptor A (IL-17RA) and interleukin 17 receptor C (IL-17RC), It is composed of two fibronectin type III domains (D1 and D2).
- the crystal structure of the complex of IL-17A and the extracellular domain of IL-17RA has been identified, and the two domains of IL-17RA contain three major binding sites (pockets) with IL-17A, namely: It includes sites formed by Ds domain Ans89-Glu92 and Asp121-Glu125, D2 domain Ser257-Asp262, and the helical linker Thr163-Ser167 linking D1 and D2 domains.
- IL-17A activity inhibitor exclusively, anti-IL-17A antibody that inhibits binding to IL-17RA by targeting IL-17A, or conversely IL-17RA by targeting IL-17RA
- Research and development has been conducted on biological preparations based on so-called neutralizing antibodies, such as anti-IL-17RA antibodies that inhibit binding.
- Patent Document 1 Japanese Patent Publication No. 2016-508508, Novartis AG discloses homodimeric IL-17A and heterodimeric IL-17AF such as human and mouse containing CDRs having a specific amino acid sequence. Is an antibody that specifically binds to but does not specifically bind to homodimeric IL-17F, and inhibits binding between IL-17A and its receptor by binding to IL-17A An antibody (anti-IL-17A antibody) has been described that can block or block and reduce or neutralize IL-17A activity. In addition to US Pat. No.
- such antibodies include autoimmune and inflammatory disorders such as arthritis, rheumatoid arthritis, psoriasis, chronic obstructive pulmonary disease, systemic lupus erythematosus (SLE), lupus nephritis, asthma. It is also described that it can be used for the treatment of multiple sclerosis, cystic fibrosis and the like.
- Patent Document 2 Japanese Translation of PCT International Publication No. 2010-505416, Amgen Inc. discloses that IL-17A and / or IL-17F, such as humans, containing a CDR having a specific amino acid sequence binds to IL-17RA such as humans.
- Inhibitory antibodies anti-IL-17RA antibodies
- pharmaceutical compositions for treating inflammation eg, arthritis
- asthma e.g., asthma, autoimmune diseases and the like containing the antibodies
- Patent document 2 further includes cytokines, chemokines, matrix metalloproteinases, or other molecules (eg, IL-6, IL-8) associated with IL-17RA activation, comprising administering said IL-17RA to a patient.
- Patent Document 3 Japanese Translation of PCT International Publication No. 2017-511316, Kirin-Amgen Incorporated includes an antibody that specifically binds to IL-17RA and has antagonist activity (preferably containing a CDR having a specific amino acid sequence) ) Is used to treat nail or scalp psoriasis.
- Non-Patent Document 3 discloses that the extracellular domain “pocket” of IL-17RA, that is, D1 domain Asn89, Thr90, Asn91, Glu92, Asp121, Pro122, Asp123, Gln124, Glu125, D2 domains Ser257, Ser258, A region composed of Cys259, Leu260, Asn261, Asp262, and the helix linker Thr163, Pro164, Cys165, Met166, Ser167 is defined as a target site of a drug that inhibits binding to IL-17A, and is represented by the following formula: It is disclosed that the cyanidin compound (A18) was able to competitively inhibit the binding of IL-17A to IL-17RA by interacting with Asp121, Gln124, Ser168 and Asp262 in the pocket.
- the amino acid concerned is important for the binding of IL-17A to IL-17RA, in particular, the hydrogen bond between the hydroxyl group (—OH) at the 3 ′ position of the B ring and Gln124, the C ring IL-17RA inhibitory activity of the hydrogen bond between the hydroxy group at position 3 of Asp262 and the hydrogen bond between Leu264 and the hydroxy group at position 5 of the C ring, although slightly less effective than that. It is also described that a compound in which the C ring is changed from a 6-membered ring to a 5-membered ring almost loses IL-17RA inhibitory activity.
- Non-Patent Document 3 Liu et al
- compound A18 was used to inhibit the expression of a gene induced by IL-17A in human and mouse cells, and that IL-17A was dependent on mouse. It was also disclosed that the skin hyperplasia could be suppressed, that Th17 cell-dependent inflammation in mice could be suppressed, and that airway inflammation in a mouse model of severe steroid-resistant asthma in mice could be alleviated. Yes.
- Drugs biological preparations
- antibodies neutralizing antibodies
- Patent Documents 1 to 3 Drugs (biological preparations) containing antibodies (neutralizing antibodies) as described in Patent Documents 1 to 3 as active ingredients may cause serious side effects or have high drug prices. Therefore, if a low molecular weight compound capable of overcoming such problems can be used as an IL-17 activity inhibitor, its value is high.
- Non-Patent Document 3 describes that a specific low molecular weight compound (cyanidine) can be used as an IL-17A activity inhibitor, but there is room for improvement in its IL-17A activity inhibition ability.
- an object of the present invention is to provide a low molecular compound (IL-17A activity inhibitor) having an IL-17A activity inhibition ability superior to that of the conventional one.
- intervertebral nucleus pulposus cells were cultured in an atmosphere of normal oxygen concentration that was significantly different from the hypoxic environment of the actual in vivo intervertebral disc tissue, and in a hypoxic environment that reproduced the microenvironment of the intervertebral disc tissue.
- the present invention in another aspect, reveals the details of the mechanism of IL-17A involvement in intervertebral disc degeneration, thereby providing a low molecular weight compound (IL-17A activity inhibitor) intervertebral disc having the ability to inhibit IL-17A activity. It is also an object to provide new uses for the treatment or prevention of degeneration.
- the present inventors conducted in silico analysis in the following three steps in order to discover IL-17A activity inhibition candidate compounds that can solve the above problems.
- PDB ID: 4HSA complex crystal structure information
- IL-17RA its receptor
- interaction region a region on IL-17RA with which IL-17A interacts
- DRFF software
- the interaction region clarified in this study is a space surrounded by 28 amino acid residues, and partially overlaps with a pocket composed of 20 amino acid residues mentioned in Non-Patent Document 3. A wider space.
- 5,500 compounds most satisfying the structural chemical conditions obtained in the previous study were searched from an in-house compound database comprising about 6 million kinds of commercially available compound information.
- the interaction between the interaction region and the 5,500 compounds is determined by docking software “ASEDock” (Goto, J .; Kataoka, R .; Muta, H .; Hirayama, N. (2008) ASEDock-docking based on alpha spheres and excluded volumes. J. Chem. Inf.
- the present inventors cultured nucleus pulposus cells (NP cells) collected from rat intervertebral discs in a hypoxic condition of 1% approximate to the growth environment of intervertebral discs in vivo, and IL-17A was cultured there. For the first time, it was found that the expression level of several genes (factors) that promote inflammation and nucleus pulposus degeneration in the intervertebral disc increases. In addition, the present inventors actually used some compounds with high IL-17A activity inhibitory activity in the in silico analysis as described above (it was low as the negative value of GBVI / WSA_dG).
- candidate compounds were added together with IL-17A to nucleus pulposus cells cultured under hypoxic conditions as described above.
- the expression level of the specific gene is suppressed by adding the candidate compound according to the present invention.
- the expression level of COX-2 which is said to be a pain inducing factor, is higher than that of the compound of Non-Patent Document 3. It was found that the expression level was remarkably suppressed, and it was demonstrated that the candidate compound according to the present invention is superior in the IL-17A activity inhibiting ability than the compound of Non-Patent Document 3.
- candidate compounds in silico that have been shown to interact with amino acid residues constituting the interaction region identified as described above with a predetermined strength are as follows: It is estimated that not only the compounds used in the examples of the present invention but also other compounds have the ability to inhibit IL-17A activity by binding to IL-17RA competitively with IL-17A. It was clarified that it was possible to complete the present invention.
- Non-Patent Document 3 The compound disclosed in Non-Patent Document 3 was found by the following procedure. First, based on the partial structure of IL-17A (ligand) that interacts with IL-17RA in the crystal structure, a site (pocket) on IL-17RA to which an inhibitor can bind was defined. Secondly, the docking method was used to search the NCI compound library consisting of about 90,000 compounds for the most appropriate binding to this pocket. On the other hand, in the approach of the present invention, based on the three-dimensional structure of IL-17RA (receptor) only, a region on IL-17RA that can interfere with the interaction with IL-17A was first identified. The area that can be specified by this method is significantly wider than the area specified in Non-Patent Document 3.
- this region includes a region that is not involved in so-called receptor-ligand binding, but the interaction between the ligand and the receptor is hindered by the binding of a low molecular weight compound. That is, a compound having a completely different structure from the compound that binds to the pocket specified in Non-Patent Document 3 can bind strongly to this region as an inhibitor. It can be said that the compound of the present invention was found as a result of searching for a compound having a strong binding force to such an interaction region. Since the compound of the present invention has a larger molecular size than the compound of Non-Patent Document 3, the IL-17A activity is more excellently inhibited by covering a wider part in the interaction region and interacting more stably. It was estimated to have the ability.
- a representative compound of the present invention is targeted in Non-Patent Document 3, such as Cys154 of IL-17RA, such as Cys154, Lys160, Ser170, etc., particularly Cys154, which has high commonality among the compounds of the present invention. It interacts with the missing amino acid residues by hydrogen bonds, CH- ⁇ interactions, and the like.
- the compound of the present invention is considered to have excellent inhibitory activity against IL-17A as described above by binding to IL-17RA so as to interact with such amino acid residues.
- Interleukin-17A to IL-17RA in human or non-human animals that can bind to IL-17RA through non-covalent interactions including van der Waals forces that work between at least 13 ( IL-17A activity inhibitor comprising a compound having an action of inhibiting the binding of IL-17A), or a pharmaceutically acceptable salt, solvate or prodrug thereof.
- the non-covalent interaction is at least one selected from the group consisting of the compound and Asp121, Pro122, Asp123, Gln124, Asp153, Cys154, Glu155, Lys160, Ser168, Ser170, Ser258, Asp262, Leu264 and His266.
- Item 1 includes at least one intermolecular interaction selected from the group consisting of an ionic bond, a hydrogen bond, a CH- ⁇ interaction, a cation- ⁇ interaction, and a hydrophobic interaction acting between amino acid residues.
- Item 3 Item 3. The IL-17A activity inhibitor according to Item 2, wherein the intermolecular interaction includes at least a hydrogen bond or a CH- ⁇ interaction with Cys154.
- the intermolecular interaction includes a hydrogen bond with Asp121, a CH- ⁇ interaction and hydrogen bond with Pro122, a CH- ⁇ interaction and hydrogen bond with Asp123, and an ionic bond with Lys160.
- An IL-17A activity inhibitor comprising a compound represented by the general formula (I) (hereinafter referred to as “compound (I)”), or a pharmaceutically acceptable salt, solvate or prodrug thereof.
- A is (A1) an optionally substituted C 3-10 cycloalkyl group, (A2) an optionally substituted C 3-10 cycloalkenyl group, (A3) an optionally substituted 6-14 member An aromatic hydrocarbon ring group (aryl group), (A4) an optionally substituted 5- to 14-membered aromatic heterocyclic group, (A5) an optionally substituted 3- to 14-membered non-aromatic heterocyclic group, Or (A6) represents an optionally substituted C 4-6 alkyl group, L 1 may be linked to a (L 1 1) single bond, (L 1 2) a divalent group (amide bond) derived from a carbamoyl group, and / or linked to an ether bond or thioether bond.
- a divalent group derived from a carbamoyl group (amide bond), optionally linked to a C 1-3 alkylene group, a divalent group derived from an (L 13 ) amino group, (L 1 4) sulfonyl group, or (L 1 5) C 1-3 alkenylene group (carbon - carbon double bonds may be formed between the carbon atoms of B or C is adjacent to the L 2.
- B is (B1) a divalent group derived from a carbamoyl group that may be substituted and / or linked to a divalent group derived from a C 1-3 alkyl-carbonyl group (Amide bond), (B2) a divalent group derived from an optionally substituted 5- to 14-membered aromatic heterocycle, (B3) from an optionally substituted 3- to 14-membered non-aromatic heterocycle A derived divalent group, (B4) an optionally substituted C 3-10 cycloalkyl group, (B5) an optionally substituted C 3-10 cycloalkenyl group, (B6) optionally substituted Represents a good 6 to 14-membered aromatic hydrocarbon ring group (aryl group), (B7) ester bond or thioester bond, or (B8) keto group or thioketo group, L 2 is a (L 2 1) single bond, (L 2 2) C 1-6 alkylene group, or (L 2 3) C 1-3 alkenylene group (the
- L 3 may be linked to (L 3 1) a single bond, (L 3 2) a divalent group derived from a carbamoyl group (amide bond) and / or a divalent group derived from an imino group.
- D is (D1) an optionally substituted C 3-10 cycloalkyl group, (D2) an optionally substituted C 3-10 cycloalkenyl group, (D3) an optionally substituted 6-14 member
- the site A which is the above (A6) having a group which becomes a donor or acceptor of a hydrogen atom;
- the moiety B which is (B1) or (B3) having a group which becomes a donor or acceptor of a hydrogen atom;
- the moiety C which is the above (C1), (C2), (C3), (C6) or (C7) having a group which becomes a donor or acceptor of a hydrogen atom;
- a site L 1 having the above-described (L 1 2) or (L 14 ) having a group that serves as a donor or acceptor of a hydrogen atom (which may have such a group as a substituent);
- a portion L 2 which is the above (L 2 2) having a group which becomes a donor or acceptor of a hydrogen atom (which may have such a group as a substituent); or the above (C 2) or a ⁇ electron
- the site C being (C6), Item 7.
- the site A which is (A3), (A4) or (A6), or the site L which is (L 1 2) comprises at least one, IL-17A activity inhibitor according to claim 5 or 6.
- the site A which is the above (A4) or (A5), or the above (B3) or (B5) Item 7.
- Item 7. The IL-17A activity inhibitor according to Item 5 or 6, having at least one of [Section 11] The compound (I) has at least one site D as the site (D1), (D3) or (D5) as a site where an ionic bond, hydrogen bond or cation- ⁇ interaction occurs with the Lys160.
- Item 6 The IL according to Item 5 or 6, wherein the compound (I) has at least one site D which is the (D3) or (D5) as a site where a CH- ⁇ interaction occurs with the Ser170. -17A activity inhibitor.
- Item 5 is a compound represented by the following structural formulas (1) to (36) (hereinafter referred to as “compounds (1) to (36)”) or derivatives thereof, The IL-17A activity inhibitor according to any one of 1 to 12.
- [Section 14] The original compound so that the compound (I) is a compound (1) or a derivative of the compound (1) and satisfies at least one condition selected from the group consisting of the following [X], [Y] and [Z] Item 14.
- the compound (1) has at least one CH- ⁇ interaction with Pro122, a hydrogen bond with Cys154 or an ionic bond with Lys160, or at least one different from these.
- Non-covalent interactions other than van der Waals forces are selected from the group consisting of Asp121, Pro122, Gln124, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Ser258, Cys259, Asp262, Cys263 and Leu264 Having a site occurring between at least one amino acid residue; [Z] At least one amino acid selected from the group consisting of Asp121, Pro122, Gln124, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Ser258, Cys259, Asp262, Cys263 and Leu264 rather than the compound (1) It has a site that reduces the exposure of the residue to the solvent side.
- [Section 15] The original compound so that the compound (I) is a compound (2) or a derivative of the compound (2) and satisfies at least one condition selected from the group consisting of the following [X], [Y] and [Z] Item 14.
- the compound (2) has a site where at least one of CH- ⁇ interaction with Asp123, hydrogen bond with Cys154 or CH- ⁇ interaction with Ser170 is enhanced, or at least different from these Non-covalent interactions other than one van der Waals force can be performed by Asp121, Pro122, Asp123,
- the IL-17A activity inhibitor according to Item 13 which is obtained by modifying (5): [X] Between Asp121, Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Cys263, Leu264 and His266 rather than the compound (5) The total van der Waals power is enhanced; [Y] The compound (5) has at least one hydrogen bond with Cys154 or at least one hydrogen bond with Lys160, or at least one non-covalent bond other than Van der Waals force different from these.
- [Section 17] The original compound so that the compound (I) is a compound (9) or a derivative of the compound (9) and satisfies at least one condition selected from the group consisting of the following [X], [Y] and [Z] Item 14.
- the compound (9) has at least one of the CH- ⁇ interaction with Asp121, the hydrogen bond with Cys154 or the CH- ⁇ interaction with Ser170, or at least different from these.
- Non-covalent interactions other than one van der Waals force can be performed by Asp121, Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Pro164, Ser167, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Having a site occurring between at least one amino acid residue selected from the group consisting of Leu264 and His266; [Z] From the group consisting of Asp121, Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Pro164, Ser167, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Leu264 and His266 rather than the compound (9) It has a site that reduces the exposure of at least one selected amino acid residue to the solvent side.
- [Section 18] The original compound so that the compound (I) is a compound (11) or a derivative of the compound (11) and satisfies at least one condition selected from the group consisting of the following [X], [Y] and [Z] Item 14.
- the compound (11) has at least one CH- ⁇ interaction or hydrogen bond with Cys154 or a non-covalent bond other than at least one van der Waals force different from these.
- the compound (11) is selected from the group consisting of Asp121, Pro122, Gln124, Asp153, Cys154, Glu155, Pro164, Cys165, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Leu264, and His266 Having a site occurring between the groups; [Z]
- the compound (11) is selected from the group consisting of Asp121, Pro122, Gln124, Asp153, Cys154, Glu155, Pro164, Cys165, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Leu264 and His266. It has a site that reduces the solvent side exposure of at least one amino acid residue.
- Item 20 The expression regulator according to Item 19, wherein the gene is a gene whose expression is enhanced by binding of IL-17A to IL-17RA, and is for suppressing the expression.
- the expression regulator according to Item 20 wherein the gene is a gene whose expression is enhanced by phosphorylation of p38, and is for suppressing the expression.
- the cell that expresses IL-17RA is an intervertebral disc nucleus pulposus cell.
- the intervertebral disc nucleus pulposus cells are intervertebral disc nucleus pulposus cells cultured under hypoxic conditions or intervertebral disc nucleus pulposus cells present in intervertebral disc tissue.
- the cells that express IL-17RA are keratinocytes or other epidermal cells.
- the medicament according to Item 26, wherein the disease in which the binding of IL-17A to IL-17RA is associated with symptoms is psoriasis vulgaris, arthritic psoriasis, pustular psoriasis, or psoriatic erythroderma.
- [Claim 31] The binding of IL-17A to IL-17RA comprising the step of contacting the IL-17A activity inhibitor of any one of Items 1 to 16 with IL-17RA in vitro in humans and other animals Inhibition method.
- [Section 32] The method of contacting IL-17RA with IL-17RA, comprising contacting the expression regulator according to any one of Items 17-22 with a cell expressing IL-17RA in vitro in humans and other animals. A method for regulating the expression of a gene whose expression level is changed by the binding of -17A.
- the present invention relates to a method for treating and preventing a given disease comprising administering an effective amount of a compound of the present invention, and a compound of the present invention used as an IL-17 activity inhibitor administered as an active ingredient.
- inventions derived from the use of the compounds of the present invention as IL-17 activity inhibitors, the use of the compounds of the present invention in the manufacture of a medicament for the treatment or prevention of certain diseases, and other uses of the compounds of the present invention Is provided.
- the low molecular weight compound provided by the present invention is superior in the ability to inhibit IL-17A activity than conventional low molecular weight compounds, and is used for the treatment or prevention of intervertebral disc degeneration and psoriasis, and for the relief of pain. It is expected that it can be used as an active ingredient.
- FIG. 1 shows a molecular structure drawn by software in an in silico analysis.
- A Molecular structure representing a complex of human IL-17A and human IL-17RA.
- B Molecular structure representing human IL-17RA. The collection of small spheres visible in the central “groove” is a pseudo-atom representing the expected position of the candidate compound's atom when the candidate compound of the human IL-17A activity inhibitor binds to human IL-17RA. It is a group of. It is presumed that non-covalent interactions including van der Waals forces between amino acid residues within 3.5 cm of these pseudo atoms and candidate compounds.
- C Molecular structure representing a partially expanded view of the “groove” of human IL-17RA and the quasi-atom population therein.
- FIG. 2 is a schematic diagram showing the mode of noncovalent interaction between the compound (1) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- the curved dotted line around the molecule represents the binding surface between the compound of the present invention and human IL-17RA (predetermined amino acid residue in the interaction region).
- a straight dotted line represents an intermolecular interaction such as a hydrogen bond or a CH- ⁇ interaction.
- the cloud surrounding the atom of the compound of the present invention represents the exposure of the molecular surface to the solvent side, and the larger the cloud, the greater the exposure.
- Amino acid residues whose circular outlines are bold lines mean acidic or basic residues.
