JP2018203708A - Agent for preventing and treating cataracts, and use of inhibitor inhibiting signaling route responding to dna damage for producing the same - Google Patents

Abstract

To provide an agent for preventing and treating cataracts having a different action mechanism from the conventional art, and use of an inhibitor that inhibits a signaling route responding to DNA damage for producing the same.SOLUTION: An agent for preventing and treating cataracts contains an inhibitor that inhibits a signaling route responding to DNA damage, as an active ingredient.SELECTED DRAWING: None

Description

  The present invention relates to preventive and therapeutic agents for cataracts, and the use of inhibitors to inhibit the signaling pathways that respond to DNA damage to produce them.

  A cataract is a disease in which visual acuity is reduced due to cloudiness (for example, white turbidity) of the lens. In individuals with cataracts, opacity of the lens, nucleus, cortex, posterior capsule, etc. generally occurs.

  Examples of the types of cataract include age-related cataract and diabetic cataract. Age-related cataract is a cataract with the largest number of affected individuals. In the case of age-related cataracts, the number of affected patients increases with age, approximately 66-85% of Japanese in their 60s, approximately 84-97% of Japanese in their 70s, and Japan over 80. There are reports that nearly 100% of people suffer from age-related cataracts. On the other hand, in the case of diabetic cataract, there are many affected persons under 60 years old, and diabetic cataract is a disease that can develop even in young people.

  Cataract treatment methods include surgery and administration of prophylactic or therapeutic agents. As an example of the prophylactic and therapeutic agents, there can be mentioned drugs containing glutathione or pirenoxine (see Non-Patent Documents 1 and 2).

Matensson.J et.al. (1989) Glutathione ester prevents buthionine sulfoximine-induced cataracts and lens epithelial cell damage, Proc Natl Acad Sci U S A, vol.86, pp.8727-8731. Ciuffi.M et.al. (1999) Protective Effect of Pirenoxine and U74389F on Induced Lipid Peroxidation in Mammalian Lenses. An in vitro, ex vivo and in vivo study, EXPERIMENTAL EYE RESEARCH, vol.68, pp.347-359.

  However, the conventional techniques as described above have room for improvement in the preventive and therapeutic effects of cataracts, and the development of a preventive and therapeutic agent for cataracts that is different from the conventional mechanism is desired.

  The present invention has been made in view of the above-mentioned conventional problems, and is a prophylactic and therapeutic agent for cataracts having a different mechanism of action from the conventional ones, and signal transduction in response to DNA damage for producing them. It is intended to provide the use of inhibitors that inhibit the pathway.

  We believe that signaling pathways that respond to DNA damage (in other words, intracellular signaling pathways and / or extracellular signaling pathways activated by DNA damage) are involved in the development and severity of cataracts. Based on the original hypothesis that it has been carried out, it was found that cataracts can be prevented and treated by an inhibitor that inhibits a signal transduction pathway that responds to DNA damage, and the present invention has been completed. That is, one embodiment of the present invention has the following configuration.

  <1> A preventive or therapeutic agent for cataract, which contains an inhibitor that inhibits a signal transduction pathway that responds to DNA damage as an active ingredient.

  <2> The inhibitor is a PLK3 inhibitor, ATM inhibitor, ATR inhibitor, p53 inhibitor, CHK1 inhibitor, CHK2 inhibitor, WEE1 inhibitor, Plk1 inhibitor, Aurora A kinase inhibitor, DNA replication inhibitor A preventive agent for cataracts according to <1>, which is one or more selected from the group consisting of: a DNA synthesis inhibitor, a mitosis inhibitor, a CDC25a inhibitor, a CDC25c inhibitor, and a DNA-PK inhibitor Or therapeutic agent.

  <3> The inhibitor includes a compound containing a simple ring in the structure, a compound containing a heterocyclic ring in the structure, a compound containing both a simple ring and a heterocyclic ring in the structure, and The preventive or therapeutic agent for cataract according to <2>, which is one or more selected from the group consisting of compounds containing an amide bond in the structure.

  <4> The preventive or therapeutic agent for cataract according to any one of <1> to <3>, which is an eye drop.

  <5> The cataract preventive agent or therapeutic agent according to any one of <1> to <4>, wherein the cataract is diabetic cataract.

  <6> Use of an inhibitor that inhibits a signal transduction pathway in response to DNA damage, for producing a prophylactic or therapeutic agent for cataract.

  According to one embodiment of the present invention, it is possible to provide a preventive agent and a therapeutic agent for cataract, which have a different mechanism of action from the conventional one.

It is a model figure showing the example of the action mechanism of the preventive agent or therapeutic agent of a cataract which concerns on one Embodiment of this invention. It is a figure which shows the effect with respect to the cataract of the preventive agent or therapeutic agent of a cataract which concerns on the Example of this invention. It is a figure which shows the effect with respect to the cataract of the preventive agent or therapeutic agent of a cataract which concerns on the Example of this invention. It is a figure which shows the effect with respect to the cataract of the preventive agent or therapeutic agent of a cataract which concerns on the Example of this invention. It is a figure which shows the effect with respect to the cataract of the preventive agent or therapeutic agent of a cataract which concerns on the Example of this invention. It is a figure which shows the effect with respect to the cataract of the preventive agent or therapeutic agent of a cataract which concerns on the Example of this invention.

  An embodiment of the present invention will be described as follows, but the present invention is not limited to this. The present invention is not limited to each configuration described below, and various modifications can be made within the scope shown in the claims, and technical means disclosed in different embodiments and examples respectively. Embodiments and examples obtained by appropriately combining them are also included in the technical scope of the present invention. Moreover, all the literatures described in this specification are used as a reference in this specification. In the present specification, when “A to B” is described with respect to a numerical range, the description intends “A or more and B or less.

[1. Basic principle of the present invention]
The basic principle of the present invention will be described with reference to FIG.

  The present inventor has conventionally conducted a test on cataract using an ex vivo diabetic cataract model using a galactose-added medium. However, the mechanism by which galactose causes cataracts and the mechanism by which galactose causes cataracts are not clear.

  In the course of the study, the inventor makes a unique hypothesis that galactose may develop and / or aggravate cataracts by the mechanism briefly described in FIG. It came to.