- a disk-shaped shadow around the circle indicates the degree of solvent exposure of the amino acid residue in the absence of the compound of the present invention, and means that the solvent exposure decreases due to the binding of the compound. To do. (The same applies to the following figures relating to other compounds of the present invention.)
- FIG. 3 is a schematic diagram showing the mode of non-covalent interaction between the compound (2) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 4 is a schematic diagram showing the mode of noncovalent interaction between the compound (4) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 5 is a schematic diagram showing the mode of noncovalent interaction between the compound (5) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA.
- FIG. 6 is a schematic diagram showing the mode of non-covalent interaction between the compound (6) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA.
- FIG. 7 is a schematic diagram showing the mode of non-covalent interaction between the compound (7) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 8 is a schematic diagram showing the mode of noncovalent interaction between the compound (8) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA.
- FIG. 9 is a schematic diagram showing the mode of non-covalent interaction between the compound (9) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 10 is a schematic diagram showing the mode of non-covalent interaction between the compound (10) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 11 is a schematic diagram showing the mode of non-covalent interaction between the compound (11) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 12 is a schematic diagram showing the mode of noncovalent interaction between the compound (12) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 13 is a schematic diagram showing the mode of noncovalent interaction between the compound (13) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 14 is a schematic diagram showing the mode of noncovalent interaction between the compound (14) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 15 is a schematic diagram showing the mode of noncovalent interaction between the compound (15) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 16 is a schematic diagram showing the mode of noncovalent interaction between the compound (16) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 17 is a schematic diagram showing the mode of noncovalent interaction between the compound (17) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 18 is a schematic diagram showing the mode of noncovalent interaction between the compound (18) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 19 is a schematic diagram showing the mode of non-covalent interaction between the compound (19) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 20 is a schematic diagram showing the mode of non-covalent interaction between the compound (20) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA.
- FIG. 21 is a schematic diagram showing the mode of non-covalent interaction between the compound (21) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 22 is a schematic diagram showing the mode of non-covalent interaction between the compound (22) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 23 is a schematic diagram showing the mode of non-covalent interaction between the compound (23) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 24 is a schematic diagram showing the mode of non-covalent interaction between the compound (24) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 25 is a schematic diagram showing the mode of non-covalent interaction between the compound (25) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA.
- FIG. 26 is a schematic diagram showing the mode of non-covalent interaction between the compound (26) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 27 is a schematic diagram showing the mode of non-covalent interaction between the compound (27) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 28 is a schematic diagram showing the mode of non-covalent interaction between the compound (28) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 29 is a schematic diagram showing the mode of non-covalent interaction between the compound (29) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 30 is a schematic diagram showing the mode of non-covalent interaction between the compound (30) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 31 is a schematic diagram showing the mode of non-covalent interaction between the compound (31) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA.
- FIG. 32 is a schematic diagram showing the mode of noncovalent interaction between the compound (32) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 33 is a schematic diagram showing the mode of non-covalent interaction between the compound (33) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 34 is a schematic diagram showing the mode of noncovalent interaction between the compound (34) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 35 is a schematic diagram showing the mode of non-covalent interaction between the compound (35) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 36 is a schematic diagram showing the mode of non-covalent interaction between the compound (36) of the present invention and an amino acid residue contained in the extracellular domain of human IL-17RA.
- FIG. 37 shows the results regarding [Reference Example 1].
- [B] COX-2 and IL-6, and ⁇ -actin protein as an internal control when rat NP cells were administered IL-17A at a concentration of 50 ng / ml and cultured under 1% oxygen conditions for 24 hours Electrophoretic diagram (left) and graph (right) showing the expression level of. * P ⁇ 0.05, n 3.
- [C] Graph showing the transcriptional activity of COX-2 when IL-17A at a concentration of 50 ng / ml was administered to rat NP cells and cultured under 1% oxygen conditions for 24 hours (evaluation by promoter assay). * P ⁇ 0.05, n 3.
- FIG. 39 shows the results for [Reference Example 3].
- [A] A group in which recombinant mouse IL-17A at a concentration of 50 ng / ml was administered to rat NP cells alone (IL-17A alone administration group: “IL-17A” was “+”, and “anti-IL-17A” was “-”), And a group administered with a mixed solution of IL-17A at a concentration of 50 ng / ml and anti-IL-17A antibody at a concentration of 0.5 ⁇ g / ml (anti-IL-17A neutralizing antibody combination group: “IL ⁇ 17A ”and“ anti-IL-17A ”are both“ + ”) when cultured under 1% oxygen conditions for 24 hours, IL-6, COX-2, mPGES1, MMP-3, MMP ⁇ The graph showing the expression level of mRNA of each 13 genes.
- FIG. 40 shows the results for [Reference Example 4].
- FIG. 41 shows the results for [Example 1].
- [A] A group in which recombinant mouse IL-17A at a concentration of 50 ng / ml was administered to rat NP cells alone (IL-17 group), and recombinant mouse IL-17A at a concentration of 50 ng / ml and a concentration of 50 ⁇ g / ml
- IL-17 group A group in which recombinant mouse IL-17A at a concentration of 50 ng / ml was administered to rat NP cells alone (IL-17 group), and recombinant mouse IL-17A at a concentration of 50 ng / ml and a concentration of 50 ⁇ g / ml
- Each of the groups administered with any one of the compounds (3), (2), (5) or (11) (IL17 + STK group, IL17 + PB group, IL17 + Z9215 group, IL17 + P2000 group, respectively) under 1% oxygen conditions
- the graph showing the expression level of mRNA of each gene of IL-6, COX-2,
- FIG. 42 shows the results regarding [Example 2].
- FIG. 43 shows the results regarding [Example 3].
- [E] A graph corresponding to the electropherogram of [C] above. * P ⁇ 0.05, n 4.
- [F] A graph corresponding to the electropherogram of [D] above. * P ⁇ 0.05, n 4.
- FIG. 44 shows the results for [Comparative Example 1].
- FIG. 45 is a schematic diagram depicting a reaction pathway involving the interleukin 17 family (A, B, C, D, E, F).
- FIG. 46 shows the result of comparing part of the amino acid sequences of human and rat IL-17RA by BLAST (https://blast.ncbi.nlm.nih.gov/Blast.cgi).
- FIG. The single underline represents the 28 predetermined amino acid residues in the interaction region, and the double underline represents the van der Waals force with a representative compound of the present invention (any of compounds (1) to (36)). Amino acid residues other than non-covalent interactions (intermolecular interactions) are shown.
- the numbers of the amino acid residues displayed on the left and right of the sequence in this figure are the same as the numbers of the amino acid residues of SEQ ID NOs: 1 and 2.
- Cys154 contained in a predetermined amino acid residue in the interaction region corresponds to C representing the 185th amino acid residue in the figure.
- FIG. 46-2 shows the result of comparing part of the amino acid sequences of IL-17RA of human and mouse by BLAST (https://blast.ncbi.nlm.nih.gov/Blast.cgi).
- FIG. The single underline represents the 28 predetermined amino acid residues in the interaction region, and the double underline represents the van der Waals force with a representative compound of the present invention (any of compounds (1) to (36)). Amino acid residues other than non-covalent interactions (intermolecular interactions) are shown.
- the numbers of the amino acid residues displayed on the left and right of the sequence in this figure are the same as the numbers of the amino acid residues of SEQ ID NOs: 1 and 2.
- Cys154 contained in a predetermined amino acid residue in the interaction region corresponds to C representing the 185th amino acid residue in the figure.
- FIG. 47 shows the results regarding [Example 4].
- [B] A graph showing the thickness of the skin layer based on the optical micrograph.
- FIG. 48 shows the results regarding [Example 4].
- FIG. 49 shows the results for [Example 5].
- [A] Optical micrograph of an immunostained specimen of rat tail vertebrae using anti-IL-6 antibody.
- mice normal group, deg: degenerative arm (rats that have undergone intervertebral disc degeneration); STK: STK group (after intervertebral disc degeneration, mice injected with DMSO solution of compound (3); sham: Sham group (after intervertebral disc degeneration, DMSO Injected mice).
- the present invention includes inventions belonging to different categories (agents, medicines, methods, etc.) in a plurality of aspects. Matters described in the present specification can be shared by different inventions in accordance with the context even if not particularly specified.
- C 1-3 alkyl group refers to a linear or branched saturated hydrocarbon group having 1 to 3 carbon atoms, and examples thereof include methyl, ethyl, propyl, and isopropyl.
- C 4-6 alkyl group refers to a straight or branched saturated hydrocarbon group having 4 to 6 carbon atoms, such as butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl. , Neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl.
- C 3-10 cycloalkyl group refers to a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- C 3-10 cycloalkenyl group refers to a cyclic unsaturated hydrocarbon group having from 3 to 10 carbon atoms and having one carbon-carbon double bond, for example, cyclopropenyl, cyclobutenyl, cyclo Examples include pentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
- the “6-14-membered aromatic hydrocarbon ring group (aryl group)” is a group derived from a 6-14-membered (preferably 6-10-membered) aromatic cyclic compound having a carbon atom as a ring atom. And includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.
- the “5- to 14-membered aromatic heterocycle” contains at least one (preferably 1 to 4) heteroatom selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
- a 5- to 14-membered (preferably 5- to 10-membered) aromatic cyclic compound includes, for example: Thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1, 5- or 6-membered monocyclic aromatic heterocycle such as 2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine; Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, ox
- the “3- to 14-membered non-aromatic heterocycle” includes at least one (preferably 1 to 4) heteroatom selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. It refers to a 3-14 membered (preferably 4-10 membered), non-aromatic cyclic compound containing, for example: Aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine , Piperazine,
- [Substituent group A] (1) a halogen atom; (2) a nitro group; (3) a cyano group; (4) an oxo group; (5) hydroxy group; (6) an optionally halogenated C 1-6 alkoxy group; (7) C 6-14 aryloxy group (eg, phenoxy, naphthoxy); (8) C 7-16 aralkyloxy group (eg, benzyloxy); (9) 5- to 14-membered aromatic heterocyclic oxy group (eg, pyridyloxy); (10) 3 to 14-membered non-aromatic heterocyclic oxy group (eg, morpholinyloxy, piperidinyloxy); (11) C 1-6 alkyl-carbonyloxy group (eg, acetoxy, propanoyloxy), C 1-6 alkyl-thiocarbonyloxy group (eg, thioacetoxy, thiopropanoyloxy); (12) C 6-14 aryl-carbonyl
- the divalent group derived from a carbamoyl group (amide bond) may have a direction of —NH—CO— or a direction of —CO—NH—.
- a divalent group derived from a carbamoyl group (amide bond) which may be N-substituted and / or linked to a divalent group derived from a C 1-6 alkyl-carbonyl group "Is an amide bond (-NH-CO- or -CO-NH-) as described above, the nitrogen atom (N) may have a substituent, and one or both ends of the amide bond ( It represents that a divalent group derived from a C 1-6 alkyl-carbonyl group may be preferably linked to one end), or both of these characteristics may be provided.
- N substitution includes the case where two bonds of N form a ring structure (for example, piperazine).
- Examples of the substituent of the nitrogen atom of the amide bond include those selected from the substituent group A.
- C 1-3 alkylene group refers to a divalent group derived from a linear or branched saturated hydrocarbon (C 1-3 alkyl group) having 1 to 3 carbon atoms. —CH 2 —, — (CH 2 ) 2 —, — (CH 2 ) 3 —, —CH (CH 3 ) —, —C (CH 3 ) 2 —, —CH (C 2 H 5 ) —, —CH (CH 3 ) —CH 2 —.
- the “C 1-6 alkylene group” refers to a divalent group derived from a linear or branched hydrocarbon having 1 to 6 carbon atoms (C 1-6 alkyl group).
- 1-3 alkylene group for example, — (CH 2 ) 4 —, — (CH 2 ) 5 —, — (CH 2 ) 6 —, —CH (CH (CH 3 ) 2 )) —, — CH (C 2 H 4 (CH 3 ) 2 ) —, —CH (C 3 H 6 (CH 3 ) 2 ) —, —CH (C (CH 3 ) 3 ) —, —CH (CH (CH 3 ) 2 ))-CH-.
- the carbon-carbon double bond is a carbon atom at the terminal of the C 1-3 alkenyl group and a carbon atom adjacent thereto (for example, “C 1-3 alkenylene group corresponding to the site L2 in the compound of the present invention”).
- C 1-3 alkenylene group Either the cis position or the trans position due to the unsaturated bond may be used.
- “Divalent group (amide bond) may be linked with C 1-3 alkylene groups derived from carbamoyl group" at one or both ends of the C 1-3 alkylene group in the above (preferably one), It means that a divalent group (amide bond) derived from a carbamoyl group may be linked in the direction of —NH—CO— or the direction of —CO—NH—.
- Examples of the C 1-3 alkylene group linked to a divalent group (amide bond) derived from a carbamoyl group include — (CH 2 ) n —NH—CO— and — (CH 2 ) n —CO. -NH-, -NH-CO- (CH 2 ) n- , -CO-NH- (CH 2 ) n- (n is an integer of 1 to 3).
- IL-17 activity inhibitor includes Phe60, Gln87, Asp121, Pro122, Asp123, contained in the extracellular domain of human interleukin 17 receptor A (IL-17RA). Gln124, Asp153, Cys154, Glu155, Lys160, Pro164, Cys165, Ser167, Ser168, Gly169, Ser170, Leu171, Trp172, Asp173, Pro174, Pro254, Phe256, Ser258, Cys259, Asp262, Cys263, Leu264 and His266 (28 of these) In the space (interaction region) surrounded by the “predetermined amino acid residues constituting the interaction region” in the present specification.
- IL-17RA human interleukin 17 receptor A
- IL-17RA interleukin 17A
- van der Waals forces or other non-covalent interactions in between A compound having a function of inhibiting the binding of IL-17A to IL-17RA (the first embodiment of the compound of the present invention), or a pharmaceutically acceptable salt, solvate or prodrug thereof.
- IL-17 activity inhibitor since the “IL-17 activity inhibitor” as described above inhibits the activation of IL-17RA caused by the binding of IL-17A to IL-17RA, it is referred to as an “IL-17RA activation inhibitor”. (“IL-17 activity inhibitor” in this specification can be read as “IL-17RA activation inhibitor”).
- the amino acid sequence of human IL-17RA is shown in SEQ ID NO: 1 (GenBank: AAH11624.1, https://www.ncbi.nlm.nih.gov/protein/AAH11624.1).
- the first amino acid residue of the extracellular domain of human IL-17RA corresponds to the 32nd amino acid residue (Ser) of SEQ ID NO: 1.
- Phe60 phenylalanine which is the 60th amino acid residue of the extracellular domain
- Cys154 cyste which is the 154th amino acid residue of the extracellular domain
- His266 histidine which is the 266th amino acid residue of the extracellular domain
- Phe 91st amino acid residue
- Cys 185th amino acid residue
- SEQ ID NO: 1 amino acid residue of SEQ ID NO: 1
- the number of amino acid residues in the “extracellular domain” treated as described above in this specification (and drawings) is SEQ ID NO: 1 (signal peptide of IL-17RA, extracellular domain, membrane It can be replaced by the number of amino acid residues in the penetrating region (including the ⁇ helix) and the cytoplasmic domain.
- the invention defined by the amino acid residue of the number after the replacement as described above is not changed in any way as the invention defined by the amino acid residue of the number before the replacement as described above. It is self-explanatory.
- FIG. 46A shows the result of comparison between human and rat in the portion containing the predetermined amino acid residue constituting the interaction region in the amino acid sequence of IL-17RA.
- the homology of the interaction region containing a given amino acid residue is high (23 of the given 28 amino acid residues are identical and the sequence homology is 82. 1%).
- Example 2 for human IL-17RA
- rat cells shown as Examples 1 and 3 From the results (for rat IL-17RA) and from the results of the in vivo test using the rat shown as Example 5, the compound of the present invention inhibits the activity against human IL-17RA and regulates the expression of a predetermined gene. It can be understood that it has an action, and further has the effect of preventing or treating a predetermined disease or the like for humans.
- FIG. 46-2 shows the result of comparison between human and mouse of a portion containing a predetermined amino acid residue constituting the interaction region in the amino acid sequence of IL-17RA.
- the interaction region containing a given amino acid residue has high homology (25 of 28 given amino acid residues are identical and the sequence homology is 89. 3%).
- the compound of the present invention has an activity inhibiting action on human IL-17RA and an expression regulating action of a predetermined gene, and further has an effect of preventing or treating a predetermined disease and the like on humans. it can.
- the IL-17A activity inhibitor of the present invention comprises a van der Waals force between a predetermined amino acid residue contained in the extracellular domain (interaction region) of human IL-17RA and It is defined by other non-covalent interactions.
- IL-17A activity inhibitor is used against IL-17RA of non-human animals, preferably non-human animals, for example, full-length sequence homology of IL-17RA, preferably cells Sequence homology of the outer domain, particularly preferably the sequence homology of the interaction region (predetermined 28 amino acid residues) is 50% or more, 60% or more, 70% or more, 75% or more, preferably 80% or more It can be understood by those skilled in the art that the same activity-inhibiting ability is exhibited even when used for IL-17RA of 85% or more, 90% or more, or 95% or more. . That is, the IL-17A activity inhibitor of the present invention is typically an activity inhibitor of human IL-17A, but is not limited thereto. IL-17A of mammals other than human (preferably the above-mentioned Activity inhibitors of those having such sequence homology).
- the IL-17A activity inhibitor of the present invention is between a predetermined amino acid residue contained in the extracellular domain (interaction region) of IL-17RA of a non-human animal. , Defined by van der Waals forces and other non-covalent interactions.
- sequence homology of the extracellular domain is 50% or more, 60% or more, 70% or more, 75% or more, preferably Those skilled in the art will understand that the same activity inhibiting ability is exhibited even when used against 80% or more, 85% or more, 90% or more, or 95% or more of IL-17RA. be able to.
- sequence homology in this specification can be calculated by using a general method (tool), for example, BLAST (Basic Local Alignment Search Tool).
- the compound of the present invention has at least 13, preferably 14 or more, 15 or more, 16 or more, 17 or more, or 18 or more, of the predetermined (28) amino acid residues constituting the interaction region. By binding van der Waals force between these amino acid residues, they bind to the interaction region.
- the compound of the present invention comprises Asp121, Pro122, Asp123, Gln124, Asp153, Cys154, Glu155, Lys160, Pro164 among the predetermined (28) amino acid residues constituting the interaction region.
- Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Cys263, Leu264 and His266 at least 13, preferably 14, or more, 15 or more, 16 or more, 17
- the van der Waals force acts between the above or 18 or more amino acid residues to bind to the interaction region.
- van der Waals force means that within the interaction region, at least one of the atoms of the compound of the present invention and at least one of the atoms of the amino acid residues are within 3.5 ⁇ m.
- a person skilled in the art can use “ASEDock” or other software (in silico analysis means) under appropriate conditions between the target compound and the amino acid residue of IL-17RA (in the interaction region).
- the Van der Waals forces and other non-covalent interactions that occur in can be estimated.
- the compounds of the present invention further comprise non-covalent interactions other than van der Waals forces (herein simply referred to as “molecules” with at least one of the predetermined amino acid residues constituting the interaction region. It may be called “interaction”). Examples of such intermolecular interactions include ionic bonds, hydrogen bonds, hydrophobic interactions, OH- ⁇ interactions, cation- ⁇ interactions, CH- ⁇ interactions (also hydrophobic interactions), ⁇ - ⁇ interaction (also a hydrophobic interaction).
- the number of amino acid residues in which intermolecular interaction works is preferably 2 or more, more preferably 3 or more. Any one kind or two or more kinds of intermolecular interactions may be used.
- the compound of the present invention comprises a predetermined amino acid residue constituting an interaction region, preferably Asp121, Pro122, Asp123, Gln124, Asp153, Cys154, Glu155, Lys160, Ser168, Ser170, Ser258, At least one selected from the group consisting of ionic bond, hydrogen bond, CH- ⁇ interaction, cation- ⁇ interaction, and hydrophobic interaction with at least one amino acid selected from the group consisting of Asp262, Leu264 and His266 Species intermolecular interactions (noncovalent interactions other than van der Waals forces) work.
- the compound of the present invention has an ionic bond, a hydrogen bond, a CH- ⁇ interaction and a hydrophobic interaction with at least one amino acid selected from the group consisting of Pro122, Cys154, Lys160, Ser170 and Leu264.
- At least one kind of intermolecular interaction selected from the group consisting of:
- the compound of the present invention is at least one amino acid residue selected from the group consisting of Asp121, Gln124, Ser168 and Asp262 targeted by the compound described in Non-Patent Document 3 above.