  In this mechanism, first, galactose generates reactive oxygen (ROS: Reactive Oxygen Species), galactitol, and advanced glycation end products (AGEs), and active oxygen, galactitol, and advanced glycation end products. Causes damage to DNA (eg, chromosomal DNA).

  When DNA damage is caused, various signaling pathways are activated inside and / or outside the cell. It should be noted that various substances (for example, proteins) are involved in the signal transduction pathway, and in FIG. 1, for example, ATM (ataxia telangiectasia mutated (protein kinase)), PLK3 (Polo-like kinase 3) And p53 are described. To date, however, many substances have been reported that are involved in signal transduction pathways that respond to DNA damage. Therefore, the active ingredient contained in the preventive or therapeutic agent for cataract described later includes inhibitors of all substances involved in the signal transduction pathway that responds to DNA damage.

  Downstream of the signaling pathways that respond to DNA damage as described above are additional signaling pathways for developing and aggravating cataracts. Therefore, galactose activates signaling pathways that respond to DNA damage and additional signaling pathways to develop and severe cataracts, resulting in the onset and severity of cataracts .

  In order to confirm that the original hypothesis described above is correct, the present inventor conducted a test to determine whether an inhibitor that inhibits a signal transduction pathway that responds to DNA damage is effective in preventing or treating cataracts. .

  And as shown in the Example mentioned later, it became clear that the hypothesis of this inventor was correct, As a result, this inventor came to complete this invention.

[2. Definition of terms〕
[2-1. Cataract]
As used herein, “cataract” refers to a disease that causes turbidity (eg, cloudiness) in the lens. The opacity produced in the lens by cataract includes, for example, cortical turbidity; nuclear turbidity; subcapsular turbidity; cortical spoke-like opacity; subcapsular opacity; There are types such as blisters; punctate turbidity; In addition, “cataract” in the present specification includes age-related cataract and concurrent cataract (for example, diabetic cataract, congenital cataract, traumatic cataract, atopic cataract, radiation cataract, and steroid cataract).

  As used herein, “diabetic cataract” refers to a disease characterized by a continuous increase in glucose concentration in blood or plasma (eg, hyperglycemia or diabetes (eg, type 1 diabetes, Alternatively, it is intended for the opacity of the lens that has developed in individuals with type 2 diabetes)). In diabetic cataracts, it is known from large-scale epidemiological studies that opacity often occurs in the cortex or posterior capsule of the lens. However, the location of opacity is not limited to these.

[2-2. Preventive agent]
In the present specification, the “prophylactic agent” intends an agent that provides a preventive effect. The preventive effect is intended to be the effect exemplified below, but is not limited thereto.
(1) Compared with the case where no prophylactic agent is administered, when the prophylactic agent is administered, the onset of one or more symptoms related to the disease is prevented or the risk of the onset is reduced.
(2) Compared with the case where no prophylactic agent is administered, when a prophylactic agent is administered, the recurrence of one or more symptoms related to the disease is prevented or the risk of recurrence is reduced.
(3) Compared to the case where no prophylactic agent is administered, when the prophylactic agent is administered, the occurrence of one or more symptoms related to the disease is prevented or the risk of the occurrence of the symptoms is reduced. To do.

  Note that one or more symptoms related to the disease may be systemic or local.

[2-3. Therapeutic agent]
As used herein, “therapeutic agent” intends an agent that provides a therapeutic effect. The therapeutic effect is intended to be the effect exemplified below, but is not limited thereto.
(1) When the therapeutic agent is administered, the severity of one or more symptoms related to the disease is reduced as compared to the case where the therapeutic agent is not administered.
(2) When a therapeutic agent is administered as compared to the case where no therapeutic agent is administered, the severity of one or more symptoms related to the disease is prevented from increasing or the progression of the severity.
(3) Compared to the case where the therapeutic agent is not administered, when the therapeutic agent is administered, the rate of increase in the severity of one or more symptoms related to the disease or the rate of progression of the severity is reduced. .

  Note that one or more symptoms related to the disease may be systemic or local.

[3. Inhibitors that inhibit signal transduction pathways in response to DNA damage]
DNA (eg, chromosomal DNA) can be damaged by exogenous factors (eg, radiation, ultraviolet light, and drugs) and / or endogenous factors (eg, free radicals and intracellular metabolites). I can receive it. When DNA is damaged, various signal transduction pathways are activated inside and / or outside the cell, thereby repairing the DNA. The “signal transduction pathway in response to DNA damage” includes all signal transduction pathways that are activated in the process of DNA repair, and includes “inhibitors that inhibit the signal transduction pathway in response to DNA damage”. Includes any inhibitor that inhibits signal transduction in any signaling pathway that is activated in the process of DNA repair.

  The inhibitor may be one that inhibits the function of a protein constituting a signal transduction pathway activated in the process of repairing DNA.

  More specifically, the inhibitors include PLK3 (Polo-like kinase 3) inhibitors, ATM (ataxia telangiectasia mutated (protein kinase)) inhibitors, ATR (ATM and Rad3-related (protein kinase)) inhibitors, p53 inhibitor, CHK1 (Checkpoint kinase 1) inhibitor, CHK2 (Checkpoint kinase 2) inhibitor, WEE1 (Wee1 kinase) inhibitor, PLK1 (Polo-like kinase 1) inhibitor, Aurora A kinase inhibitor, DNA replication inhibition Agents, DNA synthesis inhibitors, mitosis inhibitors, CDC25a (Cell division cycle 25 A) inhibitors, CDC25c (Cell division cycle 25 C) inhibitors, and DNA-PK (DNA-dependent protein kinase) inhibitors One or more selected from the group consisting of: The inhibitor may be capable of inhibiting the functions of multiple types of proteins. The inhibitor has, for example, (i) an inhibitor having a function as an ATM inhibitor and a function as an ATR inhibitor, and (ii) a function as a CHK1 inhibitor and a function as a WEE1 inhibitor. An inhibitor having both a function as an inhibitor and a CHK1 inhibitor and a function as a CHK2 inhibitor may be used.