- the compound of the present invention further includes a predetermined amino acid residue constituting the interaction region other than those described above, that is, Pro122, Asp123, Asp153, Cys154, Glu155. It is preferable that the predetermined intermolecular interaction works with at least one amino acid selected from the group consisting of Lys160, Ser170, Ser258, Leu264 and His266.
- the “IL-17 activity inhibitor” provided in another aspect of the present invention is a compound represented by the general formula (I) (compound (I), a second embodiment of the compound of the present invention), or a compound thereof Contains a pharmaceutically acceptable salt, solvate or prodrug.
- A is (A1) an optionally substituted C 3-10 cycloalkyl group, (A2) an optionally substituted C 3-10 cycloalkenyl group, (A3) an optionally substituted 6-14 member An aromatic hydrocarbon ring group (aryl group), (A4) an optionally substituted 5- to 14-membered aromatic heterocyclic group, (A5) an optionally substituted 3- to 14-membered non-aromatic heterocyclic group, Or (A6) represents an optionally substituted C 4-6 alkyl group.
- L 1 may be linked to a (L 1 1) single bond, (L 1 2) a divalent group (amide bond) derived from a carbamoyl group, and / or linked to an ether bond or thioether bond.
- a divalent group derived from a carbamoyl group (amide bond), optionally linked to a C 1-3 alkylene group, a divalent group derived from an (L 13 ) amino group, (L 1 4) sulfonyl group, or (L 1 5) C 1-3 alkenylene group (carbon - carbon double bonds may be formed between the carbon atoms of B or C is adjacent to the L 2. ).
- B is (B1) a divalent group derived from a carbamoyl group that may be substituted and / or linked to a divalent group derived from a C 1-3 alkyl-carbonyl group (Amide bond), (B2) a divalent group derived from an optionally substituted 5- to 14-membered aromatic heterocycle, (B3) from an optionally substituted 3- to 14-membered non-aromatic heterocycle A derived divalent group, (B4) an optionally substituted C 3-10 cycloalkyl group, (B5) an optionally substituted C 3-10 cycloalkenyl group, (B6) optionally substituted It represents a preferable 6 to 14-membered aromatic hydrocarbon ring group (aryl group), (B7) ester bond or thioester bond, or (B8) keto group or thioketo group.
- L 2 is a (L 2 1) single bond, (L 2 2) C 1-6 alkylene group, or (L 2 3) C 1-3 alkenylene group (the carbon-carbon double bond is B adjacent to L 2 Or may be formed between carbon atoms of C).
- C is (C1) a divalent group (amide bond) derived from an optionally substituted carbamoyl group, (C2) 2 derived from an optionally substituted 5- to 14-membered aromatic heterocyclic ring.
- L 3 represents (L 3 1) a single bond, (L 3 2) a divalent group (amide bond) derived from a carbamoyl group and / or a divalent group (—N ⁇ ) derived from an imino group.
- An optionally linked and / or optionally substituted C 1-3 alkylene group, an (L 3 3) C 1-3 alkenylene group, an ether bond or a thioether bond, or (L 3 4) represents a divalent group (amide bond) derived from a carbamoyl group which may be linked to a divalent group derived from an amino group.
- D is (D1) an optionally substituted C 3-10 cycloalkyl group, (D2) an optionally substituted C 3-10 cycloalkenyl group, (D3) an optionally substituted 6-14 member An aromatic hydrocarbon ring group (aryl group), (D4) an optionally substituted 5- to 14-membered aromatic heterocyclic group, (D5) an optionally substituted 3- to 14-membered non-aromatic heterocyclic group, Or (D6) an optionally substituted C 1-3 alkyl group.
- the compound of the present invention is represented by the general formula (I) (satisfying the requirements as the second embodiment) and constitutes an “interaction region” as described herein. Having a van der Waals force or other non-covalent interaction (satisfying the requirements as the first embodiment).
- the compound of the present invention may satisfy the requirements as the second embodiment but may not satisfy the requirements as the first embodiment as long as the effects of the present invention are exhibited. However, the requirement as the second embodiment may not be satisfied.
- A, L 1 , B, L 2 , C, L 3 and D in the general formula (I) are represented by any structural formula of the compounds (1) to (36) of the present invention. More preferable specific examples include those represented by the structural formula of any one of the compounds (1), (2), (5), (9) or (11) of the present invention.
- L 1 , B and L 2 are combined to form a predetermined structure (alkylene group), but the definition of the general formula (I) is defined for A, C, L 3 and D Can be applied.
- compound (I) has at least a site where a hydrogen bond or CH- ⁇ interaction acts with Cys154.
- the site is preferably at least one site selected from the group consisting of sites L 2 , A, B and C in compound (I). For example, it includes 2 sites of L 2 and B, and B and C It is preferable that these two locations are included.
- Compound (I) may have a ( ⁇ +) hydrogen atom to be a proton donor, or Cys154 may have.
- the compound (I) is a site where a hydrogen bond or CH- ⁇ interaction occurs with Cys154,
- the site A which is the above (A6) having a group which becomes a donor or acceptor of a hydrogen atom (which may have such a group as a substituent);
- the moiety L 1 which is (L 1 2) having a group which serves as a donor or acceptor of a hydrogen atom (which may have such a group as a substituent);
- the moiety B which has (B1) or (B3), which has a group which serves as a donor or acceptor of a hydrogen atom (which may have such a group as a substituent); Having a hydrogen atom donor or acceptor group (which may have such a group as a substituent), the above (C1), (C2), or (C3), (C6) or (C7)
- a site L 1 having the above-described (L 1 2) or (L 14 ) having a group that serves as a donor or acceptor
- hydrogen bond acting between compound (I) and Cys154 include -NH- nitrogen atom (lone electron pair), -CO- oxygen atom (lone electron pair), -S- sulfur atom (lone electron pair), etc., contained in the sites B, C, L 1 etc.
- a hydrogen bond with a hydrogen atom of —SH contained in the side chain of Cys154 (eg, compounds (1), (2), (5), (9), (11), (36));
- a hydrogen bond (for example, the compound (7), (O) in the sites B, L 1 , L 3, etc.) between the oxygen atom of ⁇ O (lone electron pair) and the hydrogen atom of —SH contained in the side chain of Cys154 14), (15), (24), (25), (26), (31), (35));
- a hydrogen atom such as ⁇ CH—, —CH 2 —, —CH (R) —, etc.
- Compound (I) is a site where a hydrogen bond, a CH- ⁇ interaction, an ionic bond, or other intermolecular interaction occurs between a predetermined amino acid residue constituting an interaction region other than Cys154 You may have.
- Typical examples of such intermolecular interactions include a site where hydrogen bonding occurs with Asp121, a site where CH- ⁇ interaction occurs with Pro122, and a CH- ⁇ interaction with Asp123. Examples thereof include a site, a site where an ionic bond or a hydrogen bond occurs with Lys160, a site where a CH- ⁇ interaction occurs with Ser170, and other intermolecular interactions depicted in FIGS.
- a typical example of a site where a hydrogen bond is formed with Asp121 is the site (A6), for example, site A which is a substituted C 4-6 alkyl group of compound (9).
- the substituent of the C 4-6 alkyl group in this embodiment is not particularly limited as long as it contains an atom which becomes a donor or acceptor for forming a hydrogen bond with an asparagine residue, and may be substituted, for example.
- An amino group is mentioned.
- the compound (4) has the — NH—, —NH— of the above (L 1 2) possessed by the compound (29), and —OH of (A3) possessed by the compound (34), an atom serving as a hydrogen bond donor or acceptor as a substituent.
- the groups (A1) to (A5) having a group to be contained can be a site where a hydrogen bond is formed with Asp121.
- a typical example of a site where CH- ⁇ interaction occurs with Pro122 is derived from an optionally substituted aromatic heterocycle of (A4), for example, compounds (1) and (28).
- a site A which is a divalent group derived from the above.
- the aromatic heterocycle or h non-aromatic heterocycle in this embodiment may be a group having a ⁇ electron capable of forming a CH- ⁇ interaction with a proline residue.
- a group other than (A4) and (A5) for example, a cyclic group of (A3) having a ⁇ electron is bonded to Pro122 with CH It can also be a site where - ⁇ interaction occurs.
- a hydrogen bond may occur between the compound (I) of the present invention and Pro122.
- the site that generates such a hydrogen bond include compounds (12), (13), and (17). (B5) having a divalent group derived from a substituted cycloalkenyl group, and (B3) the compound (19) having a divalent group derived from a substituted non-aromatic heterocyclic ring.
- part B which is group is mentioned.
- the substituent of the cycloalkenyl group or the sad news structure heterocyclic ring in this embodiment may be any as long as it contains an atom serving as a donor or acceptor for forming a hydrogen bond with a proline residue, and examples thereof include a hydroxyl group. .
- those other than (B3) and (B5) for example, a group containing an atom serving as a hydrogen bond donor or acceptor as a substituent (B1 ), (B2), (B4), and (B6) to (B8) may be sites where hydrogen bonds are formed with Pro122.
- the above-mentioned (A5) for example, compound (2), which is a non-aromatic heterocyclic group which may be substituted (however, one of the condensed rings) Part A having an aromatic ring ( ⁇ electron) as a part).
- the non-aromatic heterocyclic group is a group having ⁇ electrons, for example, a condensed ring of an aromatic ring and a non-aromatic ring so that a CH- ⁇ interaction can be formed with an aspartic acid residue (although it is non-aromatic as a whole, since there are ⁇ electrons in the aromatic ring part, an aspartic acid residue and CH- ⁇ interaction can be formed at that part.
- a group other than (A5) for example, a cyclic group of (A3) or (A4) having a ⁇ electron is bonded to Asp123 with CH It can also be a site where - ⁇ interaction occurs.
- a hydrogen bond may be generated between the compound (I) of the present invention and Asp123, and as a site for generating such a hydrogen bond, for example, the above (C6) that the compound (27) has, that is, a substitution
- the substituent of the aromatic hydrocarbon group or methylene group in this embodiment is not particularly limited as long as it contains an atom that becomes a donor or acceptor for forming a hydrogen bond with a proline residue, such as a hydroxy group (or And a substituent having a hydroxy group at the terminal).
- a group containing an atom serving as a hydrogen bond donor or acceptor as a substituent (C1 ) To (C5) or (C7) may be a site where a hydrogen bond occurs with Pro122.
- the substituent of the cycloalkyl group and the aromatic hydrocarbon ring group is an atom that forms an anion for forming an ionic bond with a lysine residue, or a donor or an acceptor for forming a hydrogen bond.
- the former includes, for example, a carboxyl group, and the latter includes, for example, a keto group (oxo group).
- the group (D6) may be a site where an ionic bond or a hydrogen bond occurs with Lys160.
- a cation- ⁇ interaction may occur between the compound (I) of the present invention and Lys160.
- the site that generates such a cation- ⁇ interaction include the compound (33) described above. (D3), that is, a site D that is an optionally substituted aromatic hydrocarbon group (phenyl group).
- the aromatic hydrocarbon group in this embodiment is a group having ⁇ electrons that can form a cation- ⁇ interaction with a lysic acid residue.
- (D1) to (D8) defined as the site D those other than (D3), such as (D4) having ⁇ electrons, or non-aromatic as a whole, but aromatic ring
- (D5) having a ⁇ electron in the portion a site where a cation- ⁇ interaction occurs with Lys160 may be used.
- the compound (2), (12), (13), (17), (19), (27), (29) has (D3 ), That is, an aromatic hydrocarbon group that may be substituted, or (D5) that the compounds (9), (15), and (16) have, that is, a non-aromatic heterocyclic group that may be substituted (provided that And a portion D which is an aromatic ring ( ⁇ electron) as a part of the condensed ring.
- the aromatic hydrocarbon group in this embodiment may be a group having ⁇ electrons that can form a CH- ⁇ interaction with a serine residue.
- the non-aromatic heterocyclic group in this embodiment is a group having a ⁇ electron such as a condensed ring of an aromatic ring and a non-aromatic ring so that a CH- ⁇ interaction can be formed with a serine residue.
- a ⁇ electron such as a condensed ring of an aromatic ring and a non-aromatic ring so that a CH- ⁇ interaction can be formed with a serine residue.
- a serine residue and a CH- ⁇ interaction can be formed in that part.
- a cyclic group of (D4) having ⁇ electrons is bonded to Ser170 with CH It can also be a site where - ⁇ interaction occurs.
- compound (I) includes a hydrogen bond with Gln124, a hydrogen bond with Asp153, a hydrogen bond with Glu155, a hydrogen bond with Ser168, a hydrogen bond with Ser258, Asp262 And a hydrogen bond with Leu264 or a CH- ⁇ interaction and a hydrogen bond with His266.
- a site where a predetermined interaction occurs between these predetermined amino acid residues can be defined in the same manner as in the above-described embodiment from the drawings or tables.
- Compound (I) may contain stereoisomers, that is, enantiomers (enantiomers) and / or diastereomers (stereoisomers other than enantiomers).
- a mixture of stereoisomers for example, a racemate which is a mixture of enantiomers
- a purified product having an increased purity of a specific stereoisomer useful for pharmacological activity For example, a purified product having a purity of 90% or more, preferably a purity of 95% or more, more preferably a purity of 99% or more, ideally consisting essentially of the stereoisomer may be used.
- Compound (I) may contain a tautomer.
- a tautomer a ketoenol tautomer having a structure that can be converted to each other as follows can be given. Regardless of the structure represented by the general formula (I), all tautomers can be included in the compound (I).
- Each site of compound (I) may be ionized under the conditions in which compound (I) is used, typically under physiological conditions.
- the carboxy group (—COOH) may exist in the form of a carboxylate ion (—COO ⁇ ).
- the compound (I) is any one of the compounds (1) to (36) shown in Table 2.
- Compound (3) represents a racemate that is a mixture of S-form and R-form, and compound (1) represents only the S-form.
- total number shown in parentheses in “the number of amino acid residues in which a non-covalent interaction other than van der Waals forces acts”, for example, for non-van der Waals forces other than two van der Waals forces for one amino acid residue
- the total number is “2”, indicating that “the total number of non-covalent interactions other than van der Waals forces (intermolecular interactions)”.
- the compounds (1) to (36) excluding the compound (3) those which interact among predetermined amino acid residues constituting the interaction region are shown in Table 3.
- GBVIWSA_dG value is -5.3894 kcal / mol, which is larger than any GBVIWSA_dG value of compounds (1) to (36) shown in the table below (maximum is -7.5007 kcal / mol of compound (36)) and inferior in binding stability. It is suggested.
- derivatives of compounds (1) to (36) can also be used as IL-17A activity inhibitors.
- a person skilled in the art can produce a derivative of compounds (1) to (36) without undue trial and error, and select a derivative having the desired ability to inhibit IL-17A activity to carry out the present invention.
- Can do For example, by referring to the description of the derivatives of the compounds (1), (5), (9) and (11) described below, and in the extracellular domain of each compound and IL-17RA shown in the drawings By referring to the contents shown in the schematic diagram showing the mode of non-covalent interaction with the amino acid residue, a derivative that can be used in the present invention is prepared from other compounds as well. can do.
- the group, bond, and other structure to be replaced from the original compound may be selected from the same type as those of the original compound, or may be selected from different types.
- the structural formula (I) six types (A1) to (A6) as the site A, eight types (B1) to (B8) as the site B, and (C1) to (C7) as the site C seven, six as site D (D1) ⁇ (D6) , as L 1 of (L 1 1) 5 kinds of ⁇ (L 1 5), as L 2 (L 2 1) ⁇ (L 2 3) three, illustrate four as L 3 (L 3 1) ⁇ (L 3 4), are also mentioned specific examples.
- the derivative when the original compound has the group (A1) as the site A, the derivative has another group selected from (A1) (the same type) as the site corresponding to the site A, Any of those having a group selected from (A2) to (A6) (different types) and those having a group selected from types other than (A1) to (A6) can be used. The same applies to other parts.
- a derivative when a derivative is produced, when the substituent is different from that of the original compound, or when a substituent that was not present in the original compound is introduced, it is exemplified as “substituent group A” in the present specification. Substituents for the derivatives can be selected from those.
- a derivative of a compound has four, five or six of the seven sites of sites A, L 1 , B, L 2 , C, L 3 and D, And the rest of the sites are selected from other groups selected from the same type as the original compound (for example, different substituents), or from different types from the original compound. It is a group.
- a derivative of a compound has 4, 5, 6 or 7 sites out of 7 sites A, L 1 , B, L 2 , C, L 3 and D. Is the same group as the original compound or another group selected from the same type (except when all seven sites are the same group), and the remaining site is the same as the original compound A group selected from different types.
- another group selected from the same type as the original compound” or “a group selected from a different type from the original compound” is the compound at the corresponding site.
- groups (1) to (36) are groups possessed by compounds other than the original compound.
- the derivative of the compound when the original compound has a cyclic structure at a certain site, the derivative of the compound also has a cyclic structure at the corresponding site. In one embodiment of the present invention, when the original compound has a chain structure at a certain site, the derivative of the compound also has a chain structure at the corresponding site.
- the derivative of the compound when the original compound has a cyclic or chain structure at a certain site, the derivative of the compound has a cyclic structure and a chain structure that are used pharmaceutically at the corresponding site. Each has a chain or cyclic structure according to the mutual conversion. In one embodiment of the present invention, when the original compound has a cyclic or chain structure having a substituent at a certain site, the derivative of the compound has the same or similar chemical property at the corresponding site. It has a chain or chain structure having a substituent.
- Derivatives of compounds (1) to (36) generally have non-covalent interactions occurring with IL-17RA as a whole (total), respectively, in the original compounds (1) to (36).
- IL-17RA are preferably more stable (stronger) than the non-covalent interactions that occur between them.
- a score unit kcal / mol shown as “GBVIWSA_dG” in Table 2 can be referred to.
- van der Waals force and / or non-covalent interaction other than van der Waals force select the structure to be introduced into the derivative while referring to the stability (strength) index of the interaction. be able to.
- compound (I) is compound (1), (2), (5), (9) or (11), or a derivative thereof.
- the derivatives of compound (1), (2), (5), (9) or (11) are four, five of A, L 1 , B, L 2 , C, L 3 and D.
- Or 6 sites are the same group as the original compound, and the remaining sites are selected from other groups selected from the same type as the original compound, or from a different type from the original compound It may be a group.
- the derivatives of the compound (1), (2), (5), (9) or (11) include four or five of A, L 1 , B, L 2 , C, L 3 and D. , 6 or 7 sites are the same group as the original compound or other groups selected from the same type (except when all 7 sites are the same group), and the rest The site may be a group selected from a type different from the original compound. The same applies to the compounds other than the compounds (1), (2), (5), (9) and (11).
- Compound (1) is a compound represented by the following structural formula (1).
- compound (1) includes Asp121, Pro122, Gln124, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Ser258, Cys259 among the predetermined amino acid residues constituting the interaction region. , Asp262, Cys263, and Leu264, van der Waals forces, and non-covalent interactions other than those of some amino acid residues and van der Waals forces act in the interaction region. Can be stably bonded.
- the “phthalazine ring” (the benzene ring portion of the condensed ring) contained in the site A in the general formula (I) is a moiety that causes a CH- ⁇ interaction with Pro122, two “carbamoyl groups” contained in the site B and the site C, respectively.
- “(Amide bond) is a part that forms a hydrogen bond with Cys154 (to be a donor), and” ion (ionized) carboxyl group as a substituent of cyclohexyl group "contained in site D is between the ionized amino group of Lys160 This is the part that generates ionic bonds.
- the derivative of the compound (1) as compared with the compound (1), Asp121, Pro122, Gln124, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Ser258, Cys259, Asp262, Cys263 and Leu264
- Examples thereof include a derivative (1-X) obtained by modifying the original compound (1) so that the van der Waals force is enhanced.
- the dotted line depicted in FIG. 2 represents the contact surface between the atom of compound (1) (and other compounds of the present invention) and the atoms of the amino acid residues surrounding it.
- the compound (1) and the compound of the present invention
- the amino acid residue and other interaction regions
- van der Waals force between a certain amino acid residue can be enhanced.
- a site where the compound (1) has at least one of CH- ⁇ interaction with Pro122, hydrogen bond with Cys154 and ionic bond with Lys160, or At least one non-covalent interaction that differs from these (in the type and strength of intermolecular interactions and at least one of the target amino acid residues) can be expressed as Asp121, Pro122, Gln124, Cys154, Glu155, Lys160, Pro164.