  The inhibitor includes a compound containing a monocyclic ring in the structure, a compound containing a heterocyclic ring in the structure, a compound containing both a monocyclic ring and a heterocyclic ring in the structure, and a structure containing It may be one or more selected from the group consisting of compounds containing an amide bond.

  The kind of element which comprises the said monocyclic ring is not specifically limited. From the viewpoint of realizing a higher desired effect, it is preferable that the simple ring is formed only of carbon. Moreover, the kind of element which comprises the said heterocyclic ring is not specifically limited. From the viewpoint of realizing a higher desired effect, the heterocycle is formed by only (i) carbon and (ii) at least one selected from the group consisting of sulfur, nitrogen and oxygen. It is preferable. The number of elements constituting the monocyclic ring and the heterocyclic ring is not particularly limited. From the viewpoint of realizing a higher desired effect, the monocyclic ring and the heterocyclic ring are formed of 3 to 20 elements, 3 to 15 elements, or 3 to 10 elements. Is preferred.

  In the case of a compound having an amide bond, the number of amide bonds contained in the compound is not particularly limited. From the viewpoint of realizing a higher desired effect, the number of amide bonds contained in the compound is preferably 1 to 10, and more preferably 1 to 5.

  Below, the detail of each inhibitor is further demonstrated.

  As used herein, “PLK3 inhibitor” intends a substance that inhibits the function of PLK3. At this time, PLK3 may be derived from humans or derived from organisms other than humans (for example, non-human mammals). For example, PLK3 has an amino acid level identity of preferably 90% or higher, more preferably 92% or higher, more preferably 95% or higher, and most preferably 98% or higher compared to human-derived PLK3. possible. The PLK3 inhibitor may be one that inhibits the function of PLK3 “directly” by binding to PLK3 or the like, or “directly” by capturing a substance necessary for the function of PLK3. It may be one that inhibits the function of PLK3.

  Specific examples of PLK3 inhibitors include GW843682X (IUPAC name: 5- (5,6-dimethoxy-1H-benzimidazole-1-yl) -3-{[2- (trifluoromethyl) -benzyl] oxy} thiophene-2- carboxamide), TC-S7005 (IUPAC name: 3- (1,3-Benzodioxol-5-yl) -N-[(1S) -1-phenylethyl] -isoxazolo [5,4-c] pyridin-5-amine) , BI2536 (IUPAC name: (R) -4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl) amino) -3-methoxy -N- (1-methylpiperidin-4-yl) benzamide) and their derivatives or salts. Of course, the present invention is not limited to these specific examples.

  As used herein, “ATM inhibitor” intends a substance that inhibits the function of ATM. At this time, the ATM may be derived from a human or an organism other than a human (for example, a non-human mammal). For example, an ATM has an amino acid level identity that is preferably 90% or higher, more preferably 92% or higher, more preferably 95% or higher, and most preferably 98% or higher, compared to human-derived ATM. possible. The ATM inhibitor may be one that inhibits the function of ATM “directly” by binding to ATM or the like, or “indirectly” by capturing a substance necessary for the function of ATM. It may be one that inhibits the function of ATM.

  Specific examples of ATM inhibitors include CGK733 (IUPAC name: 2,2-diphenyl-n- (2,2,2-trichloro-1- [3- (4-fluoro-3-nitrophenyl) thioureide] ethyl) acetamide ), KU55933 (IUPAC name: 2- (4-Morpholinyl) -6- (1-thianthrenyl) -4H-Pyran-4-one, 2- (Morpholin-4-yl) -6- (thianthren-1-yl) -4H-pyran-4-one), CP466722 (IUPAC name: 2- (6,7-Dimethoxy-quinazolin-4-yl) -5-pyridin-2-yl-2H- [1,2,4] triazol- 3-ylamine), KU60019 (IUPAC name: 2-((2S, 6R) -2,6-dimethylmorpholino) -N- (5- (6-morpholino-4-oxo-4H-pyran-2-yl) -9H -thioxanthen-2-yl) acetamide), AZD0156 (IUPAC name: 8- [6- [3- (dimethylamino) propoxy] -3-pyridyl] -3-methyl-1-tetrahydropyran-4-yl-imidazo [4, 5-c] quinolin-2-one), Mirin (IUPAC name: (5Z) -2-amino-5-[(4-hydroxyphenyl) methylidene] -1,3-thiazol-4-one), KU59403 (IUPAC name) : 3- (4-methylpiperazin-1-yl) -N- (6- (6-morpholino-4-oxo-4H-pyran-2-yl) thi anthren-2-yl) propanamide), Torin2 (IUPAC name: 9- (6-aminopyridin-3-yl) -1- [3- (trifluoromethyl) phenyl] benzo [h] [1,6] naphthyridin-2-one ), Caffeine (IUPAC name: 1,3,7-Trimethylpurine-2,6-dione), LY294002 (IUPAC name: 2-morpholin-4-yl-8-phenylchromen-4-one), Wortmannin (IUPAC name: ( 1S, 6bR, 9aS, 11R, 11bR) -1- (Methoxymethyl) -9a, 11b-dimethyl-3,6,9-trioxo-1,6,6b, 7,8,9,9a, 10,11,11b -decahydro-3H-furo [4,3,2-de] indeno [4,5-h] isochromen-11-yl acetate) and derivatives or salts thereof. Of course, the present invention is not limited to these specific examples.

  As used herein, “ATR inhibitor” intends a substance that inhibits the function of ATR. At this time, the ATR may be derived from a human, or may be derived from a non-human organism (for example, a non-human mammal). For example, ATR has an amino acid level identity of preferably 90% or higher, more preferably 92% or higher, more preferably 95% or higher, and most preferably 98% or higher compared to human-derived ATR. possible. An ATR inhibitor may be one that inhibits the function of ATR “directly”, such as by binding to ATR, or “directly” by capturing a substance necessary for the function of ATR, etc. It may be one that inhibits the function of ATR.

  Specific examples of ATR inhibitors include CGK733 (IUPAC name: 2,2-diphenyl-n- (2,2,2-trichloro-1- [3- (4-fluoro-3-nitrophenyl) thioureide] ethyl) acetamide ), VE-821 (IUPAC name: 3-Amino-6- (4- (methylsulfonyl) phenyl) -N-phenylpyrazine-2-carboxamide, 3-Amino-6- [4- (methylsulfonyl) phenyl] -N-phenyl -2-pyrazinecarboxamide), DACTOLISIB (IUPAC name: 2-methyl-2- (4- (3-methyl-2-oxo-8- (quinolin-3-yl) -2,3-dihydroimidazo [4,5-c ] quinolin-1-yl) phenyl) propanenitrile), AZD6738 (IUPAC name: 4- [4- [1-[[S (R)]-S-methylsulfonimidoyl] cyclopropyl] -6-[(3R) -3-methyl -4-morpholinyl] -2-pyrimidinyl] -1H-pyrrolo [2,3-b] pyridine), VE-822 (IUPAC name: 5- (4- (isopropylsulfonyl) phenyl) -3- (3- (4- ((methylamino) methyl) phenyl) isoxazol-5-yl) pyrazin-2-amine), AZ-20 (IUPAC name: (R) -4- (2- (1H-indol-4-yl) -6- ( 1- (methylsulfonyl) cyclopropyl) pyrimidin-4-yl) -3-methylmorpholine), Tor n2 (IUPAC name: 9- (6-aminopyridin-3-yl) -1- [3- (trifluoromethyl) phenyl] benzo [h] [1,6] naphthyridin-2-one), Caffeine (IUPAC name: 1, 3,7-Trimethylpurine-2,6-dione), LY294002 (IUPAC name: 2-morpholin-4-yl-8-phenylchromen-4-one), Wortmannin (IUPAC name: (1S, 6bR, 9aS, 11R, 11bR) ) -1- (Methoxymethyl) -9a, 11b-dimethyl-3,6,9-trioxo-1,6,6b, 7,8,9,9a, 10,11,11b-decahydro-3H-furo [4, 3,2-de] indeno [4,5-h] isochromen-11-yl acetate), Swissrin B (IUPAC name: (6R, 7S) -1,2,3,13-Tetramethoxy-6,7-dimethyl- 5,6,7,8-tetrahydrobenzo [3 ', 4'] cycloocta [1 ', 2': 4,5] benzo [1,2-d] [1,3] dioxole), NU6027 (IUPAC name: 4 -{[4-Amino-6- (cyclohexylmethoxy) -5-nitroso-2-pyrimidinyl] amino} benzamide), NVP-BEZ235 (IUPAC name: 2-Methyl-2- {4- [3-methyl-2-oxo -8- (quinolin-3-yl) -2,3-dihydro-1H-imidazo [4,5-c] quinolin-1-yl] phenyl} propanenitrile), ET P46464 (IUPAC name: 2-methyl-2- {4- [2-oxo-9- (quinolin-3-yl) -4H- [1,3] oxazino [5,4-c] quinolin-1-yl] phenyl} propanenitrile), and derivatives or salts thereof. Of course, the present invention is not limited to these specific examples.

  As used herein, “p53 inhibitor” intends a substance that inhibits the function of p53. At this time, p53 may be derived from a human or a living organism other than a human (for example, a non-human mammal). For example, p53 has an amino acid level identity of preferably 90% or higher, more preferably 92% or higher, more preferably 95% or higher, and most preferably 98% or higher compared to human-derived p53. possible. The p53 inhibitor may be one that inhibits the function of p53 “directly” by binding to p53 or the like, or “directly” by capturing a substance necessary for the function of p53. It may be one that inhibits the function of p53.

Specific examples of p53 inhibitors include PFTα (IUPAC name: 2- (2-imino-4,5,6,7-tetrahydrobenzothiazole-3-yl) -1-p-tolylethanone hydrobromide), Pifithrin-μ (IUPAC name) : 2-Phenylacetylenesulfonamide), Nutlin-3 (IUPAC name: 4-{[(4R, 5S) -4,5-Bis (4-chlorophenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4,5- dihydro-1H-imidazol-1-yl] carbonyl} -2-piperazinone), Ellipticine (IUPAC name: 5,11-Dimethyl-6H-pyrido [4,3-b] carbazole), Roscovitene (IUPAC name: (2R) -2-{[6- (Benzylamino) -9-isopropyl-9H-purin-2-yl] amino} -1-butanol), Pifithrin-α (IUPAC name: 2-Amino-3- [2- (4- methylphenyl) -2-oxoethyl] -2,3,4,5,6,7-hexahydro-1,3-benzothiazol-2-ylium bromide), 9-hydroxylipticine (IUPAC name: 5,11-Dimethyl-6H-pyrido) [4,3-b] carbazol-9-ol hydrochloride), Cyclic Pifthrin-α h drobromide (IUPAC name: 4- (4-methylphenyl) -7 -thia-2,5-diazatricyclo [6.4.0.0 2, 6] dodeca-1 (8), 3,5-triene hydrobromide), SJ 172550 (IUPAC name : Methyl 2- (2-chloro-6-ethoxy-4-((3-methyl-5-oxo-1-phenyl-1H-pyrazol-4 (5H) -ylidene) methyl) phenoxy) acetate), and these And derivatives or salts thereof. Of course, the present invention is not limited to these specific examples.

  As used herein, “CHK1 inhibitor” intends a substance that inhibits the function of CHK1. At this time, CHK1 may be derived from humans or derived from organisms other than humans (for example, non-human mammals). For example, CHK1 has an amino acid level identity of preferably 90% or higher, more preferably 92% or higher, more preferably 95% or higher, and most preferably 98% or higher compared to human-derived CHK1. possible. The CHK1 inhibitor may be one that inhibits the function of CHK1 “directly” by binding to CHK1 or the like, or indirectly captures a substance necessary for the function of CHK1. It may be one that inhibits the function of CHK1.