- the derivative (1-Y) modified from the above viewpoint may be, for example, as follows: A derivative in which the stability of CH- ⁇ interaction with Pro122 is improved by modifying site A (phthalazine ring substituted with a hydroxyl group) in general formula (I); A derivative having improved stability of hydrogen bond with Cys154 by modifying site B and / or C (both carbamoyl groups) in general formula (I); A derivative having improved ionic bond stability with Lys160 by modifying site D (cyclohexyl group substituted with a carboxyl group) in general formula (I); In addition, by modifying the sites A, L 1 , B, L 2 , C, L 3 and D in the general formula (I), Asp121, Gln124, Glu155, Pro164, Ser168, Gly169, Ser170, Ser258, Cys259, New non-covalent bonds with Asp262, Cys263 or Leu264 (amino acid residues other than Pro122, Cys154 and Lys160), and with other amino
- the derivative of the compound (1) it consists of Asp121, Pro122, Gln124, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Ser258, Cys259, Asp262, Cys263 and Leu264 rather than the compound (1).
- a derivative (1-Z) obtained by modifying the original compound (1) so as to have a site that reduces the exposure of at least one amino acid residue selected from the group to the solvent side.
- the shadow around the circle representing the amino acid residues constituting the interaction region depicted in FIG. 2 (and other figures) is due to the binding of compound (1) (and other compounds of the present invention). This means that the exposure to the solvent side is reduced, and the greater the shadow, the greater the degree of reduction (see, for example, Leu264 in FIG. 2).
- Such an amino acid residue with reduced exposure to the solvent side has a strong hydrophobic interaction with the compound of the present invention, and it can be said that the binding of IL-17A to IL-17RA is more strongly inhibited competitively. .
- the derivative of the compound (1) may satisfy two or all of the three conditions (1-X), (1-Y) and (1-Z) at the same time.
- Compound (2) is a compound represented by the following structural formula (2).
- compound (2) includes Asp121, Pro122, Asp123, Gln124, Asp153, Cys154, Glu155, Pro164, Ser168, Gly169, Ser170, Trp172 among the predetermined amino acid residues constituting the interaction region.
- Pro254, Phe256, Ser258, Cys259, Asp262, Leu264, and His266 have van der Waals forces, and some non-covalent interactions other than van der Waals forces with some of their amino acid residues By working, it can be stably bonded in the interaction region.
- the ring contained in the site A in the general formula (I) (the benzene ring portion of the condensed ring) generates a CH- ⁇ interaction with Asp123, and the carbamoyl group contained in the site B forms a hydrogen bond with Cys154 (with the donor).
- the phenyl group (substituted with two methoxy groups) contained in the site D is a portion that causes a Ser-170 and CH- ⁇ interaction.
- At least one of the CH- ⁇ interaction with Asp123, the hydrogen bond with Cys154 or the CH- ⁇ interaction with Ser170 possessed by compound (2) is enhanced.
- Non-covalent interactions other than the site, or at least one van der Waals force different from these, can be performed by Asp121, Pro122, Asp123, Gln124, Asp153, Cys154, Glu155, Pro164, Ser168, Gly169, Ser170, Trp172, A derivative (2-Y) obtained by modifying the original compound (2) to have a site generated between at least one amino acid residue selected from the group consisting of Pro254, Phe256, Ser258, Cys259, Asp262, Leu264 and His266 Is mentioned.
- Compound (5) is a compound represented by the following structural formula (5).
- compound (5) includes Asp121, Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Trp172 among the predetermined amino acid residues constituting the interaction region.
- Ser258, Cys259, Asp262, Cys263, Leu264, and His266 have van der Waals forces and non-covalent interactions other than van der Waals forces with some of their amino acid residues. Thus, it is possible to stably bond within the interaction region.
- the keto group (oxo group as a substituent) contained in the site B in the general formula (I) forms a hydrogen bond with Cys154 (becomes an acceptor), the keto group contained in the site D (as a phenyl group substituent)
- the oxo group that binds to the carbon atom of the pyrrolidine ring (substitutes a hydrogen atom) forms a hydrogen bond with Lys160 (acts as an acceptor).
- Asp121, Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Cys263 are more preferable than compound (5).
- At least one fan different from the site where compound (5) has at least one of the hydrogen bond with Cys154 or the hydrogen bond with Lys160 is enhanced.
- Examples thereof include a derivative (5-Y) obtained by modifying the original compound (5) so as to have a site generated between at least one amino acid residue selected from the group consisting of
- Asp121, Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Cys263 are more preferable than compound (5).
- Compound (9) is a compound represented by the following structural formula (9).
- compound (9) comprises Asp121, Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Pro164, Ser167, Ser168, Gly169, Ser170 among the predetermined amino acid residues constituting the interaction region.
- Trp172, Ser258, Cys259, Asp262, Leu264 and His266 have van der Waals forces and non-covalent interactions other than van der Waals forces with some of their amino acid residues Thus, it is possible to stably bond within the interaction region.
- the substituted amino group contained in the site A forms a hydrogen bond (donor) with Asp121
- the ring keto group (oxo group as a substituent) contained in the site B is Cys154.
- a part that forms a hydrogen bond (becomes an acceptor)
- a ring included in part D is a part that causes a Ser-170 and CH- ⁇ interaction.
- At least one of the CH- ⁇ interaction with Asp121, the hydrogen bond with Cys154 or the CH- ⁇ interaction with Ser170 possessed by compound (9) is enhanced.
- Non-covalent interactions other than the site, or at least one van der Waals force, which are different from these, are represented by Asp121, Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Pro164, Ser167, Ser168, Gly169, Ser170,
- a derivative (9-Y) obtained by modifying the original compound (9) to have a site generated between at least one amino acid residue selected from the group consisting of Trp172, Ser258, Cys259, Asp262, Leu264 and His266 It is done.
- Compound (11) is a compound represented by the following structural formula (11).
- compound (11) includes Asp121, Pro122, Gln124, Asp153, Cys154, Glu155, Pro164, Cys165, Ser168, Gly169, Ser170, Trp172 among the predetermined amino acid residues constituting the interaction region.
- Ser258, Cys259, Asp262, Leu264 and His266, van der Waals forces work, and further, non-covalent interactions other than van der Waals forces with some of their amino acid residues, It can be stably bound in the interaction region.
- the hydroxyl group contained in the site A forms a hydrogen bond with Cys154 (becomes a donor), and the carbamoyl group (oxygen atom) contained in the site B produces a hydrogen bond with Cys154 (becomes an acceptor).
- the ring included in the part C is a part that causes a CH- ⁇ interaction with Cys154.
- Asp121, Pro122, Gln124, Asp153, Cys154, Glu155, Pro164, Cys165, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Leu264 are more preferable than compound (11).
- compound (11) has a site where at least one of CH- ⁇ interaction or hydrogen bond with Cys154 is enhanced, or at least one fan different from these A group consisting of Asp121, Pro122, Gln124, Asp153, Cys154, Glu155, Pro164, Cys165, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Leu264, and His266.
- Examples thereof include a derivative (11-Y) obtained by modifying the original compound (11) so as to have a site generated between at least one amino acid residue selected from the above.
- Asp121, Pro122, Gln124, Asp153, Cys154, Glu155, Pro164, Cys165, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Leu264 are more preferable than compound (11).
- Derivatives of compounds other than the compounds (1), (2), (5), (9), and (11) can be similarly derived based on the contents shown in the drawings and tables. That is, among predetermined amino acid residues constituting the interaction region, a set of amino acid residues in which van der Waals force acts on the original compound is defined as “P”, and van der Waals between the original compound and the original compound.
- the set of amino acid residues in which a non-covalent interaction other than force acts is “Q”
- the derivative of each compound is selected from the group consisting of the following [x], [y] and [z] A modification of the original compound to satisfy at least one condition.
- [X] An enhancement of the total van der Waals force between the amino acid residues of the set P over the original compound; [Y] A site where the original compound has at least one non-covalent interaction other than van der Waals force with at least one selected from the group consisting of amino acid residues in the set Q, or at least one different from it Having a site where non-covalent interactions other than van der Waals forces occur with at least one amino acid residue selected from the group consisting of the set P; [Z] It has a site that reduces the exposure to the solvent side of at least one amino acid residue selected from the group consisting of the set P than the original compound.
- Compound (I) can be in the form of a pharmaceutically acceptable salt, solvate or prodrug.
- the compound (I) (the compound represented by the general formula (I)) and pharmaceutically acceptable salts, solvates and prodrugs thereof may be collectively referred to as “the compound of the present invention”.
- a pharmaceutically acceptable salt means that the salt of the compound is not harmful for therapeutic, prophylactic or other purposes when used as an active ingredient of a medicament.
- pharmaceutically acceptable salts include the following: Examples of basic salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt Aliphatic amine salts such as triethanolamine salt and brocaine salt; aralkylamine salts such as N, N-dibenzylethylenediamine; heterocyclic aromatic amine salts such as pyridine salt, picoline salt, quinoline salt and isoquinoline salt; tetramethyl Quaternary ammonia such as ammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltribu
- the solvate is typically a hydrate and may be a monosolvate (monohydrate), a disolvate (dihydrate) or a larger number of solvates. (Hydrate) may also be used.
- Prodrugs are derivatives having groups that can be chemically or metabolically degraded and may be solvolyzed (eg, degradation in phosphate buffer (pH 7.4) -ethanol) or under physiological conditions (in vivo ) To be a pharmaceutically active compound.
- esters as prodrugs include methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, tert-butyl ester, morpholinoethyl ester, N, N-diethylglycolamide ester and the like. Can be mentioned.
- Examples of the prodrug of the compound having hydroxy include acyloxy derivatives produced by reacting a compound having an original hydroxyl group with an appropriate acyl halide or an appropriate acid anhydride.
- Particularly preferred acyloxy as a prodrug includes —O ( ⁇ O) —CH 3 , —OC ( ⁇ O) —C 2 H 5 , —OC ( ⁇ O) — (tert-Bu), —OC ( ⁇ O).
- prodrugs of amino-containing compounds include amide derivatives produced by reacting an original amino-containing compound with an appropriate acid halide or an appropriate mixed acid anhydride.
- Particularly preferred amides as prodrugs include —NHC ( ⁇ O) — (CH 2 ) 20 CH 3 , —NHC ( ⁇ O) —CH (NH 2 ) CH 3 and the like.
- IL-17 activity inhibitor of the present invention is not particularly limited, and IL-17 against IL-17RA, typically IL-17RA (extracellular domain) in a state expressed on the cell surface. Depending on the purpose of inhibiting the binding, it can be used in various situations in vitro, ex vivo, or in vivo.
- an IL-17 activity inhibitor is used as an expression regulator as described later (or as an ingredient when an expression regulator is prepared as a composition).
- the IL-17 activity inhibitor is used as a medicament as described later (when the medicament is prepared as a composition, as an active ingredient thereof).
- the IL-17 activity inhibitor is used to produce a medicament (pharmaceutical composition) as described below.
- an IL-17 activity inhibitor is used in a method for inhibiting the binding of IL-17A to IL-17RA as described below.
- the “expression regulator” provided in one aspect of the present invention is for regulating the expression level of a gene whose expression level is changed by the binding of IL-17A to IL-17RA in a cell expressing IL-17RA.
- An IL-17A activity inhibitor of the present invention as described above.
- the “gene whose expression level is changed by the binding of IL-17A to IL-17RA” is not particularly limited.
- the expression level is increased or decreased by a signal transduction reaction as shown in FIG. Gene (expression is enhanced or suppressed).
- the gene whose expression level is changed by the binding of IL-17A to IL-17RA is a gene whose expression is enhanced by the binding of IL-17A to IL-17RA.
- IL-17A is an inflammatory cytokine, and it is widely known to induce the expression of transmitter substances (proteins such as cytokines, chemokines, and growth factors) that cause inflammation and the like by binding to IL-17RA (for example, (See the aforementioned Patent Document 2).
- the gene whose expression is enhanced by binding of IL-17A to IL-17RA is a group consisting of IL-6, COX-2, mPGES1, MMP-3, MMP-13 and CXCL1. It is at least one selected from. These genes are deeply involved in symptoms such as intervertebral disc degeneration. It is demonstrated in Examples described later that the expression of these genes is enhanced by the binding of IL-17A to IL-17RA, and that the compound of the present invention can inhibit the binding and reduce the expression level of the above genes. Yes.
- IL-6 is known as a cytokine that cooperates with TGF ⁇ to induce the expression of IL-17A by Th17 cells (Ivanov, II et al., Cell 126, 1121-1133, 2006; Gaffen, S. L ., Current opinion in immunology 23, 613-619, 2011). IL-6 is secreted even in the absence of macrophages in the intervertebral disc (Rand et al., Spine 22, 2598-2601, 1997), and the expression level is increased in cells of intervertebral hernia (Andrade, P. et al., European spine journal 22, 714-720, 2013).
- IL-6 reduces extracellular matrix production in the intervertebral disc and accelerates degeneration (Kang, J. D. et al., Spine 21, -271-277, 1996; Phillips, K. L. et al ., Arthritis research & therapy 15, R213, 2013; Studer. RK et al., Spine 36, 593-599, 2011; Patel, K. P. et al., Spine 32, 2596-2603, 2007), and TNF ⁇ Also contributes to the expression of inflammatory mediators such as PGE-2 (Phillips, K. L. et al., 2013; Patel, K. P. et al., 2007), causing neuropathic pain (Murata, Y.
- IL-6 plays an important role in the progression of nucleus pulposus cell degeneration and the symptoms associated with degenerative diseases. By suppressing its expression, the progression of intervertebral disc degeneration is suppressed, and the symptoms associated with degenerative diseases are suppressed. The effect of reducing can be expected.
- COX-2 cyclooxygenase-2
- COX-2 is a key enzyme for biosynthesis of prostaglandins in intervertebral disc cells (Miyamoto et al., Spine 27, 2477-2483, 2002; van Dijk. B. et al ., Journal of orthopaedic research 33, 1724-1731, 2015)
- its biosynthesis is induced by mechanical stress and triggers the degeneration cascade (Seibert, K. et al., Proceedings of the National Academy of Sciences of the United States of America 91, 12013-12017, 1994; Williams, C. S. et al., Oncogene 18, 7908-7916, 1999).
- MPGES1 microsomal prostaglandin E synthase-1 produces PGE2 (prostaglandin E2) selectively associated with COX-2. PGE2 sensitizes nerves and increases back pain (Kang, J. D. et al., 1996).
- MMP-3 matrix metalloproteinases-3
- MMP-13 matrix metalloproteinases-13
- stromemycin-1 proteins also known as collagenase-3, respectively, which enable collagen fibers, hydrophilic proteoglycans, etc. Degradation of the extracellular matrix promotes the degeneration process of the intervertebral disc (Antoniou, J..et al., The Journal of Clinical Investigation 98, 996-1003, 1996).
- CXCL1 is one of chemokines that induces neutrophil activation and migration and is involved in the formation of inflammation (Charo et al., N Engl J Med. 354, 610-621, 2006), macrophages, mast cells, Produced from keratinocytes (De Filippo et al., Blood. 121, 4930-4937, 2013; Lowes et al., Trends Immunol. 34.174-181, 2013). CXCL1 production by these cells also occurs upon stimulation with IL-17A (Iwakura et al.,. Immunity. 34, 149-162, 2011).
- IL-17A acts on keratinocytes and promotes production of CXCL1, thereby causing neutrophil infiltration into the stratum corneum of the skin, which is involved in the formation of microabscess, hyperproliferation and keratinization of the epidermis It is thought to be involved in abnormalities (Girolomoni et al., Br J Dermatol., 167 (4), 717-724, 2012; Lin et al., FASEB. 32, 2018).
- p38 and JNK which are MAPK factors, are activated by stimulating inflammatory cytokines such as TNF ⁇ and promote the expression of CXCL1 (Shieh et al., Cell Physiol Biochem. 34, 1373- 1384, 2014).
- the gene whose expression is enhanced by binding of IL-17A to IL-17RA is a gene whose expression is enhanced by phosphorylation of p38.
- genes include COX-2, IL-6, CXCL1, and the like.
- COX-2 is expressed in the p38 pathway and the JNK (c-JunaseN-terminal kinase) pathway in the MAPK (mitogen-activated protein-kinase) pathway (see FIG. 45), respectively, with p38 and JNK being phosphorylated by IL-17A. It has been reported to be oxidized and activated (Li. J. K. et al., Journal of translational medicine 14, 77, 2013). As shown by [Example 3] (FIG. 43), in the present invention, at least p38 phosphorylation can be suppressed by administering an expression regulator, which means that COX-2, It is considered that it also affects the suppression of the expression of IL-6, CXCL1, and the like.
- an expression regulator which means that COX-2, It is considered that it also affects the suppression of the expression of IL-6, CXCL1, and the like.
- the use of the expression regulator of the present invention is not particularly limited, and the purpose is to regulate the expression level of a gene whose expression level is changed by binding of IL-17A to IL-17RA in cells expressing IL-17RA. Depending on the, it can be used in various situations in in vitro, ex vivo or in vivo.
- the expression regulator of the present invention is preferably targeted for intervertebral disc nucleus pulposus cells or epidermal cells as cells expressing IL-17RA.
- Disc nucleus pulposus cells are cultured under low oxygen conditions (for example, an oxygen concentration in the atmosphere of the medium is about 1%) or an intervertebral disc nucleus pulposus cell present in an intervertebral disc tissue (the nucleus pulposus) It is more preferable to target.
- Intervertebral disc nucleus cells, epidermis cells, and other IL-17RA-expressing cells may be human cells or non-human mammals such as non-human primates (cynomolgus monkeys, rhesus monkeys, chimpanzees, etc.), cows, pigs Alternatively, cells of disease model animals such as mice and rats may be used. That is, the expression regulator of the present invention may target human IL-17RA, or may target IL-17RA of mammals other than humans (for example, rats used in Examples).
- Intervertebral disc nucleus pulposus cells, epidermal cells (keratinocytes, etc.), and other IL-17RA expressing cells include IL-17RA expressing cells such as human or non-human mammal intervertebral disc tissue (nucleus nucleus), skin tissue (epidermis), etc. Primary cells collected from a tissue containing or a subcultured cell thereof, or cells established (immortalized) may be used.
- IL-17RA-expressing cells When IL-17RA-expressing cells are cultured in vitro or ex-vivo, they are cultured under conditions that are as close as possible to the microenvironment of the tissue in which IL-17RA-expressing cells are present, particularly the microenvironment in which symptoms such as inflammation and degeneration occur. It is desirable to do.
- intervertebral disc nucleus pulposus cells are desirably cultured under hypoxic conditions close to degenerated intervertebral disc tissue (medullary nucleus).
- “Low oxygen condition” generally refers to a condition where the oxygen concentration in the atmosphere of the medium is 0.5 to 10%, preferably 1 to 5%, for example about 1%.
- the disc nucleus pulposus cells may be cultured under conditions such as acidity, low glucose (hypoglycemia), and high osmotic pressure as necessary.
- Acid condition refers to a range where the pH of a medium at room temperature (eg, 25 ° C.) is 6.5 to 7.4 or less.
- Low glucose refers to, for example, that the glucose concentration in the medium is 4.5 g / L or less.
- the expression regulator is used as the medicament of the present invention as described later (when the medicament is prepared as a composition, as an active ingredient thereof). In other words, in one embodiment of the present invention, the expression regulator is used to produce the medicament (pharmaceutical composition) of the present invention.
- the expression regulator is used in a method for regulating the expression of a gene whose expression level is changed by the binding of IL-17A to IL-17RA as described below.
- the “medicament for treatment or prevention” provided in one aspect of the present invention is a medicament containing the IL-17A activity inhibitor of the present invention or the expression suppressor of the present invention as an active ingredient as described above. , "A disease in which the binding of IL-17A to IL-17RA is associated with a symptom”.
- Treatment is to reduce, ameliorate, or reduce symptoms, or to make a disease, disorder, or condition more tolerable to a subject ( (For example, by reducing pain and itching), slowing down the rate of degeneration or deterioration, reducing the degree of end point of degeneration or deterioration, improving the physical or mental health of the subject, or extending survival
- a disease, disorder, or condition including any objective or subjective parameters.
- prevention refers to inhibiting the occurrence of symptoms.
- the effects of “treatment” and “prevention” can be evaluated based on objective or subjective parameters, including the results of physical examinations and / or neurological examinations (such as psychological tests).
- “Disease in which binding of IL-17A to IL-17RA is associated with symptoms” is not particularly limited, but is generally classified into inflammatory, allergic, immune, etc., for example, vulgaris Inflammatory skin diseases such as psoriasis, arthritic psoriasis, pustular psoriasis, erythrodermic psoriasis; inflammatory joint diseases such as ankylosing spondylitis and rheumatoid arthritis; inflammatory bowel diseases such as Crohn's disease; and Behcet's disease Autoimmune diseases; organ / tissue transplant rejection, sepsis, etc.
- the medicament of the present invention may be formulated so as to be suitable for delivery to an organ, tissue or cell associated with the symptoms of each disease.