  Specific examples of the CHK1 inhibitor include PD407824 (IUPAC name: 9-Hydroxy-4-phenylpyrrolo [3,4-c] carbazole-1,3 (2H, 6H) -dione), AZD7762 (IUPAC name: 5- ( 3-Fluorophenyl) -3-ureidothiophene-2-carboxylic acid N-[(S) -piperidin-3-yl] amide hydrochloride), CHIR-124 (IUPAC name: (S) -3- (1H-benzo [d] imidazol-2-yl) -6-chloro-4- (quinuclidin-3-ylamino) quinolin-2 (1H) -one), LY2603618 (IUPAC name: (S) -1- (5-bromo-4-methyl-) 2- (morpholin-2-ylmethoxy) phenyl) -3- (5-methylpyrazin-2-yl) urea), UCN01 (IUPAC name: (9S, 10R, 11R, 13R) -2,3,10,11,12 , 13-Hexahydro-10-methoxy-9-methyl-11- (methylamino) -9,13-epoxy-1H, 9H-diindolo [1,2,3-gh: 3 ', 2', 1'-lm] pyrrolo [3,4-j] [1,7] benzodiazonin-1-one), MK8776 (IUPAC name: 6-bromo-3- (1-methylpyrazol-4-yl) -5-[(3R) -piperidin- 3-yl] pyrazolo [1,5-a] pyrimidin-7-amine), PF47777 (IUPAC name: (R) -2-Amino-2-cycl ohexyl-N- [2- (1-methyl-1H-pyrazol-4-yl) -6-oxo-5,6-dihydro-1H- [1,2] diazepino [4,5,6-cd] indol- 8-yl] -acetamide), SB218078 (IUPAC name: 9,10,11,12-Tetrahydro-9,12-epoxy-1H-diindolo [1,2,3-fg: 3 ', 2', 1'- kl] pyrrolo [3,4-i] [1,6] benzodiazocine-1,3 (2H) -dione), TCS2312 (IUPAC name: 4 '-[5-[[3-[(Cyclopropylamino) methyl] phenyl] amino] -1H-pyrazol-3-yl]-[1,1′-biphenyl] -2,4-diol) and their derivatives or salts. Of course, the present invention is not limited to these specific examples.

  As used herein, “CHK2 inhibitor” intends a substance that inhibits the function of CHK2. At this time, CHK2 may be derived from humans or derived from organisms other than humans (for example, non-human mammals). For example, CHK2 has an amino acid level identity of preferably 90% or more, more preferably 92% or more, more preferably 95% or more, and most preferably 98% or more compared to human-derived CHK2. possible. The CHK2 inhibitor may be one that inhibits the function of CHK2 "directly" by binding to CHK2 or the like, or indirectly captures a substance necessary for the function of CHK2. It may be one that inhibits the function of CHK2.

  Specific examples of the CHK2 inhibitor include AZD7762 (IUPAC name: 5- (3-Fluorophenyl) -3-ureidothiophene-2-carboxylic acid N-[(S) -piperidin-3-yl] amide hydrochloride), Chk2 inhibitor II. (IUPAC name: 2- (4- (4-Chlorophenoxy) phenyl) -1H-benzimidazole-5-carboxamide hydrate), CCT241533 (IUPAC name: (3R, 4S) -4-[[2- (5-Fluoro-2 -hydroxyphenyl) -6,7-dimethoxy-4-quinazolinyl] amino] -α, α-dimethyl-3-pyrrolidinemethanol dihydrochloride), PV1019 (IUPAC name: 7-nitro-1H-indole-2-carboxylic acid {4- [ 1- (guanidinohydrazone) -ethyl] -phenyl} -amide), Debromohymenidine (IUPAC name: (4Z) -4- (2-Amino-5-oxo-1,5-dihydro-4H-imidazol-4-ylidene)- 4,5,6,7-tetrahydropyrrolo [2,3-c] azepin-8 (1H) -one), VRX0466617 (IUPAC name: 5- [4- (4-Bromoanilino) anilino] -N '-(1- hydroxypropan-2-yl) -3-oxo-1,2-thiazole-4-carboximidami de) and derivatives or salts thereof. Of course, the present invention is not limited to these specific examples.

  As used herein, the term “WEE1 inhibitor” intends a substance that inhibits the function of WEE1. At this time, WEE1 may be derived from humans or derived from organisms other than humans (for example, non-human mammals). For example, WEE1 has an amino acid level identity of preferably 90% or higher, more preferably 92% or higher, more preferably 95% or higher, and most preferably 98% or higher compared to human-derived WEE1. possible. The WEE1 inhibitor may be one that inhibits the function of WEE1 “directly”, for example, by binding to WEE1, or “directly” by capturing a substance necessary for the function of WEE1. It may be one that inhibits the function of WEE1.

  Specific examples of WEE1 inhibitors include PD407824 (IUPAC name: 9-Hydroxy-4-phenylpyrrolo [3,4-c] carbazole-1,3 (2H, 6H) -dione), MK1775 (IUPAC name: 2-allyl). -1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (4- (4-methylpiperazin-1-yl) phenylamino) -1,2-dihydropyrazolo [3,4-d ) pyrimidin-3-one) and their derivatives or salts. Of course, the present invention is not limited to these specific examples.

  As used herein, “PLK1 inhibitor” intends a substance that inhibits the function of PLK1. At this time, PLK1 may be derived from a human or a living organism other than a human (for example, a non-human mammal). For example, PLK1 has an amino acid level identity of preferably 90% or higher, more preferably 92% or higher, more preferably 95% or higher, and most preferably 98% or higher compared to human-derived PLK1. possible. The PLK1 inhibitor may be one that inhibits the function of PLK1 “directly” by binding to PLK1 or the like, or indirectly captures a substance necessary for the function of PLK1. It may be one that inhibits the function of PLK1.

  Specific examples of PLK1 inhibitors include BI2536 (IUPAC name: (R) -4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2- yl) amino) -3-methoxy-N- (1-methylpiperidin-4-yl) benzamide), VOLASERTIB (IUPAC name: N-((1r, 4r) -4- (4- (cyclopropylmethyl) piperazin-1-yl) ) cyclohexyl) -4-((R) -7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino) -3-methoxybenzamide), GSK461364 (IUPAC) Name: 5- (6-((4-methylpiperazin-1-yl) methyl) -1H-benzo [d] imidazol-1-yl) -3-((R) -1- (2- (trifluoromethyl) phenyl) ethoxy) thiophene-2-carboxamide) and their derivatives or salts. Of course, the present invention is not limited to these specific examples.

  As used herein, “Aurora A kinase inhibitor inhibitor” intends a substance that inhibits the function of an Aurora A kinase inhibitor. At this time, the Aurora A kinase inhibitor may be derived from a human, or may be derived from a non-human organism (for example, a non-human mammal). For example, the Aurora A kinase inhibitor is preferably 90% or more, more preferably 92% or more, more preferably 95% or more, and most preferably 98% or more amino acids as compared to a human-derived Aurora A kinase inhibitor. It may have a level of identity. The Aurora A kinase inhibitor may be one that directly inhibits the function of the Aurora A kinase inhibitor, such as by binding to the Aurora A kinase inhibitor, It may be one that inhibits the function of an Aurora A kinase inhibitor “indirectly”, such as by capturing a substance necessary for the function.

  Specific examples of Aurora A kinase inhibitor include MLN8237 (IUPAC name: 4-{[9-Chloro-7- (2-fluoro-6-methoxyphenyl) -5H-pyrimido [5,4-d] [2 ] benzazepin-2-yl] amino} -2-methoxybenzoic acid), AURORA A INHIBITOR I (IUPAC name: N- (2-chlorophenyl) -4- (2- (4- (2- (4-ethylpiperazin-1- yl) -2-oxoethyl) phenylamino) -5-fluoropyrimidin-4-ylamino) benzamide) and their derivatives or salts. Of course, the present invention is not limited to these specific examples.

  As used herein, “DNA replication inhibitor” intends a substance that prevents any of a plurality of steps for replicating DNA (specifically, chromosomal DNA) from being performed. The DNA replication inhibitor may be one that directly inhibits the function of the protein by binding to any of a plurality of proteins necessary for replicating the DNA, or replicates the DNA. For example, a substance necessary for the function of any one of a plurality of proteins necessary for the purpose may be captured to indirectly inhibit the function of the protein.

  Specific examples of DNA replication inhibitors include Etoposide (IUPAC name: 4′-dimethylepipodophyllotoxin 9- (4,6-O-ethylidene-β-D-glucopyranoside)), ELLIPTICINE (IUPAC name: 5,11-Dimethyl-6H). -pyrido [4,3-b] carbazole) and their derivatives or salts. Of course, the present invention is not limited to these specific examples.

  As used herein, “DNA synthesis inhibitor” means a substance that prevents any of a plurality of steps for synthesizing DNA (specifically, chromosomal DNA) from being performed. The DNA synthesis inhibitor may be one that inhibits the function of the protein “directly” by binding to any of a plurality of proteins necessary for synthesizing DNA, or synthesizes DNA. For example, a substance necessary for the function of any one of a plurality of proteins necessary for the purpose may be captured to indirectly inhibit the function of the protein.

  Specific examples of the DNA synthesis inhibitor include HU (IUPAC name: Hydroxycarbamide), 5-FU (IUPAC name: 5-Fluorouracil), and derivatives or salts thereof. Of course, the present invention is not limited to these specific examples.

  As used herein, the term “mitotic inhibitor” means a substance that prevents any one of a plurality of steps for performing mitosis from being performed. The mitosis inhibitor may be one that inhibits the function of the protein “directly” by binding to any of a plurality of proteins necessary for mitosis. It may be one that “indirectly” inhibits the function of the protein, for example, by capturing a substance necessary for the function of any of a plurality of necessary proteins.

  Specific examples of mitotic inhibitors include Taxol (IUPAC name: (2α, 4α, 5β, 7β, 10β, 13α) -4,10-bis (acetyloxy) -13-{[(2R, 3S) -3 -(benzoylamino) -2-hydroxy-3-phenylpropanoyl] oxy} -1,7-dihydroxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate), NOCODAZOLE (IUPAC name: Methyl [5 -(2-thienylcarbonyl) -1H-benzimidazol-2-yl] carbamate), and derivatives or salts thereof. Of course, the present invention is not limited to these specific examples.

  As used herein, “CDC25a inhibitor” intends a substance that inhibits the function of CDC25a. At this time, the CDC 25a may be derived from a human or a living organism other than a human (for example, a non-human mammal). For example, CDC25a has an amino acid level identity of preferably 90% or higher, more preferably 92% or higher, more preferably 95% or higher, and most preferably 98% or higher compared to human-derived CDC25a. possible. The CDC25a inhibitor may be one that directly inhibits the function of CDC25a, such as by binding to CDC25a, or that indirectly captures a substance necessary for the function of CDC25a. It may inhibit the function of CDC25a.

  Specific examples of the CDC25a inhibitor include PM-20 (IUPAC name: 1- [1,1′-Biphenyl] -4-yl-3,4-bis [(2-hydroxyethyl) thio] -1H-Pyrrole-2 , 5-dione), NSC95397 (IUPAC name: 2,3-bis [(2-Hydroxyethyl) thiol] -1,4-naphthoquinone), NSC663284 (IUPAC name: 6-Chloro-7-[[2- (4- morpholinyl) ethyl] amino] -5,8-quinolinedione), K-252a (IUPAC name: (9S- (9α, 10β, 12α))-2,3,9,10,11,12-hexahydro-10-hydroxy -10- (methoxycarbonyl) -9-methyl-9,12-epoxy-1H-diindolo [1,2,3-fg: 3 ', 2', 1'-kl] pyrrolo [3,4-i] [1 , 6] benzodiazocin-1-one), CDC25 Phosphatase Inhibitor I, BN82002 (IUPAC name: 4- (dimethylamino) -2-methoxy-6-[[methyl- [2- (4-nitrophenyl) ethyl] amino] methyl] phenol) and their derivatives or salts. Of course, the present invention is not limited to these specific examples.

  As used herein, “CDC25c inhibitor” intends a substance that inhibits the function of CDC25c. At this time, the CDC25c may be derived from a human or a living organism other than a human (for example, a non-human mammal). For example, CDC25c has an amino acid level identity of preferably 90% or higher, more preferably 92% or higher, more preferably 95% or higher, and most preferably 98% or higher compared to human-derived CDC25c. possible. The CDC25c inhibitor may be one that directly inhibits the function of CDC25c, such as by binding to CDC25c, or “directly” by capturing a substance necessary for the function of CDC25c. It may inhibit the function of CDC25c.