- the medicament of the present invention is a disease in which the binding of IL-17A to IL-17RA is associated with a symptom, such as a disease in which inflammation or degeneration of the intervertebral disc (nuclear nucleus) is manifested as a symptom,
- a symptom such as a disease in which inflammation or degeneration of the intervertebral disc (nuclear nucleus) is manifested as a symptom
- a symptom such as a disease in which inflammation or degeneration of the intervertebral disc (nuclear nucleus) is manifested as a symptom
- herniated disc cervical spondylotic myelopathy, radiculopathy, spondylolysis or spondylosis, lumbar spinal canal stenosis, lumbar degenerative spondylolisthesis, lumbar degenerative scoliosis, etc. It is a medicine.
- the medicament of the present invention is formulated to be suitable for delivery to cells within intervertebral disc tissue (nuclear nucleus, transition zone, annulus fibrosus), particularly nucleus pulposus cells.
- the intervertebral disc tissue may be a tissue having any degree of degeneration, aging, disorder, damage, etc. (including healthy tissue substantially free of degeneration, etc.), or may be a hernia tissue.
- the medicament of the present invention is used as a disease in which binding of IL-17A to IL-17RA is associated with symptoms, psoriasis vulgaris, arthritic psoriasis, pustular psoriasis, It is a medicament for treating or preventing inflammatory skin diseases such as psoriatic erythroderma.
- the medicament of the present invention contains cells in skin tissue (epidermis, dermis), particularly cells such as basal layer, spiny layer, granule layer, stratum corneum of epidermis (keratinocytes or stratum corneum). To be suitable for delivery to cells).
- the skin tissue may be a tissue exhibiting symptoms such as erythema, infiltration / thickness, scales, and desquamation of any degree.
- psoriasis may cause joint symptoms such as joint pain and deformation. Both skin and joint symptoms can be treated or prevented.
- the medicament of the present invention is produced by a method known in the pharmaceutical technical field using the IL-17A activity inhibitor of the present invention or the expression inhibitor of the present invention and a pharmaceutically acceptable carrier (pharmaceutical composition).
- a pharmaceutical dosage form for example, a preparation for parenteral administration (for example, a liquid preparation such as an injection) containing conventional auxiliaries such as a buffer and / or a stabilizer, and an ointment containing a conventional pharmaceutical carrier And topical preparations such as creams, solutions or salves.
- the “subject” to which the medicament of the present invention is administered is a subject that develops a disease in which the binding of IL-17A to IL-17RA is associated with a symptom (for treatment) or a subject that is likely to develop (for prevention) is there.
- the “subject” may be a human or a mammal other than a human, for example, a disease model animal such as a non-human primate (cynomolgus monkey, rhesus monkey, chimpanzee, etc.), cow, pig, mouse, rat or the like. Good.
- the pharmaceutical agent of the present invention may be administered in an amount effective for achieving a desired therapeutic or prophylactic effect.
- an effective amount can be appropriately adjusted according to the dosage per administration, the number of administrations, the administration interval (the number of administrations within a certain period), etc., taking into consideration the dosage form, administration subject, administration route and the like.
- the medicament of the present invention may be administered in an effective amount in order to achieve a desired therapeutic or preventive effect.
- an effective amount can be appropriately adjusted according to the dosage per administration, the number of administrations, the administration interval (the number of administrations within a certain period), etc., taking into consideration the dosage form, administration subject, administration route and the like.
- the “method for screening an inhibitor of IL-17A activity” provided in one aspect of the present invention is a Phe60, Gln87, Asp121, Pro122, Asp123, Gln124, Asp153, Cys154, Glu155, which is contained in the extracellular domain of IL-17RA.
- Lys160, Pro164, Cys165, Ser167, Ser168, Gly169, Ser170, Leu171, Trp172, Asp173, Pro174, Pro254, Phe256, Ser258, Cys259, Asp262, Cys263, Leu264, and His266, and candidate compounds A non-covalent bond including a van der Waals force generated between an atom or atomic group possessed by at least 13 of the amino acid residues and an atom or atomic group possessed by the candidate compound.
- the binding stability between the candidate compound and IL-17RA is evaluated, and the candidate compound binds to IL-17RA competitively with IL-17A.
- the screening method for IL-17A activity inhibitor may further include a step of comparing the binding stability of the candidate compound with the binding stability of the compounds (1) to (36).
- the screening method for an IL-17A activity inhibitor of such an embodiment is, for example, to produce a derivative of compounds (1) to (36), and thus inhibits IL-17A activity more specifically than compounds (1) to (36). It is preferable to use it for producing a derivative with improved performance.
- IL-17A activity inhibitor and other matters described above for other inventions can be applied mutatis mutandis to “binding inhibition method”.
- the “binding inhibition method” provided in one aspect of the present invention is for inhibiting the binding of IL-17A to IL-17RA, and comprises the IL-17A activity inhibitor of the present invention as described above, Contacting with IL-17RA.
- the contact between the IL-17A activity inhibitor and IL-17RA is performed in any of in vitro, ex vivo, in vivo, in other words, both in vivo and in vitro in humans and other animals. Can do.
- IL-17A activity inhibitor and other matters described above for other inventions can be applied mutatis mutandis to “binding inhibition method”.
- the “expression regulation method” provided in one aspect of the present invention is for regulating the expression of a gene whose expression level is changed by the binding of IL-17A to IL-17RA.
- the contact between the IL-17A activity inhibitor and IL-17RA is performed in any of in vitro, ex vivo, in vivo, in other words, both in vivo and in vitro in humans and other animals. Can do.
- the “treatment method” provided in one aspect of the present invention includes the above-described IL-17A activity inhibitor, expression regulator or medicament of the present invention, wherein “IL-17A binding to IL-17RA is a symptom.
- the level of degeneration of the resected disc samples was evaluated according to the MRI Pfirrmann classification, and samples excised from patients with lumbar disc herniation were degenerated (grades 3, 4 or 5), while idiopathic scoliosis Disc samples excised from the patient were normal (grade 1 or 2).
- tissue immunostaining was performed according to the following procedure. Samples were fixed with PBS containing 4% paraformaldehyde and embedded in paraffin. Anti-IL-17A antibody (# bs-2140R, Bioss, human IL-17A specific) diluted in PBS containing 1% BSA after sections were deparaffinized with xylene, reconstituted with ethanol with serial dilution And incubated overnight at 4 ° C.
- the sample was stained with a conjugate of goat anti-rabbit IgG antibody (Sigma-Aldrich) with horseradish peroxidase (HRP) and reacted with diaminobenzidine (Nacalai Tesque) for visualization.
- Cell nuclei were stained with hematoxylin. All specimens were observed with a microscope (IX70, Olympus Corporation), and for each specimen, the total number of cells contained in the high-power field and the number of stained cells were measured to determine the ratio of the latter to the former.
- the lumbar and coccyx discs of rats deeply anesthetized under aseptic conditions are dissected and the gel nucleus pulposus is separated from the intervertebral disc annulus (AF), then minced and pipetted, 20% Cultivate in Dulbecco's modified Eagle's medium (DMEM) supplemented with FBS and antibiotics at 20% O 2 , 5% CO 2 and 37 ° C. for about 1 to 2 weeks, and then in DMEM supplemented with 10% FBS and antibiotics Cultured for about 1-2 weeks.
- the nucleus pulposus cells thus obtained were cultured for 15 minutes to 24 hours in a hypoxic chamber (MIC-101, Billos Rothenberg Inc., USA) containing 1% O 2 , 5% CO 2 and 94% N 2 .
- the purified DNA-free RNA was converted to cDNA using High Capacity cDNA Reverse Transcribation Kit (Applied Biosystems, USA). Template cDNA and primers specific to each gene are added to Power SYBR Green master mix (Applied Biosystems), and Step One Plus Real-time PCR System (Applied Biosystems) is used to quantify the amount of mRNA expression of each gene. . The expression level was normalized with ⁇ -actin. The specificity of RT-PCR and the absence of primer dimers were verified by analysis of melting curves.
- IL-6 and COX-2 and ⁇ -actin as a control for rat nucleus pulposus cells after 24 hours of treatment with 50 ng / mL IL-17A, with the most significant increase observed for IL-6 and COX-2
- the expression level of the protein was quantified by Western blotting according to the following procedure. The nucleus pulposus cells were placed on ice and washed with ice-cold PBS.
- the membrane was blocked with blocking buffer (PBS in which 5% BSA and 0.1% NaN 3 were dissolved), and then anti-IL-6 antibody (# bs-0782R, Bios), anti-COX-2 antibody (# NB100 -689SS, Novus) or anti- ⁇ -actin antibody (# A2228, Sigma-Aldrich) overnight at 4 ° C.
- Each antibody was diluted with Can Get Signal Immunoreaction Enhancer Solution (Toyobo, Japan). Chemiluminescence signals were visualized using Immobilion Western Chemistry HRP Substrate (Millipore) and scanned using an Ez-Capture MG imaging system (ATTO, Japan). Western blotting data was quantified by film density measurement scans using Macintosh computer software “CS Analyzer” (ATTO, Japan). In this case, the concentration of each gene band was normalized by the concentration of ⁇ -actin band as a control.
- COX-2 transcriptional activity of rat nucleus pulposus cells after treatment with 50 ng / mL recombinant mouse IL-17A for 24 hours was measured by a promoter assay according to the following procedure. Rat nucleus pulposus cells were transferred to 96-well plates (8 ⁇ 10 3 cells / well) 24 hours prior to transfection. PhPES2-1432 / + 59, a plasmid containing the COX-2 promoter and luciferase construct (kindly received from Dr.
- 50 ng / ml recombinant mouse IL-17A and 0.5 ⁇ g / ml anti-IL-17A antibody as its neutralizing antibody # DDX0336P-50 (Novus, human and mouse IL-17A specific) and the procedure similar to [Reference Example 2] except that a group for administering a solution prepared by reacting for 1 hour was prepared.
- Quantifying the expression levels of IL-6, COX-2, mPGES1, MMP-3 and MMP-13 mRNA quantifying the expression levels of IL-6 and COX-2 proteins, and the transcriptional activity of COX-2. It was measured.
- Results are shown in FIG. 39 [A], [B] and [C], respectively.
- [A] IL-6, COX-2, mPGES1, MMP-3, and MMP-13 mRNA expression levels were all in the anti-IL-17A neutralizing antibody combination group and in the IL-17A single administration group (“IL-17A” is “+” and “anti-IL-17A” is “ ⁇ ”).
- [B] it is recognized that the expression levels of IL-6 and COX-2 proteins are also significantly decreased in the anti-IL-17A neutralizing antibody combination group than in the IL-17A alone administration group.
- [C] it is recognized that the transcriptional activity of COX-2 is also significantly decreased in the anti-IL-17A neutralizing antibody combination group than in the IL-17A alone administration group. From these results, it was confirmed that the anti-IL-17A neutralizing antibody inhibits the enhancing action of IL-17A on the expression level of each of the above genes.
- Results are shown in FIG. 40 [A], [B] and [C], respectively.
- [A] the IL-6 administration group showed a significant increase in the expression levels of COX-2, MMP-3 and MMP-13 mRNA than the untreated group, but the expression level of IL-17A mRNA. There was no significant change.
- [B] it was also observed that the expression level of COX-2 protein was significantly increased in the IL-6 administration group than in the untreated group.
- From [C] it was also recognized that COX-2 transcriptional activity was significantly improved in the IL-6 administration group than in the untreated group.
- Example 1 Evaluation of the compound of the present invention as an IL-17A activity inhibitor in rat nucleus pulposus (NP) cells
- 50 ng / ml recombinant mouse IL-17A and 50 ⁇ g / ml compound (3) (STK630921) Except that a group for administering a solution prepared by mixing any of compound (2) (PB203263256), compound (5) (Z9215) or compound (11) (P2000N-53454) is administered [Reference In the same manner as in Example 2], in other words, instead of anti-IL-17A antibody at a concentration of 0.5 ⁇ g / ml, compound (3), (2), (5), (11) at a concentration of 50 ⁇ g / ml (A) IL-6, COX-2, mPGES1, MMP-3 by the same procedure as in the “anti-IL-17A neutralizing antibody combination group” in [Reference Example 3] except that any one of the above was used.
- the expression level of IL-6 mRNA was quantified in the same manner as described above.
- the group of IL-17A and compound (9) were used in combination.
- the expression level was significantly decreased compared to the group administered with IL-17A alone (* p ⁇ 0.05, not shown), and compound (11) was also similar to the other compounds of the present invention.
- IL-17A has an action of inhibiting the enhancing action on the expression level of each of the above genes.
- Example 2 Evaluation of the compound of the present invention as an IL-17A activity inhibitor in human nucleus pulposus (NP) cells
- the sample was changed from rat NP cells to human NP cells (obtained in [Reference Example 1]). Except that Compound 1 (STK) was used as a compound of the present invention at two concentrations of 50 ⁇ g / ml and 100 ⁇ g / ml, and the procedures similar to those in [Example 1] were followed to obtain IL-6 and COX- 2 mRNA expression levels were quantified.
- STK Compound 1
- IL-6 mRNA expression in human NP cells showed a tendency to decrease after administration of STK 50 ⁇ g / ml for 24 hours, and administration of STK 100 ⁇ g / ml showed a significant decrease compared to the group administered with IL-17A alone.
- the COX-2 mRNA expression did not show a clear inhibitory effect 24 hours after administration of STK 50 ⁇ g / ml or 100 ⁇ g / ml, but a significant decrease was observed 36 hours after administration of 50 ⁇ g / ml.
- Example 3 Verification of the effects of IL-17A and the compound of the present invention on the MAPK pathway It has been reported that IL-17A may be involved in COX-2 expression via the MAPK pathway. Evaluation of the involvement of MAPK factors (p38, JNK and ERK) in the expression of IL-17A, COX-2, and IL-6 and the effect of the compound (1) of the present invention on those MAPK factors by the following methods did.
- rat NP cells In rat NP cells, together with recombinant mouse IL-17A at a concentration of 50 ng / ml, p38 phosphorylation inhibitor “SB203580”, JNK phosphorylation inhibitor “SP600125”, or ERK phosphorylation inhibitor “PD98059” at a concentration of 10 ⁇ M, respectively. Or cultured for 24 hours under 1% oxygen condition without administration of these inhibitors, and in the same manner as in [Reference Example 2], COX-2 and IL-6 were analyzed by real-time RT-PCR. The amount of mRNA expression was quantified.
- Results are shown in FIGS. 43 [A] and [B]. Significant suppression of COX-2 mRNA expression level in each of the SB, SP, and PD administration groups and significant suppression of IL-6 mRNA expression level in the SB and PD administration groups were observed. These results indicate that COX-2 expression by IL-17A may be associated with p38, JNK and ERK activation, and IL-6 expression may involve p38 and ERK activation. It was done.
- the rat NP cells were then incubated with IL-17A at a concentration of 50 ng / ml with or without 50 ⁇ g / ml compound (1) and incubated for 15 or 30 minutes under 1% oxygen conditions. Thereafter, the expression levels of phosphorylated p38, p38, phosphorylated JNK, JNK, phosphorylated ERK, and ERK proteins were quantified by Western blotting in the same manner as in [Reference Example 2].
- Results are shown in FIG. 43 [C], [D], [E] and [F].
- the phosphorylation of p38 decreased 15 minutes after administration of compound (1) (C, E), and 30 minutes after administration, a significant decrease was observed compared to the group administered with IL-17A alone (D, F).
- IL-17A promotes phosphorylation (activation) of p38 and ERK in the MAPK pathway, and administration of compound (1) affects at least the suppression of p38 activation by IL-17A, resulting in COX -2 and IL-6 may be involved in the suppression of expression.
- Results are shown in FIGS. 44 [A] and [B].
- the action of inhibiting the activity of IL-17A and lowering the expression level of COX-2 mRNA in rat NP cells was not observed for the compound of Non-patent Document 3, and the action of the compound of the present invention (1) was shown to be superior.
- Example 4 Confirmation of therapeutic effect of a drug containing the compound of the present invention using a mouse psoriasis skin model
- the back of a 10-week-old male BJ6J mouse was shaved approximately 1 ⁇ 1.5 cm, and imiquimod (IMQ Mice were applied daily from day 1 to day 4 with a drug that caused psoriasis-like dermatitis.
- IMQ Mice were applied daily from day 1 to day 4 with a drug that caused psoriasis-like dermatitis.
- HE hematoxylin-eosin
- FIGS. 47 and 48 The results regarding the thickness of the skin layer and the expression of CXCL1 are shown in FIGS. 47 and 48, respectively.
- STK group compound (3) treatment group
- p ⁇ 0.05 A significant reduction (p ⁇ 0.05) in the expression of CXCL1, which is one of the factors causing the disease, that is, a therapeutic effect on psoriasis was observed.
- each specimen section was immunostained with anti-IL-6 antibody.
- the number of IL-6 positive cells in a spot of the same area arbitrarily set at 3 to 4 in the disc tissue is measured in the same magnification field of view, and the total number of cells in the same spot is measured.
- the expression rate of IL-6 positive cells was calculated.
- results are shown in FIG. In the STK group (compound (3) treatment group), a significant decrease in the expression rate of IL-6 positive cells (p ⁇ 0.05), that is, a therapeutic effect on disc degeneration was observed.