  Specific examples of the CDC25c inhibitor include NSC95397 (IUPAC name: 2,3-bis [(2-Hydroxyethyl) thiol] -1,4-naphthoquinone), NSC663284 (IUPAC name: 6-Chloro-7-[[2- (4-morpholinyl) ethyl] amino] -5,8-quinolinedione), K-252a (IUPAC name: (9S- (9α, 10β, 12α))-2,3,9,10,11,12-hexahydro- 10-hydroxy-10- (methoxycarbonyl) -9-methyl-9,12-epoxy-1H-diindolo [1,2,3-fg: 3 ', 2', 1'-kl] pyrrolo [3,4-i ] [1,6] benzodiazocin-1-one), CDC25 Phosphatase Inhibitor I, BN82002 (IUPAC name: 4- (dimethylamino) -2-methoxy-6-[[methyl- [2- (4-nitrophenyl) ethyl] amino methyl] phenol), mpV (pic) (IUPAC name: hydrogen peroxide; 5-hydroxypyridine-2-carboxylic acid; oxovanadium), and derivatives or salts thereof. Of course, the present invention is not limited to these specific examples.

  As used herein, “DNA-PK inhibitor” intends a substance that inhibits the function of DNA-PK. At this time, the DNA-PK may be derived from a human or a living organism other than a human (for example, a non-human mammal). For example, DNA-PK has an amino acid level identity of preferably 90% or higher, more preferably 92% or higher, more preferably 95% or higher, and most preferably 98% or higher compared to human-derived DNA-PK. It may have. The DNA-PK inhibitor may be one that directly inhibits the function of DNA-PK, such as by binding to DNA-PK, or captures a substance necessary for the function of DNA-PK. For example, the function of DNA-PK may be inhibited indirectly.

  Specific examples of DNA-PK inhibitors include PIK-75 HCL (IUPAC name: (E) -N ′-((6-bromoH-imidazo [1,2-a] pyridin-3-yl) methylene) -N , 2-dimethyl-5-nitrobenzenesulfonohydrazide hydrochloride), NU7441 (IUPAC name: 8- (4-Dibenzothienyl) -2- (4-morpholinyl) -4H-1-benzopyran-4-one), PI-103 (IUPAC name: 3- (4-Morpholin-4-ylpyrido [2,3] furo [2,4-b] pyrimidin-2-yl) phenol), NU9056 (IUPAC name: 2-morpholin-4-ylbenzo [h] chromen-4 -one), KU-0060648 (IUPAC name: 2- (4-ethylpiperazin-1-yl) -N- [4- (2-morpholin-4-yl-4-oxochromen-8-yl) dibenzothiophen-1-yl ] acetamide), CC-115 (IUPAC name: 1-ethyl-7- (2-methyl-6- (1H-1,2,4-triazol-5-yl) pyridin-3-yl) -3,4- dihydropyrazino [2,3-b] pyrazin-2 (1H) -one), DMNB (IUPAC name: 2,3-Dimethyl-2,3-dinitrobutane), IC86621 (IUPAC name: 1- [2-hydroxy-4-) (morpholin-4-yl) phenyl] ethan-1-one), DNA- Mention may be made of PK inhibitor V (IUPAC name: 2-benzoyl-5- (morpholin-4-yl) phenol) and derivatives or salts thereof. Of course, the present invention is not limited to these specific examples.

  Below, the structure is described about the representative example of the inhibitor mentioned above. However, the present invention is not limited to these inhibitors.

  In one embodiment of the inhibitors, derivatives or salts of the substances mentioned above may be used. By using the derivatives or salts of the above-mentioned substances, (1) the preventive and / or therapeutic effects of cataract can be increased, (2) the safety of the substance to the human body can be increased, and (3) easy-to-handle substances are used. The effect that it can be formulated can be obtained.

  In the present specification, the “derivative” means a group of compounds generated by substituting a part of the compound in the molecule with another functional group or another atom for the specific compound.

  Examples of the other functional groups include alkyl groups, alkoxy groups, alkylthio groups, aryl groups, aryloxy groups, arylthio groups, arylalkyl groups, arylalkoxy groups, arylalkylthio groups, arylalkenyl groups, arylalkynyl groups, allyls. Group, amino group, substituted amino group, silyl group, substituted silyl group, silyloxy group, substituted silyloxy group, arylsulfonyloxy group, alkylsulfonyloxy group, nitro group and the like. Examples of the other atoms include a carbon atom, a hydrogen atom, an oxygen atom, a nitrogen atom, a sulfur atom, a phosphorus atom, and a halogen atom.

  As used herein, “salt” intends a salt that is physiologically acceptable for administration to a subject. Examples of salts include alkali metal salts (potassium salts, etc.), alkaline earth metal salts (calcium salts, magnesium salts, etc.), ammonium salts, organic base salts (trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamines). Salt, N, N'-dibenzylethylenediamine salt), organic acid salt (acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate Etc.) and inorganic acid salts (hydrochloride, hydrobromide, sulfate, phosphate, etc.).

  The inhibitor mentioned above can be manufactured according to a well-known method. Moreover, it is also possible to use a commercially available inhibitor as the above-described inhibitor.

[4. (Prevention or treatment of cataract)
The preventive or therapeutic agent for cataract according to one embodiment of the present invention contains an inhibitor that inhibits the above-described signal transduction pathway in response to DNA damage as an active ingredient. Below, the preventive agent or therapeutic agent of the cataract of this Embodiment is demonstrated.

[4-1. Dosage form and dosage form]
The prophylactic or therapeutic agent for cataract according to one embodiment of the present invention is administered to a subject. In one embodiment, the subject is a human. In other embodiments, the subject is a non-human animal. Examples of the non-human animals include mammals other than humans (cow, pig, sheep, goat, horse, dog, cat, rabbit, mouse, rat, etc.).

  The prophylactic or therapeutic agent for cataract according to one embodiment of the present invention can be administered to a subject by any administration route. Examples of the administration route include oral administration, parenteral administration, transdermal administration, transmucosal administration, and intravenous administration. Therefore, the dosage form of the prophylactic or therapeutic agent for cataract can be an internal medicine, an external medicine, an injection, a suppository, an inhalant, an eye drop and the like.