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Abstract
Description
[項1]
ヒトのインターロイキン17受容体A(IL-17RA)の細胞外ドメインに含まれる、Phe60、Gln87、Asp121、Pro122、Asp123、Gln124、Asp153、Cys154、Glu155、Lys160、Pro164、Cys165、Ser167、Ser168、Gly169、Ser170、Leu171、Trp172、Asp173、Pro174、Pro254、Phe256、Ser258、Cys259、Asp262、Cys263、Leu264およびHis266によって囲まれる空間において、それらのアミノ酸残基のうちの少なくとも13個との間で働くファンデルワールス力を含む非共有結合的な相互作用によってIL-17RAと結合することができる、またはヒト以外の動物のIL-17RAの細胞外ドメインに含まれる上記28個のアミノ酸残基に相当するアミノ酸残基(ただし、それらのアミノ酸残基の相同性は80%以上であるものとする。)によって囲まれる空間において、それらのアミノ酸残基のうちの少なくとも13個との間で働くファンデルワールス力を含む非共有結合的な相互作用によってIL-17RAと結合することができる、ヒトまたはヒト以外の動物のIL-17RAへのインターロイキン-17A(IL-17A)の結合を阻害する作用を有する化合物、あるいはその製薬上許容される塩、溶媒和物またはプロドラッグを含有する、IL-17A活性阻害剤。
[項2]
前記非共有結合的な相互作用が、前記化合物と、Asp121、Pro122、Asp123、Gln124、Asp153、Cys154、Glu155、Lys160、Ser168、Ser170、Ser258、Asp262、Leu264およびHis266からなる群より選ばれる少なくとも1つのアミノ酸残基との間で働く、イオン結合、水素結合、CH-π相互作用、カチオン-π相互作用および疎水性相互作用からなる群より選ばれる少なくとも1種の分子間相互作用を含む、項1に記載のIL-17A活性阻害剤。
[項3]
前記分子間相互作用が、少なくとも、Cys154との間で水素結合またはCH-π相互作用を含む、項2に記載の載のIL-17A活性阻害剤。
[項4]
前記分子間相互作用が、Asp121との間の水素結合、Pro122との間のCH-π相互作用および水素結合、Asp123との間のCH-π相互作用および水素結合、Lys160との間のイオン結合、水素結合およびCH-π相互作用、ならびにSer170との間のCH-π相互作用からなる群より選ばれる少なくとも1つを有していてもよい、項2または3に記載のIL-17A活性阻害剤。
一般式(I)で表される化合物(以下「化合物(I)」という。)、あるいはその製薬上許容される塩、溶媒和物またはプロドラッグを含有する、IL-17A活性阻害剤。
Aは、(A1)置換されていてもよいC3-10シクロアルキル基、(A2)置換されていてもよいC3-10シクロアルケニル基、(A3)置換されていてもよい6~14員芳香族炭化水素環基(アリール基)、(A4)置換されていてもよい5~14員芳香族複素環基、(A5)置換されていてもよい3~14員非芳香族複素環基、または(A6)置換されていてもよいC4-6アルキル基を表し、
L1は、(L11)単結合、(L12)カルバモイル基から誘導される2価の基(アミド結合)と連結していてもよい、および/またはエーテル結合もしくはチオエーテル結合と連結していてもよい、C1-3アルキレン基、(L13)アミノ基から誘導される2価の基と連結していてもよい、カルバモイル基から誘導される2価の基(アミド結合)、(L14)スルホニル基、または(L15)C1-3アルケニレン基(炭素-炭素二重結合はL2に隣接するBまたはCの炭素原子との間で形成されていてもよい。)を表し、
Bは、(B1)置換されていてもよい、および/またはC1-3アルキル-カルボニル基から誘導される2価の基と連結していてもよい、カルバモイル基から誘導される2価の基(アミド結合)、(B2)置換されていてもよい5~14員芳香族複素環から誘導される2価の基、(B3)置換されていてもよい3~14員非芳香族複素環から誘導される2価の基、(B4)置換されていてもよいC3-10シクロアルキル基、(B5)置換されていてもよいC3-10シクロアルケニル基、(B6)置換されていてもよい6~14員芳香族炭化水素環基(アリール基)、(B7)エステル結合もしくはチオエステル結合、または(B8)ケト基もしくはチオケト基を表し、
L2は、(L21)単結合、(L22)C1-6アルキレン基、または(L23)C1-3アルケニレン基(炭素-炭素二重結合はL2に隣接するBまたはCの炭素原子との間で形成されていてもよい。)を表し、
Cは、(C1)N置換されていてもよいカルバモイル基から誘導される2価の基(アミド結合)、(C2)置換されていてもよい5~14員芳香族複素環から誘導される2価の基、(C3)置換されていてもよい3~14員非芳香族複素環から誘導される2価の基、(C4)置換されていてもよいC3-10シクロアルキル基、(C5)置換されていてもよいC3-10シクロアルケニル基、(C6)置換されていてもよい6~14員芳香族炭化水素環基(アリール基)、または(C7)エステル結合もしくはチオエステル結合を表し、
L3は、(L31)単結合、(L32)カルバモイル基から誘導される2価の基(アミド結合)および/またはイミノ基から誘導される2価の基と連結していてもよい、および/または置換されていてもよい、C1-3アルキレン基、(L33)C1-3アルケニレン基と連結していてもよい、エーテル結合もしくはチオエーテル結合、または(L34)アミノ基から誘導される2価の基と連結していてもよい、カルバモイル基から誘導される2価の基(アミド結合)を表し、
Dは、(D1)置換されていてもよいC3-10シクロアルキル基、(D2)置換されていてもよいC3-10シクロアルケニル基、(D3)置換されていてもよい6~14員芳香族炭化水素環基(アリール基)、(D4)置換されていてもよい5~14員芳香族複素環基、(D5)置換されていてもよい3~14員非芳香族複素環基、または(D6)置換されていてもよいC1-3アルキル基を表す。
[項6]
項1~4のいずれか一項に記載の要件をさらに満たす、項5に記載のIL-17A活性阻害剤。
[項7]
前記化合物(I)が、前記Cys154との間で水素結合またはCH-π相互作用が生じる部位として、
水素原子のドナーまたはアクセプターとなる基を有する前記(A6)である前記部位A;
水素原子のドナーまたはアクセプターとなる基を有する、前記(B1)または(B3)である前記部位B;
水素原子のドナーまたはアクセプターとなる基を有する、前記(C1)、(C2)、(C3)、(C6)または(C7)である前記部位C;
水素原子のドナーまたはアクセプターとなる基を有する(そのような基を置換基として有していてもよい)前記(L12)または(L14)である部位L1;
水素原子のドナーまたはアクセプターとなる基を有する(そのような基を置換基として有していてもよい)前記(L22)である部位L2;あるいは
π電子を有する、前記(C2)または(C6)である前記部位C、
の少なくとも1つを有する、項5または6に記載のIL-17A活性阻害剤。
[項8]
前記化合物(I)が、前記Asp121との間で水素結合が生じる部位として、前記(A3)、(A4)もしくは(A6)である前記部位A、または前記(L12)である前記部位L1を、少なくとも1つ有する、項5または6に記載のIL-17A活性阻害剤。
[項9]
前記化合物(I)が、前記Pro122との間でCH-π相互作用または水素結合が生じる部位として、前記(A4)もしくは(A5)である前記部位A、または前記(B3)もしくは(B5)である前記部位Bを、少なくとも1つ有する、項5または6に記載のIL-17A活性阻害剤。
[項10]
前記化合物(I)が、前記Asp123との間でCH-π相互作用または水素結合が生じる部位として、前記(A5)である前記部位A、または前記(C6)もしくは(C8)である前記部位Cを、少なくとも1つ有する、項5または6に記載のIL-17A活性阻害剤。
[項11]
前記化合物(I)が、前記Lys160との間でイオン結合、水素結合またはカチオン-π相互作用が生じる部位として、前記(D1)、(D3)または(D5)である前記部位Dを少なくとも1つ有する、項5または6に記載のIL-17A活性阻害剤。
[項12]
前記化合物(I)が、前記Ser170との間でCH-π相互作用が生じる部位として、前記(D3)または(D5)である前記部位Dを少なくとも1つ有する、項5または6に記載のIL-17A活性阻害剤。
前記化合物(I)が、下記構造式(1)~(36)で表される化合物(以下、それぞれ「化合物(1)~(36)」という。)またはその誘導体のいずれかである、項5~12のいずれか一項に記載のIL-17A活性阻害剤。
前記化合物(I)が、化合物(1)、または化合物(1)の誘導体であって下記[X]、[Y]および[Z]からなる群より選ばれる少なくとも1つの条件を満たすよう元の化合物(1)を改変したものである、項13に記載のIL-17A活性阻害剤:
[X]前記化合物(1)よりも、Asp121、Pro122、Gln124、Cys154、Glu155、Lys160、Pro164、Ser168、Gly169、Ser170、Ser258、Cys259、Asp262、Cys263およびLeu264との間の総和のファンデルワールス力が増強されたものである;
[Y]前記化合物(1)が有する、Pro122とのCH-π相互作用、Cys154との水素結合またはLys160とのイオン結合の少なくとも1個が増強される部位、あるいはこれらとは異なる少なくとも1個のファンデルワールス力以外の非共有結合的な相互作用を、Asp121、Pro122、Gln124、Cys154、Glu155、Lys160、Pro164、Ser168、Gly169、Ser170、Ser258、Cys259、Asp262、Cys263およびLeu264からなる群より選ばれる少なくとも1つのアミノ酸残基との間で生じる部位を有する;
[Z]前記化合物(1)よりも、Asp121、Pro122、Gln124、Cys154、Glu155、Lys160、Pro164、Ser168、Gly169、Ser170、Ser258、Cys259、Asp262、Cys263およびLeu264からなる群より選ばれる少なくとも1つのアミノ酸残基の溶媒側への露出を減少させる部位を有する。
[項15]
前記化合物(I)が、化合物(2)、または化合物(2)の誘導体であって下記[X]、[Y]および[Z]からなる群より選ばれる少なくとも1つの条件を満たすよう元の化合物(2)を改変したものである、項13に記載のIL-17A活性阻害剤:
[X]前記化合物(2)よりも、Asp121、Pro122、Asp123、Gln124、Asp153、Cys154、Glu155、Pro164、Ser168、Gly169、Ser170、Trp172、Pro254、Phe256、Ser258、Cys259、Asp262、Leu264およびHis266との間の総和のファンデルワールス力が増強されたものである;
[Y]前記化合物(2)が有する、Asp123とのCH-π相互作用、Cys154との水素結合またはSer170とのCH-π相互作用の少なくとも1個が増強される部位、あるいはこれらとは異なる少なくとも1個のファンデルワールス力以外の非共有結合的な相互作用を、Asp121、Pro122、Asp123、Gln124、Asp153、Cys154、Glu155、Pro164、Ser168、Gly169、Ser170、Trp172、Pro254、Phe256、Ser258、Cys259、Asp262、Leu264およびHis266からなる群より選ばれる少なくとも1つのアミノ酸残基との間で生じる部位を有する;
[Z]前記化合物(2)よりも、Asp121、Pro122、Asp123、Gln124、Asp153、Cys154、Glu155、Pro164、Ser168、Gly169、Ser170、Trp172、Pro254、Phe256、Ser258、Cys259、Asp262、Leu264およびHis266からなる群より選ばれる少なくとも1つのアミノ酸残基の溶媒側への露出を減少させる部位を有する。
[項16]
前記化合物(I)が、化合物(5)、または化合物(5)の誘導体であって下記[X]、[Y]および[Z]からなる群より選ばれる少なくとも1つの条件を満たすよう元の化合物(5)を改変したものである、項13に記載のIL-17A活性阻害剤:
[X]前記化合物(5)よりも、Asp121、Pro122、Asp123、Asp153、Cys154、Glu155、Lys160、Pro164、Ser168、Gly169、Ser170、Trp172、Ser258、Cys259、Asp262、Cys263、Leu264およびHis266との間の総和のファンデルワールス力が増強されたものである;
[Y]前記化合物(5)が有する、Cys154との水素結合またはLys160との水素結合の少なくとも1個が増強される部位、あるいはこれらとは異なる少なくとも1個のファンデルワールス力以外の非共有結合的な相互作用を、Asp121、Pro122、Asp123、Asp153、Cys154、Glu155、Lys160、Pro164、Ser168、Gly169、Ser170、Trp172、Ser258、Cys259、Asp262、Cys263、Leu264およびHis266からなる群より選ばれる少なくとも1つのアミノ酸残基との間で生じる部位を有する;
[Z]前記化合物(5)よりも、Asp121、Pro122、Asp123、Asp153、Cys154、Glu155、Lys160、Pro164、Ser168、Gly169、Ser170、Trp172、Ser258、Cys259、Asp262、Cys263、Leu264およびHis266からなる群より選ばれる少なくとも1つのアミノ酸残基の溶媒側への露出を減少させる部位を有する。
[項17]
前記化合物(I)が、化合物(9)、または化合物(9)の誘導体であって下記[X]、[Y]および[Z]からなる群より選ばれる少なくとも1つの条件を満たすよう元の化合物(9)を改変したものである、項13に記載のIL-17A活性阻害剤:
[X]前記化合物(9)よりも、Asp121、Pro122、Asp123、Asp153、Cys154、Glu155、Lys160、Pro164、Ser167、Ser168、Gly169、Ser170、Trp172、Ser258、Cys259、Asp262、Leu264およびHis266との間の総和のファンデルワールス力が増強されたものである;
[Y]前記化合物(9)が有する、Asp121とのCH-π相互作用、Cys154との水素結合またはSer170とのCH-π相互作用の少なくとも1個が増強される部位、あるいはこれらとは異なる少なくとも1個のファンデルワールス力以外の非共有結合的な相互作用を、Asp121、Pro122、Asp123、Asp153、Cys154、Glu155、Lys160、Pro164、Ser167、Ser168、Gly169、Ser170、Trp172、Ser258、Cys259、Asp262、Leu264およびHis266からなる群より選ばれる少なくとも1つのアミノ酸残基との間で生じる部位を有する;
[Z]前記化合物(9)よりも、Asp121、Pro122、Asp123、Asp153、Cys154、Glu155、Lys160、Pro164、Ser167、Ser168、Gly169、Ser170、Trp172、Ser258、Cys259、Asp262、Leu264およびHis266からなる群より選ばれる少なくとも1つのアミノ酸残基の溶媒側への露出を減少させる部位を有する。
[項18]
前記化合物(I)が、化合物(11)、または化合物(11)の誘導体であって下記[X]、[Y]および[Z]からなる群より選ばれる少なくとも1つの条件を満たすよう元の化合物(11)を改変したものである、項13に記載のIL-17A活性阻害剤:
[X]前記化合物(11)よりも、Asp121、Pro122、Gln124、Asp153、Cys154、Glu155、Pro164、Cys165、Ser168、Gly169、Ser170、Trp172、Ser258、Cys259、Asp262、Leu264およびHis266との間の総和のファンデルワールス力が増強されたものである;
[Y]前記化合物(11)が有する、Cys154とのCH-π相互作用または水素結合の少なくとも1個が増強される部位、あるいはこれらとは異なる少なくとも1個のファンデルワールス力以外の非共有結合的な相互作用を、Asp121、Pro122、Gln124、Asp153、Cys154、Glu155、Pro164、Cys165、Ser168、Gly169、Ser170、Trp172、Ser258、Cys259、Asp262、Leu264およびHis266からなる群より選ばれる少なくとも1つのアミノ酸残基との間で生じる部位を有する;
[Z]前記化合物(11)よりも、Asp121、Pro122、Gln124、Asp153、Cys154、Glu155、Pro164、Cys165、Ser168、Gly169、Ser170、Trp172、Ser258、Cys259、Asp262、Leu264およびHis266からなる群より選ばれる少なくとも1つのアミノ酸残基の溶媒側への露出を減少させる部位を有する。
項1~18のいずれか一項に記載のIL-17A活性阻害剤を含有し、IL-17RAを発現する細胞において、IL-17RAへのIL-17Aの結合により発現量が変化する遺伝子の発現量を調節するための、発現調節剤。
[項20]
前記遺伝子が、IL-17AのIL-17RAへの結合により発現が亢進する遺伝子であり、その発現を抑制するためのものである、項19に記載の発現調節剤。
[項21]
前記遺伝子が、IL-6、COX-2、mPGES1、MMP-3、MMP-13およびCXCL1からなる群より選ばれる少なくとも1つである、項20に記載の発現調節剤。
[項22]
前記遺伝子が、p38のリン酸化により発現が亢進する遺伝子であり、その発現を抑制するためのものである、項20に記載の発現調節剤。
[項23]
前記IL-17RAを発現する細胞が椎間板髄核細胞である、項19~22のいずれか一項に記載の発現調節剤。
[項24]
前記椎間板髄核細胞が、低酸素条件下で培養されている椎間板髄核細胞、または椎間板組織内に存在する椎間板髄核細胞である、項23に記載の発現調節剤。
[項25]
前記IL-17RAを発現する細胞が角化細胞またはその他の表皮の細胞である、項19~24のいずれか一項に記載の発現調節剤。
項1~18のいずれか一項に記載のIL-17A活性阻害剤、または項19~25のいずれか一項に記載の発現調節剤を有効成分として含有する、IL-17AのIL-17RAへの結合が症状と関連する疾患の治療または予防のための医薬。
[項27]
前記IL-17AのIL-17RAへの結合が症状と関連する疾患が、腰部または頚部の椎間板症、椎間板ヘルニア、脊椎分離症・すべり症、腰部脊柱管狭窄症、腰椎変性すべり症、または腰椎変性側弯症である、項26に記載の医薬。
[項28]
前記IL-17AのIL-17RAへの結合が症状と関連する疾患が、尋常性乾癬、関節症性乾癬、膿疱性乾癬、または乾癬性紅皮症である、項26に記載の医薬。
ヒトのIL-17RAの細胞外ドメインに含まれる、Phe60、Gln87、Asp121、Pro122、Asp123、Gln124、Asp153、Cys154、Glu155、Lys160、Pro164、Cys165、Ser167、Ser168、Gly169、Ser170、Leu171、Trp172、Asp173、Pro174、Pro254、Phe256、Ser258、Cys259、Asp262、Cys263、Leu264およびHis266によって囲まれる空間の立体分子モデル、またはヒト以外の動物のIL-17RAの細胞外ドメインに含まれる上記28個のアミノ酸残基に相当するアミノ酸残基(ただし、それらのアミノ酸残基の相同性は80%以上であるものとする。)によって囲まれる空間の立体分子モデルと、候補化合物の立体分子モデルとから、
前記アミノ酸残基のうちの少なくとも13個が有する原子または原子団と、前記候補化合物が有する原子または原子団との間で生じるファンデルワールス力を含む非共有結合的な相互作用によって、候補化合物とIL-17RAとの結合安定性を評価し、
前記候補化合物が、IL-17Aと競合的にIL-17RAと結合することにより、IL-17RAへのIL-17Aの結合を阻害する作用を有するか否かを推定する工程を含む、IL-17A活性阻害剤のスクリーニング方法。
[項30]
さらに、前記候補化合物の結合安定性と、前記化合物(1)~(36)の結合安定性とを対比する工程を含む、項29に記載のスクリーニング方法。
ヒトおよびその他の動物の生体外において、項1~16のいずれか一項に記載のIL-17A活性阻害剤とIL-17RAとを接触させる工程を含む、IL-17RAへのIL-17Aの結合阻害方法。
[項32]
ヒトおよびその他の動物の生体外において、項17~22のいずれか一項に記載の発現調節剤と、IL-17RAを発現している細胞とを接触させる工程を含む、IL-17RAへのIL-17Aの結合により発現量が変化する遺伝子の発現調節方法。
チオフェン、フラン、ピロール、イミダゾール、ピラゾール、チアゾール、イソチアゾール、オキサゾール、イソオキサゾール、ピリジン、ピラジン、ピリミジン、ピリダジン、1,2,4-オキサジアゾール、1,3,4-オキサジアゾール、1,2,4-チアジアゾール、1,3,4-チアジアゾール、トリアゾール、テトラゾール、トリアジンなどの5または6員単環式芳香族複素環;
ベンゾチオフェン、ベンゾフラン、ベンゾイミダゾール、ベンゾオキサゾール、ベンゾイソオキサゾール、ベンゾチアゾール、ベンゾイソチアゾール、ベンゾトリアゾール、イミダゾピリジン、チエノピリジン、フロピリジン、ピロロピリジン、ピラゾロピリジン、オキサゾロピリジン、チアゾロピリジン、イミダゾピラジン、イミダゾピリミジン、チエノピリミジン、フロピリミジン、ピロロピリミジン、ピラゾロピリミジン、オキサゾロピリミジン、チアゾロピリミジン、ピラゾロピリミジン、ピラゾロトリアジン、ナフト[2,3-b]チオフェン、フェノキサチイン、インド-ル、イソインドール、1H-インダゾール、プリン、イソキノリン、キノリン、フタラジン、ナフチリジン、キノキサリン、キナゾリン、シンノリン、カルバゾール、β-カルボリン、フェナントリジン、アクリジン、フェナジン、フェノチアジン、フェノキサジンなどの8~14員縮合多環式(好ましくは2または3環式)芳香族複素環。
アジリジン、オキシラン、チイラン、アゼチジン、オキセタン、チエタン、テトラヒドロチオフェン、テトラヒドロフラン、ピロリン、ピロリジン、イミダゾリン、イミダゾリジン、オキサゾリン、オキサゾリジン、ピラゾリン、ピラゾリジン、チアゾリン、チアゾリジン、テトラヒドロイソチアゾール、テトラヒドロオキサゾール、テトラヒドロイソオキサゾール、ピペリジン、ピペラジン、テトラヒドロピリジン、ジヒドロピリジン、ジヒドロチオピラン、テトラヒドロピリミジン、テトラヒドロピリダジン、ジヒドロピラン、テトラヒドロピラン、テトラヒドロチオピラン、モルホリン、チオモルホリン、アゼパニン、ジアゼパン、アゼピン、アゾカン、ジアゾカン、オキセパンなどの3~8員単環式非芳香族複素環;
ジヒドロベンゾフラン、ジヒドロベンゾイミダゾール、ジヒドロベンゾオキサゾール、ジヒドロベンゾチアゾール、ジヒドロベンゾイソチアゾール、ジヒドロナフト[2,3-b]チオフェン、テトラヒドロイソキノリン、テトラヒドロキノリン、4H-キノリジン、インドリン、イソインドリン、テトラヒドロチエノ[2,3-c]ピリジン、テトラヒドロベンゾアゼピン、テトラヒドロキノキサリン、テトラヒドロフェナントリジン、ヘキサヒドロフェノチアジン、ヘキサヒドロフェノキサジン、テトラヒドロフタラジン、テトラヒドロナフチリジン、テトラヒドロキナゾリン、テトラヒドロシンノリン、テトラヒドロカルバゾール、テトラヒドロ-β-カルボリン、テトラヒドロアクリジン、テトラヒドロフェナジン、テトラヒドロチオキサンテン、オクタヒドロイソキノリンなどの9~14員縮合多環式(好ましくは2または3環式)非芳香族複素環。
[置換基群A]
(1)ハロゲン原子;
(2)ニトロ基;
(3)シアノ基;
(4)オキソ基;
(5)ヒドロキシ基;
(6)ハロゲン化されていてもよいC1-6アルコキシ基;
(7)C6-14アリールオキシ基(例、フェノキシ、ナフトキシ);
(8)C7-16アラルキルオキシ基(例、ベンジルオキシ);
(9)5~14員芳香族複素環オキシ基(例、ピリジルオキシ);
(10)3~14員非芳香族複素環オキシ基(例、モルホリニルオキシ、ピペリジニルオキシ);
(11)C1-6アルキル-カルボニルオキシ基(例、アセトキシ、プロパノイルオキシ)、C1-6アルキル-チオカルボニルオキシ基(例、チオアセトキシ、チオプロパノイルオキシ);
(12)C6-14アリール-カルボニルオキシ基(例、ベンゾイルオキシ、1-ナフトイルオキシ、2-ナフトイルオキシ);
(13)C1-6アルコキシ-カルボニルオキシ基(例、メトキシカルボニルオキシ、エトキシカルボニルオキシ、プロポキシカルボニルオキシ、ブトキシカルボニルオキシ);
(14)モノ-またはジ-C1-6アルキル-カルバモイルオキシ基(例、メチルカルバモイルオキシ、エチルカルバモイルオキシ、ジメチルカルバモイルオキシ、ジエチルカルバモイルオキシ);
(15)C6-14アリール-カルバモイルオキシ基(例、フェニルカルバモイルオキシ、ナフチルカルバモイルオキシ);
(16)5~14員芳香族複素環カルボニルオキシ基(例、ニコチノイルオキシ);
(17)3~14員非芳香族複素環カルボニルオキシ基(例、モルホリニルカルボニルオキシ、ピペリジニルカルボニルオキシ);
(18)ハロゲン化されていてもよいC1-6アルキルスルホニルオキシ基(例、メチルスルホニルオキシ、トリフルオロメチルスルホニルオキシ);
(19)C1-6アルキル基で置換されていてもよいC6-14アリールスルホニルオキシ基(例、フェニルスルホニルオキシ、トルエンスルホニルオキシ);
(20)ハロゲン化されていてもよいC1-6アルキルチオ基;
(21)置換されていてもよい5~14員芳香族複素環基;
(22)置換されていてもよい3~14員非芳香族複素環基;
(23)ホルミル基;
(24)カルボキシ基、チオカルボキシ基;
(25)ハロゲン化されていてもよいC1-6アルキル-カルボニル基;
(26)C6-14アリール-カルボニル基;
(27)5~14員芳香族複素環カルボニル基;
(28)3~14員非芳香族複素環カルボニル基;
(29)C1-6アルコキシ-カルボニル基;
(30)C6-14アリールオキシ-カルボニル基(例、フェニルオキシカルボニル、1-ナフチルオキシカルボニル、2-ナフチルオキシカルボニル);
(31)C7-16アラルキルオキシ-カルボニル基(例、ベンジルオキシカルボニル、フェネチルオキシカルボニル);
(32)カルバモイル基;
(33)チオカルバモイル基;
(34)モノ-またはジ-C1-6アルキル-カルバモイル基;
(35)C6-14アリール-カルバモイル基(例、フェニルカルバモイル);
(36)5~14員芳香族複素環カルバモイル基(例、ピリジルカルバモイル、チエニルカルバモイル);
(37)3~14員非芳香族複素環カルバモイル基(例、モルホリニルカルバモイル、ピペリジニルカルバモイル);
(38)ハロゲン化されていてもよいC1-6アルキルスルホニル基;
(39)C6-14アリールスルホニル基;
(40)5~14員芳香族複素環スルホニル基(例、ピリジルスルホニル、チエニルスルホニル);
(41)ハロゲン化されていてもよいC1-6アルキルスルフィニル基;
(42)C6-14アリールスルフィニル基(例、フェニルスルフィニル、1-ナフチルスルフィニル、2-ナフチルスルフィニル);
(43)5~14員芳香族複素環スルフィニル基(例、ピリジルスルフィニル、チエニルスルフィニル);
(44)アミノ基、イミノ基;
(45)モノ-またはジ-C1-6アルキルアミノ基(例、メチルアミノ、エチルアミノ、プロピルアミノ、イソプロピルアミノ、ブチルアミノ、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、ジブチルアミノ、N-エチル-N-メチルアミノ);
(46)モノ-またはジ-C6-14アリールアミノ基(例、フェニルアミノ);
(47)5~14員芳香族複素環アミノ基(例、ピリジルアミノ);
(48)C7-16アラルキルアミノ基(例、ベンジルアミノ);
(49)ホルミルアミノ基;
(50)C1-6アルキル-カルボニルアミノ基(例、アセチルアミノ、プロパノイルアミノ、ブタノイルアミノ);
(51)(C1-6アルキル)(C1-6アルキル-カルボニル)アミノ基(例、N-アセチル-N-メチルアミノ);
(52)C6-14アリール-カルボニルアミノ基(例、フェニルカルボニルアミノ、ナフチルカルボニルアミノ);
(53)C1-6アルコキシ-カルボニルアミノ基(例、メトキシカルボニルアミノ、エトキシカルボニルアミノ、プロポキシカルボニルアミノ、ブトキシカルボニルアミノ、tert-ブトキシカルボニルアミノ);
(54)C7-16アラルキルオキシ-カルボニルアミノ基(例、ベンジルオキシカルボニルアミノ);
(55)C1-6アルキルスルホニルアミノ基(例、メチルスルホニルアミノ、エチルスルホニルアミノ);
(56)C1-6アルキル基で置換されていてもよいC6-14アリールスルホニルアミノ基(例、フェニルスルホニルアミノ、トルエンスルホニルアミノ);
(57)ハロゲン化されていてもよいC1-6アルキル基;
(58)C2-6アルケニル基;
(59)C2-6アルキニル基;
(60)C3-10シクロアルキル基;
(61)C3-10シクロアルケニル基;
(62)C6-14アリール基。
本発明の一側面において提供される「IL-17活性阻害剤」は、ヒトのインターロイキン17受容体A(IL-17RA)の細胞外ドメインに含まれる、Phe60、Gln87、Asp121、Pro122、Asp123、Gln124、Asp153、Cys154、Glu155、Lys160、Pro164、Cys165、Ser167、Ser168、Gly169、Ser170、Leu171、Trp172、Asp173、Pro174、Pro254、Phe256、Ser258、Cys259、Asp262、Cys263、Leu264およびHis266(これらの28個のアミノ酸残基を本明細書において「相互作用領域を構成する所定のアミノ酸残基」と総称することがある。)によって囲まれる空間(相互作用領域)において、それらのアミノ酸残基のいくつかとの間に働くファンデルワールス力またはそれ以外の非共有結合的な相互作用によって、インターロイキン17A(IL-17A)とは競合的にIL-17RAと結合することにより、IL-17RAへのIL-17Aの結合を阻害する作用を有する化合物(本発明の化合物の第1実施形態)、あるいはその製薬上許容される塩、溶媒和物またはプロドラッグを含有する。
Aは、(A1)置換されていてもよいC3-10シクロアルキル基、(A2)置換されていてもよいC3-10シクロアルケニル基、(A3)置換されていてもよい6~14員芳香族炭化水素環基(アリール基)、(A4)置換されていてもよい5~14員芳香族複素環基、(A5)置換されていてもよい3~14員非芳香族複素環基、または(A6)置換されていてもよいC4-6アルキル基を表す。
水素原子のドナーまたはアクセプターとなる基を有する(そのような基を置換基として有していてもよい)前記(A6)である前記部位A;
水素原子のドナーまたはアクセプターとなる基を有する(そのような基を置換基として有していてもよい)前記(L12)である前記部位L1;
水素原子のドナーまたはアクセプターとなる基を有する(そのような基を置換基として有していてもよい)、前記(B1)または(B3)である前記部位B;
水素原子のドナーまたはアクセプターとなる基を有する(そのような基を置換基として有していてもよい)、前記(C1),(C2),または(C3)、(C6)または(C7)である前記部位C;
水素原子のドナーまたはアクセプターとなる基を有する(そのような基を置換基として有していてもよい)前記(L12)または(L14)である部位L1;
水素原子のドナーまたはアクセプターとなる基を有する(そのような基を置換基として有していてもよい)前記(L22)である部位L2;
水素原子のドナーまたはアクセプターとなる基を有する(そのような基を置換基として有していてもよい)前記(L32)である部位L3;あるいは
π電子を有する(全体として非芳香族性である縮合環のうちの一部の環が有していてもよい)、前記(C2)または(C6)である前記部位C、
の少なくとも1つを有していてもよい。
部位B、C、L1等に含まれる、-NH-の窒素原子(孤立電子対)、-CO-の酸素原子(孤立電子対)、-S-の硫黄原子(孤立電子対)等と、Cys154の側鎖に含まれる-SHの水素原子との間の水素結合(例えば化合物(1)、(2)、(5)、(9)、(11)、(36));
部位B、L1、L3等に含まれる=Oの酸素原子(孤立電子対)と、Cys154の側鎖に含まれる-SHの水素原子との間の水素結合(例えば化合物(7)、(14)、(15)、(24)、(25)、(26)、(31)、(35));
部位Aに含まれる-OHの水素原子と、Cys154のの側鎖に含まれる-SHの硫黄原子(孤立電子対)との間の水素結合(例えば化合物(11));
部位B、L1、L2等に含まれる=CH-、-CH2-、-CH(R)-等の水素原子、またはBに含まれる-NH-の水素原子と、Cys154のの側鎖に含まれる-SHの硫黄原子(孤立電子対)との間の水素結合(例えば化合物(6)、(8)、(10)、(16)、(27)、(35))が挙げられる。
また、化合物(I)とCys154との間で働くCH-π相互作用の具体例としては、
部位Cに含まれる芳香族複素環(C2)または芳香族炭化水素基(C6)のπ電子とCys154の側鎖に含まれる-SHの水素原子との間のCH-π相互作用(例えば化合物(11)、(22)、(23)、(27))が挙げられる。
化合物(I)とCys154との間で働く水素結合またはCH-π相互作用は、上記以外の、図2~36に描かれている分子間相互作用であってもよい。
一般式(I)中の部位A(水酸基で置換されたフタラジン環)を改変することにより、Pro122とのCH-π相互作用の安定性が向上した誘導体;
一般式(I)中の部位Bおよび/またはC(ともにカルバモイル基)を改変することにより、Cys154との水素結合の安定性が向上した誘導体;
一般式(I)中の部位D(カルボキシル基で置換されたシクロヘキシル基)を改変することにより、Lys160とのイオン結合の安定性が向上した誘導体;
その他、一般式(I)中の部位A、L1、B、L2、C、L3およびDを改変することにより、Asp121、Gln124、Glu155、Pro164、Ser168、Gly169、Ser170、Ser258、Cys259、Asp262、Cys263またはLeu264(Pro122、Cys154およびLys160以外のアミノ酸残基)との間で、さらにはそれ以外の相互作用領域を構成する所定のアミノ酸残基との間で、新たな非共有結合的な相互作用を生じるようになった誘導体。
[x]元の化合物よりも、集合Pのアミノ酸残基との間の総和のファンデルワールス力が増強されたものである;
[y]元の化合物が有する、集合Qのアミノ酸残基からなる群より選ばれる少なくとも1つとのファンデルワールス力以外の非共有結合的な相互作用が増強される部位、あるいはそれとは異なる少なくとも1個のファンデルワールス力以外の非共有結合的な相互作用を、集合Pからなる群より選ばれる少なくとも1つのアミノ酸残基との間で生じる部位を有する;
[z]元の化合物よりも、集合Pからなる群より選ばれる少なくとも1つのアミノ酸残基の溶媒側への露出を減少させる部位を有する。
塩基性塩として、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩;カルシウム塩、マグネシウム塩等のアルカリ土類金属塩;アンモニウム塩;トリメチルアミン塩、トリエチルアミン塩、ジシクロヘキシルアミン塩、エタノールアミン塩、ジエタノールアミン塩、トリエタノールアミン塩、ブロカイン塩等の脂肪族アミン塩;N,N-ジベンジルエチレンジアミン等のアラルキルアミン塩;ピリジン塩、ピコリン塩、キノリン塩、イソキノリン塩等のヘテロ環芳香族アミン塩;テトラメチルアンモニウム塩、テトラエチルアモニウム塩、ベンジルトリメチルアンモニウム塩、ベンジルトリエチルアンモニウム塩、ベンジルトリブチルアンモニウム塩、メチルトリオクチルアンモニウム塩、テトラブチルアンモニウム塩等の第4級アンモニウム塩;アルギニン塩、リジン塩等の塩基性アミノ酸塩など;
酸性塩として、例えば、塩酸塩、硫酸塩、硝酸塩、リン酸塩、炭酸塩、炭酸水素塩、過塩素酸塩等の無機酸塩;酢酸塩、プロピオン酸塩、乳酸塩、マレイン酸塩、フマール酸塩、酒石酸塩、リンゴ酸塩、クエン酸塩、アスコルビン酸塩等の有機酸塩;メタンスルホン酸塩、イセチオン酸塩、ベンゼンスルホン酸塩、p-トルエンスルホン酸塩等のスルホン酸塩;アスパラギン酸塩、グルタミン酸塩等の酸性アミノ酸など。
本発明の一側面において提供される「発現調節剤」は、IL-17RAを発現する細胞において、IL-17RAへのIL-17Aの結合により発現量が変化する遺伝子の発現量を調節するための剤であって、上述したような本発明のIL-17A活性阻害剤を含有する。
本発明の一側面において提供される「治療または予防のための医薬」は、上述したような本発明のIL-17A活性阻害剤または本発明の発現抑制剤を有効成分として含有する医薬であって、「IL-17AのIL-17RAへの結合が症状と関連する疾患」を治療または予防するためのものである。
本発明の一側面において提供される「IL-17A活性阻害剤のスクリーニング方法」は、IL-17RAの細胞外ドメインに含まれる、Phe60、Gln87、Asp121、Pro122、Asp123、Gln124、Asp153、Cys154、Glu155、Lys160、Pro164、Cys165、Ser167、Ser168、Gly169、Ser170、Leu171、Trp172、Asp173、Pro174、Pro254、Phe256、Ser258、Cys259、Asp262、Cys263、Leu264およびHis266によって囲まれる空間の立体分子モデルと、候補化合物の立体分子モデルとから、前記アミノ酸残基のうちの少なくとも13個が有する原子または原子団と、前記候補化合物が有する原子または原子団との間で生じるファンデルワールス力を含む非共有結合的な相互作用によって、候補化合物とIL-17RAとの結合安定性を評価し、前記候補化合物が、IL-17Aと競合的にIL-17RAと結合することにより、IL-17RAへのIL-17Aの結合を阻害する作用を有するか否かを推定する工程を含む。
本発明の一側面において提供される「結合阻害方法」は、IL-17RAへのIL-17Aの結合を阻害するためのものであって、前述したような本発明のIL-17A活性阻害剤とIL-17RAとを接触させる工程を含む。
本発明の一側面において提供される「発現調節方法」は、IL-17RAへのIL-17Aの結合により発現量が変化する遺伝子の発現を調節するためのものであって、前述したような本発明のIL-17A活性阻害剤と、IL-17RAを発現している細胞とを接触させる工程を含む。
本発明の一側面において提供される「治療方法」は、上述したような本発明のIL-17A活性阻害剤、発現調節剤または医薬を、「IL-17AのIL-17RAへの結合が症状と関連する疾患」が発症した対象または発症するおそれがある対象に投与する工程を含む。
患者に対してヘルシンキ宣言に基づくインフォームドコンセントを行った。東海大学医学部の倫理委員会より倫理審査の承認を得た。それぞれ16歳未満の、腰椎椎間板ヘルニアの患者3名および特発性側弯症の患者3名から、椎間板組織を合計10サンプル切除した。切除された椎間板サンプルの変性レベルをMRIのフィルマン(Pfirrmann)分類に従って評価したところ、腰椎椎間板ヘルニア患者から切除したサンプルは変性していた(グレード3、4または5)一方で、特発性側弯症の患者から切除した椎間板サンプルは正常であった(グレード1または2)。
Risbud et al(Journal of cellular biochemistry 98, 152-159, 2006; doi:10.1002/jcb.20765)の方法に従って、11週齢のSprague Dawleyラットから髄核細胞を単離した。簡潔に言えば、無菌条件下で深く麻酔させたラットの腰椎および尾骨の椎間板を解剖し、ゲル状の髄核を椎間板線維輪(AF)から分離した後、細かく刻んでピペッティングし、20%FBSおよび抗生物質を添加したダルベッコ変法イーグル培地(DMEM)で、20%O2、5%CO2、37℃で約1~2週間培養し、その後10%FBSと抗生物質を添加したDMEMで約1~2週間培養した。こうして得られた髄核細胞を、1%O2、5%CO2および94%N2を含有する低酸素チャンバー(MIC-101、Billups Rothenberg Inc.,米国)で15分間~24時間培養した。
あらかじめ、50ng/mlのリコンビナントマウスIL-17Aとその中和抗体として0.5μg/mlの抗IL-17A抗体(#DDX0336P-50、Novus社、ヒトおよびマウスIL-17A特異的)とを混合し1時間反応させて調製した溶液を投与する群を設けるよう変更したこと以外は[参考例2]と同様の手順により、IL-6、COX-2、mPGES1、MMP-3およびMMP-13のmRNAの発現量の定量、IL-6およびCOX-2のタンパク質の発現量の定量、およびCOX-2の転写活性を測定した。
IL-17AによりmRNAの発現量が著明に増加したIL-6を分析対象とし、IL-6がラットNP細胞に与える影響を評価した。ラットNP細胞にIL-6を50ng/ml投与し、1%酸素条件下で24時間培養した後、[参考例2]と同様の手順で、リアルタイムRT-PCRによりCOX-2、IL-17A、MMP-3およびMP-13のmRNAの発現量を定量した。さらに、[参考例2]と同様の手順で、COX-2のタンパク質の発現量の定量、およびCOX-2の転写活性の評価も行った。
あらかじめ、50ng/mlのリコンビナントマウスIL-17Aと50μg/mlの化合物(3)(STK630921)、化合物(2)(PB203263256)、化合物(5)(Z9215)または化合物(11)(P2000N-53454)のいずれかとを混合して調製した溶液を投与する群を設けるよう変更したこと以外は[参考例2]と同様の手順により、換言すれば0.5μg/mlの濃度の抗IL-17A抗体の代わりに50μg/mlの濃度の化合物(3)、(2)、(5)、(11)のいずれかを用いるよう変更したこと以外は[参考例3]の「抗IL-17A中和抗体併用群」と同様の手順により、(A)IL-6、COX-2、mPGES1、MMP-3およびMMP-13のmRNAの発現量の定量、(B)IL-6およびCOX-2のタンパク質の発現量の定量、および(C)COX-2の転写活性の測定を行った。(B)および(C)では、本発明の化合物のうち、下記に述べる(A)の結果のうちIL-6およびCOX-2に対して最も効果が高いと考えられる化合物(3)だけを用いた。
サンプルをラットNP細胞からヒトNP細胞([参考例1]において入手したもの)に変更したこと、および本発明の化合物として化合物1(STK)を50μg/mlおよび100μg/mlの2通りの濃度で用いたこと以外は、[実施例1]と同様の手順により、IL-6およびCOX-2のmRNAの発現量を定量した。
IL-17AはMAPK経路を介してCOX-2発現に関与する可能性が報告されている。IL-17AとCOX-2、IL-6発現に対するMAPK因子(p38、JNKおよびERK)の関与と、本発明の化合物(1)がそれらのMAPK因子に及ぼす影響を、次のような手法で評価した。
あらかじめ、50ng/mlのリコンビナントマウスIL-17Aと50μg/mlの前掲非特許文献3(Liu et al., Science Signaling 2017)の化合物とを混合して1時間反応させて調製した溶液を投与する群(synd群)を設けるよう変更したこと以外は[参考例2]と同様の手順により、COX-2のmRNAの発現量を定量した。また、そのsynd群のCOX-2のmRNAの発現量と、[実施例1]において得られたIL-17+STK群のCOX-2のmRNAの発現量とを対比した。
10週齢の雄のBJ6Jマウスの背部を約1×1.5cm剃毛し、イミキモド(IMQ、マウスに乾癬様の皮膚炎を引き起こす薬物)クリームをday1からday4まで連日塗布した。最初のIMQクリームの塗布から5日目(day5)からは、IMQクリームから6~8時間後に、1mgの化合物(3)(データベース登録名:STK630921)を含むDMSO溶液を塗布した(STK群=化合物(3)処理群)。同様のIMQクリームの塗布および化合物(3)の溶液の塗布を、6日目(day6)から9日目(day9)にかけて毎日行った。対照群として、5日目(day5)から9日目(day9)にかけて、IMQクリームと、1mgの化合物(3)を含むDMSO溶液の代わりに当該溶液の溶媒であるDMSOを同量塗布した群(Sham群);5日目(day5)から9日目(day9)にかけて、IMQクリームのみを塗布した群(IMQ群);および最初のIMQクリームの塗布や、5日目(day5)から9日目(day9)にかけての処置を何もしなかった群(正常群)を設けた。各群のマウスは3匹ずつとした。
11週齢の雄のSDラット(体重300~350g)の尾椎椎間板に、23G針を約5mm刺入し、360°回転させて30秒間留置し、椎間板変性を生じさせた(day0)。椎間板変性から14日後(day14)、1mgの化合物(3)(データベース登録名:STK630921)を含む10μLのDMSO溶液を変性させた椎間板に注射した(STK群=化合物(3)処理群)。対照群として、1mgの化合物(3)を含む10μLのDMSO溶液の代わりに、当該溶液の溶媒であるDMSOのみを同量注射した群(Sham群)、椎間板変性後に何も処置をしなかった群(変性群)、および椎間板変性やその後の処置をしなかった群(正常群)を設けた。
Claims (32)
- ヒトのインターロイキン17受容体A(IL-17RA)の細胞外ドメインに含まれる、Phe60、Gln87、Asp121、Pro122、Asp123、Gln124、Asp153、Cys154、Glu155、Lys160、Pro164、Cys165、Ser167、Ser168、Gly169、Ser170、Leu171、Trp172、Asp173、Pro174、Pro254、Phe256、Ser258、Cys259、Asp262、Cys263、Leu264およびHis266によって囲まれる空間において、それらのアミノ酸残基のうちの少なくとも13個との間で働くファンデルワールス力を含む非共有結合的な相互作用によってIL-17RAと結合することができる、またはヒト以外の動物のIL-17RAの細胞外ドメインに含まれる上記28個のアミノ酸残基に相当するアミノ酸残基(ただし、それらのアミノ酸残基の相同性は80%以上であるものとする。)によって囲まれる空間において、それらのアミノ酸残基のうちの少なくとも13個との間で働くファンデルワールス力を含む非共有結合的な相互作用によってIL-17RAと結合することができる、ヒトまたはヒト以外の動物のIL-17RAへのインターロイキン-17A(IL-17A)の結合を阻害する作用を有する化合物、あるいはその製薬上許容される塩、溶媒和物またはプロドラッグを含有する、IL-17A活性阻害剤。
- 前記非共有結合的な相互作用が、前記化合物と、Asp121、Pro122、Asp123、Gln124、Asp153、Cys154、Glu155、Lys160、Ser168、Ser170、Ser258、Asp262、Leu264およびHis266からなる群より選ばれる少なくとも1つのアミノ酸残基との間で働く、イオン結合、水素結合、CH-π相互作用、カチオン-π相互作用および疎水性相互作用からなる群より選ばれる少なくとも1種の分子間相互作用を含む、請求項1に記載のIL-17A活性阻害剤。
- 前記分子間相互作用が、少なくとも、Cys154との間で水素結合またはCH-π相互作用を含む、請求項2に記載のIL-17A活性阻害剤。
- 前記分子間相互作用が、Asp121との間の水素結合、Pro122との間のCH-π相互作用および水素結合、Asp123との間のCH-π相互作用および水素結合、Lys160との間のイオン結合、水素結合およびCH-π相互作用、ならびにSer170との間のCH-π相互作用からなる群より選ばれる少なくとも1つを有していてもよい、請求項2または3に記載のIL-17A活性阻害剤。
- 一般式(I)で表される化合物(以下「化合物(I)」という。)、あるいはその製薬上許容される塩、溶媒和物またはプロドラッグを含有する、IL-17A活性阻害剤。
Aは、(A1)置換されていてもよいC3-10シクロアルキル基、(A2)置換されていてもよいC3-10シクロアルケニル基、(A3)置換されていてもよい6~14員芳香族炭化水素環基(アリール基)、(A4)置換されていてもよい5~14員芳香族複素環基、(A5)置換されていてもよい3~14員非芳香族複素環基、または(A6)置換されていてもよいC4-6アルキル基を表し、
L1は、(L11)単結合、(L12)カルバモイル基から誘導される2価の基(アミド結合)と連結していてもよい、および/またはエーテル結合もしくはチオエーテル結合と連結していてもよい、C1-3アルキレン基、(L13)アミノ基から誘導される2価の基と連結していてもよい、カルバモイル基から誘導される2価の基(アミド結合)、(L14)スルホニル基、または(L15)C1-3アルケニレン基(炭素-炭素二重結合はL2に隣接するBまたはCの炭素原子との間で形成されていてもよい。)を表し、
Bは、(B1)置換されていてもよい、および/またはC1-3アルキル-カルボニル基から誘導される2価の基と連結していてもよい、カルバモイル基から誘導される2価の基(アミド結合)、(B2)置換されていてもよい5~14員芳香族複素環から誘導される2価の基、(B3)置換されていてもよい3~14員非芳香族複素環から誘導される2価の基、(B4)置換されていてもよいC3-10シクロアルキル基、(B5)置換されていてもよいC3-10シクロアルケニル基、(B6)置換されていてもよい6~14員芳香族炭化水素環基(アリール基)、(B7)エステル結合もしくはチオエステル結合、または(B8)ケト基もしくはチオケト基を表し、
L2は、(L21)単結合、(L22)C1-6アルキレン基、または(L23)C1-3アルケニレン基(炭素-炭素二重結合はL2に隣接するBまたはCの炭素原子との間で形成されていてもよい。)を表し、
Cは、(C1)N置換されていてもよいカルバモイル基から誘導される2価の基(アミド結合)、(C2)置換されていてもよい5~14員芳香族複素環から誘導される2価の基、(C3)置換されていてもよい3~14員非芳香族複素環から誘導される2価の基、(C4)置換されていてもよいC3-10シクロアルキル基、(C5)置換されていてもよいC3-10シクロアルケニル基、(C6)置換されていてもよい6~14員芳香族炭化水素環基(アリール基)、または(C7)エステル結合もしくはチオエステル結合を表し、
L3は、(L31)単結合、(L32)カルバモイル基から誘導される2価の基(アミド結合)および/またはイミノ基から誘導される2価の基と連結していてもよい、および/または置換されていてもよい、C1-3アルキレン基、(L33)C1-3アルケニレン基と連結していてもよい、エーテル結合もしくはチオエーテル結合、または(L34)アミノ基から誘導される2価の基と連結していてもよい、カルバモイル基から誘導される2価の基(アミド結合)を表し、
Dは、(D1)置換されていてもよいC3-10シクロアルキル基、(D2)置換されていてもよいC3-10シクロアルケニル基、(D3)置換されていてもよい6~14員芳香族炭化水素環基(アリール基)、(D4)置換されていてもよい5~14員芳香族複素環基、(D5)置換されていてもよい3~14員非芳香族複素環基、または(D6)置換されていてもよいC1-3アルキル基を表す。 - 請求項1~4のいずれか一項に記載の要件をさらに満たす、請求項5に記載のIL-17A活性阻害剤。
- 前記化合物(I)が、前記Cys154との間で水素結合またはCH-π相互作用が生じる部位として、
水素原子のドナーまたはアクセプターとなる基を有する前記(A6)である前記部位A;
水素原子のドナーまたはアクセプターとなる基を有する、前記(B1)、または(B3)である前記部位B;
水素原子のドナーまたはアクセプターとなる基を有する、前記(C1)、(C2)、(C3)、(C6)または(C7)である前記部位C;
水素原子のドナーまたはアクセプターとなる基を有する(そのような基を置換基として有していてもよい)前記(L12)または(L14)である部位L1;
水素原子のドナーまたはアクセプターとなる基を有する(そのような基を置換基として有していてもよい)前記(L22)である部位L2;あるいは
π電子を有する、前記(C2)または(C6)である前記部位C、
の少なくとも1つを有する、請求項5または6に記載のIL-17A活性阻害剤。 - 前記化合物(I)が、前記Asp121との間で水素結合が生じる部位として、前記(A3)、(A4)もしくは(A6)である前記部位A、または前記(L12)である前記部位L1を、少なくとも1つ有する、請求項5または6に記載のIL-17A活性阻害剤。
- 前記化合物(I)が、前記Pro122との間でCH-π相互作用または水素結合が生じる部位として、前記(A4)もしくは(A5)である前記部位A、または前記(B3)もしくは(B5)である前記部位Bを、少なくとも1つ有する、請求項5または6に記載のIL-17A活性阻害剤。
- 前記化合物(I)が、前記Asp123との間でCH-π相互作用または水素結合が生じる部位として、前記(A5)である前記部位A、または前記(C6)もしくは(C8)である前記部位Cを、少なくとも1つ有する、請求項5または6に記載のIL-17A活性阻害剤。
- 前記化合物(I)が、前記Lys160との間でイオン結合、水素結合またはカチオン-π相互作用が生じる部位として、前記(D1)、(D3)または(D5)である前記部位Dを少なくとも1つ有する、請求項5または6に記載のIL-17A活性阻害剤。
- 前記化合物(I)が、前記Ser170との間でCH-π相互作用が生じる部位として、前記(D3)または(D5)である前記部位Dを少なくとも1つ有する、請求項5または6に記載のIL-17A活性阻害剤。
- 前記化合物(I)が、化合物(1)、または化合物(1)の誘導体であって下記[X]、[Y]および[Z]からなる群より選ばれる少なくとも1つの条件を満たすよう元の化合物(1)を改変したものである、請求項13に記載のIL-17A活性阻害剤:
[X]前記化合物(1)よりも、Asp121、Pro122、Gln124、Cys154、Glu155、Lys160、Pro164、Ser168、Gly169、Ser170、Ser258、Cys259、Asp262、Cys263およびLeu264との間の総和のファンデルワールス力が増強されたものである;
[Y]前記化合物(1)が有する、Pro122とのCH-π相互作用、Cys154との水素結合またはLys160とのイオン結合の少なくとも1個が増強される部位、あるいはこれらとは異なる少なくとも1個のファンデルワールス力以外の非共有結合的な相互作用を、Asp121、Pro122、Gln124、Cys154、Glu155、Lys160、Pro164、Ser168、Gly169、Ser170、Ser258、Cys259、Asp262、Cys263およびLeu264からなる群より選ばれる少なくとも1つのアミノ酸残基との間で生じる部位を有する;
[Z]前記化合物(1)よりも、Asp121、Pro122、Gln124、Cys154、Glu155、Lys160、Pro164、Ser168、Gly169、Ser170、Ser258、Cys259、Asp262、Cys263およびLeu264からなる群より選ばれる少なくとも1つのアミノ酸残基の溶媒側への露出を減少させる部位を有する。 - 前記化合物(I)が、化合物(2)、または化合物(2)の誘導体であって下記[X]、[Y]および[Z]からなる群より選ばれる少なくとも1つの条件を満たすよう元の化合物(2)を改変したものである、請求項13に記載のIL-17A活性阻害剤:
[X]前記化合物(2)よりも、Asp121、Pro122、Asp123、Gln124、Asp153、Cys154、Glu155、Pro164、Ser168、Gly169、Ser170、Trp172、Pro254、Phe256、Ser258、Cys259、Asp262、Leu264およびHis266との間の総和のファンデルワールス力が増強されたものである;
[Y]前記化合物(2)が有する、Asp123とのCH-π相互作用、Cys154との水素結合またはSer170とのCH-π相互作用の少なくとも1個が増強される部位、あるいはこれらとは異なる少なくとも1個のファンデルワールス力以外の非共有結合的な相互作用を、Asp121、Pro122、Asp123、Gln124、Asp153、Cys154、Glu155、Pro164、Ser168、Gly169、Ser170、Trp172、Pro254、Phe256、Ser258、Cys259、Asp262、Leu264およびHis266からなる群より選ばれる少なくとも1つのアミノ酸残基との間で生じる部位を有する;
[Z]前記化合物(2)よりも、Asp121、Pro122、Asp123、Gln124、Asp153、Cys154、Glu155、Pro164、Ser168、Gly169、Ser170、Trp172、Pro254、Phe256、Ser258、Cys259、Asp262、Leu264およびHis266からなる群より選ばれる少なくとも1つのアミノ酸残基の溶媒側への露出を減少させる部位を有する。 - 前記化合物(I)が、化合物(5)、または化合物(5)の誘導体であって下記[X]、[Y]および[Z]からなる群より選ばれる少なくとも1つの条件を満たすよう元の化合物(5)を改変したものである、請求項13に記載のIL-17A活性阻害剤:
[X]前記化合物(5)よりも、Asp121、Pro122、Asp123、Asp153、Cys154、Glu155、Lys160、Pro164、Ser168、Gly169、Ser170、Trp172、Ser258、Cys259、Asp262、Cys263、Leu264およびHis266との間の総和のファンデルワールス力が増強されたものである;
[Y]前記化合物(5)が有する、Cys154との水素結合またはLys160との水素結合の少なくとも1個が増強される部位、あるいはこれらとは異なる少なくとも1個のファンデルワールス力以外の非共有結合的な相互作用を、Asp121、Pro122、Asp123、Asp153、Cys154、Glu155、Lys160、Pro164、Ser168、Gly169、Ser170、Trp172、Ser258、Cys259、Asp262、Cys263、Leu264およびHis266からなる群より選ばれる少なくとも1つのアミノ酸残基との間で生じる部位を有する;
[Z]前記化合物(5)よりも、Asp121、Pro122、Asp123、Asp153、Cys154、Glu155、Lys160、Pro164、Ser168、Gly169、Ser170、Trp172、Ser258、Cys259、Asp262、Cys263、Leu264およびHis266からなる群より選ばれる少なくとも1つのアミノ酸残基の溶媒側への露出を減少させる部位を有する。 - 前記化合物(I)が、化合物(9)、または化合物(9)の誘導体であって下記[X]、[Y]および[Z]からなる群より選ばれる少なくとも1つの条件を満たすよう元の化合物(9)を改変したものである、請求項13に記載のIL-17A活性阻害剤:
[X]前記化合物(9)よりも、Asp121、Pro122、Asp123、Asp153、Cys154、Glu155、Lys160、Pro164、Ser167、Ser168、Gly169、Ser170、Trp172、Ser258、Cys259、Asp262、Leu264およびHis266との間の総和のファンデルワールス力が増強されたものである;
[Y]前記化合物(9)が有する、Asp121とのCH-π相互作用、Cys154との水素結合またはSer170とのCH-π相互作用の少なくとも1個が増強される部位、あるいはこれらとは異なる少なくとも1個のファンデルワールス力以外の非共有結合的な相互作用を、Asp121、Pro122、Asp123、Asp153、Cys154、Glu155、Lys160、Pro164、Ser167、Ser168、Gly169、Ser170、Trp172、Ser258、Cys259、Asp262、Leu264およびHis266からなる群より選ばれる少なくとも1つのアミノ酸残基との間で生じる部位を有する;
[Z]前記化合物(9)よりも、Asp121、Pro122、Asp123、Asp153、Cys154、Glu155、Lys160、Pro164、Ser167、Ser168、Gly169、Ser170、Trp172、Ser258、Cys259、Asp262、Leu264およびHis266からなる群より選ばれる少なくとも1つのアミノ酸残基の溶媒側への露出を減少させる部位を有する。 - 前記化合物(I)が、化合物(11)、または化合物(11)の誘導体であって下記[X]、[Y]および[Z]からなる群より選ばれる少なくとも1つの条件を満たすよう元の化合物(11)を改変したものである、請求項13に記載のIL-17A活性阻害剤:
[X]前記化合物(11)よりも、Asp121、Pro122、Gln124、Asp153、Cys154、Glu155、Pro164、Cys165、Ser168、Gly169、Ser170、Trp172、Ser258、Cys259、Asp262、Leu264およびHis266との間の総和のファンデルワールス力が増強されたものである;
[Y]前記化合物(11)が有する、Cys154とのCH-π相互作用または水素結合の少なくとも1個が増強される部位、あるいはこれらとは異なる少なくとも1個のファンデルワールス力以外の非共有結合的な相互作用を、Asp121、Pro122、Gln124、Asp153、Cys154、Glu155、Pro164、Cys165、Ser168、Gly169、Ser170、Trp172、Ser258、Cys259、Asp262、Leu264およびHis266からなる群より選ばれる少なくとも1つのアミノ酸残基との間で生じる部位を有する;
[Z]前記化合物(11)よりも、Asp121、Pro122、Gln124、Asp153、Cys154、Glu155、Pro164、Cys165、Ser168、Gly169、Ser170、Trp172、Ser258、Cys259、Asp262、Leu264およびHis266からなる群より選ばれる少なくとも1つのアミノ酸残基の溶媒側への露出を減少させる部位を有する。 - 請求項1~18のいずれか一項に記載のIL-17A活性阻害剤を含有し、IL-17RAを発現する細胞において、IL-17RAへのIL-17Aの結合により発現量が変化する遺伝子の発現量を調節するための、発現調節剤。
- 前記遺伝子が、IL-17AのIL-17RAへの結合により発現が亢進する遺伝子であり、その発現を抑制するためのものである、請求項19に記載の発現調節剤。
- 前記遺伝子が、IL-6、COX-2、mPGES1、MMP-3、MMP-13およびCXCL1からなる群より選ばれる少なくとも1つである、請求項20に記載の発現調節剤。
- 前記遺伝子が、p38のリン酸化により発現が亢進する遺伝子であり、その発現を抑制するためのものである、請求項20に記載の発現調節剤。
- 前記IL-17RAを発現する細胞が椎間板髄核細胞である、請求項19~22のいずれか一項に記載の発現調節剤。
- 前記椎間板髄核細胞が、低酸素条件下で培養されている椎間板髄核細胞、または椎間板組織内に存在する椎間板髄核細胞である、請求項23に記載の発現調節剤。
- 前記IL-17RAを発現する細胞が角化細胞またはその他の表皮の細胞である、請求項19~24のいずれか一項に記載の発現調節剤。
- 請求項1~18のいずれか一項に記載のIL-17A活性阻害剤、または請求項19~25のいずれか一項に記載の発現調節剤を有効成分として含有する、IL-17AのIL-17RAへの結合が症状と関連する疾患の治療または予防のための医薬。
- 前記IL-17AのIL-17RAへの結合が症状と関連する疾患が、腰部または頚部の椎間板症、椎間板ヘルニア、脊椎分離症・すべり症、腰部脊柱管狭窄症、腰椎変性すべり症、または腰椎変性側弯症である、請求項26に記載の医薬。
- 前記IL-17AのIL-17RAへの結合が症状と関連する疾患が、尋常性乾癬、関節症性乾癬、膿疱性乾癬、または乾癬性紅皮症である、請求項26に記載の医薬。
- ヒトのIL-17RAの細胞外ドメインに含まれる、Phe60、Gln87、Asp121、Pro122、Asp123、Gln124、Asp153、Cys154、Glu155、Lys160、Pro164、Cys165、Ser167、Ser168、Gly169、Ser170、Leu171、Trp172、Asp173、Pro174、Pro254、Phe256、Ser258、Cys259、Asp262、Cys263、Leu264およびHis266によって囲まれる空間の立体分子モデル、またはヒト以外の動物のIL-17RAの細胞外ドメインに含まれる上記28個のアミノ酸残基に相当するアミノ酸残基(ただし、それらのアミノ酸残基の相同性は80%以上であるものとする。)によって囲まれる空間の立体分子モデルと、候補化合物の立体分子モデルとから、
前記アミノ酸残基のうちの少なくとも13個が有する原子または原子団と、前記候補化合物が有する原子または原子団との間で生じるファンデルワールス力を含む非共有結合的な相互作用によって、候補化合物とIL-17RAとの結合安定性を評価し、
前記候補化合物が、IL-17Aと競合的にIL-17RAと結合することにより、IL-17RAへのIL-17Aの結合を阻害する作用を有するか否かを推定する工程を含む、IL-17A活性阻害剤のスクリーニング方法。 - さらに、前記候補化合物の結合安定性と、前記化合物(1)~(36)の結合安定性とを対比する工程を含む、請求項29に記載のスクリーニング方法。
- ヒトおよびその他の動物の生体外において、請求項1~16のいずれか一項に記載のIL-17A活性阻害剤とIL-17RAとを接触させる工程を含む、IL-17RAへのIL-17Aの結合阻害方法。
- ヒトおよびその他の動物の生体外において、請求項17~22のいずれか一項に記載の発現調節剤と、IL-17RAを発現している細胞とを接触させる工程を含む、IL-17RAへのIL-17Aの結合により発現量が変化する遺伝子の発現調節方法。
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Cited By (1)
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CN115103835A (zh) * | 2019-09-16 | 2022-09-23 | 戴斯阿尔法公司 | Il-17a调节剂及其用途 |
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CN111757756B (zh) | 2023-08-01 |
JPWO2019163945A1 (ja) | 2021-02-18 |
KR20200123435A (ko) | 2020-10-29 |
US20200392223A1 (en) | 2020-12-17 |
EP3756689A1 (en) | 2020-12-30 |
AU2019224354A1 (en) | 2020-10-08 |
EP3756689A4 (en) | 2022-07-27 |
CA3091598A1 (en) | 2019-08-29 |
AU2019224354A2 (en) | 2020-10-15 |
TW202000233A (zh) | 2020-01-01 |
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