  Among the administration routes described above, parenteral administration is preferred, ophthalmic administration, intraconjunctival administration, intravitreal administration, subconjunctival administration, and subtenon administration are more preferred, and ophthalmic administration is even more preferred. Accordingly, among the above-mentioned dosage forms, eye drops or injections are preferable, and eye drops are more preferable. The reasons why ophthalmic solutions are preferable are that the route to deliver the active ingredient to the lens is short, that it is difficult to irritate other organs, that there is little invasion, and that the effect on the whole body is small (the punctum after instillation) The effects on the whole body can be further suppressed by the compression), the administration is simple, the repeated administration is possible, and the patient can be self-managed. If it is the said structure, it can anticipate that the prevention effect or treatment effect of a cataract will be made quicker or will be increased more.

[4-2. Ingredients]
The preventive or therapeutic agent for cataract according to one embodiment of the present invention contains an inhibitor that inhibits a signal transduction pathway that responds to DNA damage as an active ingredient. As used herein, “active ingredient” intends a substance that can provide a prophylactic or therapeutic effect against one or more symptoms.

  The concentration of the inhibitor contained in the preventive or therapeutic agent for cataract according to one embodiment of the present invention depends on the type of inhibitor, the administration route of the preventive or therapeutic agent, the dosage form of the preventive or therapeutic agent, and the like. Can be different.

  In one example, the lower limit of the inhibitor concentration in the prophylactic or therapeutic agent is 0.001 μM or more, 0.002 μM or more, 0.005 μM or more, 0.01 μM or more, 0.02 μM or more, 0.05 μM or more, 0.1 μM. Above, 0.2 μM or more, 0.5 μM or more, 1 μM or more, 2 μM or more, 3 μM or more, 4 μM or more, 5 μM or more, 6 μM or more, 7 μM or more, 8 μM or more, 9 μM or more, 10 μM or more, 20 μM or more, 30 μM or more, 40 μM or more 50 μM or more, 60 μM or more, 70 μM or more, 80 μM or more, 90 μM or more, 100 μM or more, 200 μM or more, 300 μM or more, 400 μM or more, 500 μM or more, or 1000 μM or more.

  In one example, the upper limit of the inhibitor concentration in the prophylactic or therapeutic agent is 0.01 μM or less, 0.02 μM or less, 0.05 μM or less, 0.1 μM or less, 0.2 μM or less, 0.5 μM or less, 1 μM or less, 2 μM or less, 3 μM or less, 4 μM or less, 6 μM or less, 7 μM or less, 8 μM or less, 9 μM or less, 10 μM or less, 20 μM or less, 30 μM or less, 40 μM or less, 50 μM or less, 60 μM or less, 70 μM or less, 80 μM or less, 90 μM or less 100 μM or less, 200 μM or less, 300 μM or less, 400 μM or less, 500 μM or less, 1000 μM or less, 2000 μM or less, or 5000 μM or less.

  In one example, the concentration of the inhibitor in the prophylactic or therapeutic agent is 0.001 μM to 5000 μM, 0.001 to 0.01 μM, 0.002 to 0.02 μM, 0.005 to 0.05 μM, 0.01 to 0.1 μM, 0.02 to 0.2 μM, 0.05 to 0.5 μM, 0.1 to 1 μM, 0.2 to 2 μM, 0.3 to 3 μM, 0.4 to 4 μM, 0.5 to 5 μM, 0.6-6 μM, 0.7-7 μM, 0.8-8 μM, 0.9-9 μM, 1-10 μM, 2-20 μM, 3-30 μM, 4-40 μM, 5-50 μM, 6-60 μM, 7- 70 μM, 8-80 μM, 9-90 μM, 10-100 μM, 20-200 μM, 30-300 μM, 40-400 μM, 50-500 μM, 60-600 μM, 70-700 μM, 80-800 μM, 90-900 μM, 100-1000 μM, 2 0~2000μM or, is a 500~5000μM.

  The preventive or therapeutic agent for cataract according to one embodiment of the present invention may contain components other than the inhibitor.

  Components other than the above inhibitors include buffers, pH adjusters, isotonic agents, preservatives, antioxidants, high molecular weight polymers, excipients, carriers, diluents, solvents, solubilizers, stabilizers. , Fillers, binders, surfactants, stabilizers, and the like.

  Examples of the buffer include phosphoric acid, phosphate, boric acid, borate, citric acid, citrate, acetic acid, acetate, carbonic acid, carbonate, tartaric acid, tartrate, ε-aminocaproic acid, and And trometamol. Examples of the phosphate include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate. Examples of the borate include borax, sodium borate, and potassium borate. Examples of the citrate include sodium citrate, disodium citrate, and trisodium citrate. Examples of the acetate include sodium acetate and potassium acetate. Examples of the carbonate include sodium carbonate and sodium bicarbonate. Examples of the tartrate salt include sodium tartrate and potassium tartrate.

  Examples of pH adjusters include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, and the like.

  Examples of the tonicity agents include ionic tonicity agents (such as sodium chloride, potassium chloride, calcium chloride, and magnesium chloride) and nonionic tonicity agents (glycerin, propylene glycol, sorbitol, And mannitol).

  Examples of the preservative include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methyl paraoxybenzoate, propyl paraoxybenzoate, and chlorobutanol.

  Examples of the antioxidant include ascorbic acid, tocophenol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, and sodium sulfite.

  Examples of the high molecular weight polymer include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate Carboxymethyl ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, and atelocollagen.

  In particular, it is preferable that the preventive or therapeutic agent for cataract according to one embodiment of the present invention contains atelocollagen because the absorption rate of the inhibitor is increased.

  The concentration of components other than the inhibitor contained in the preventive or therapeutic agent for cataract according to one embodiment of the present invention is not particularly limited. For example, the concentration of components other than the inhibitor in the preventive or therapeutic agent is 0 μM, 0.001 μM to 5000 μM, 0.001 to 0.01 μM, 0.002 to 0.02 μM, 0.005 to 0.05 μM, 0.01 to 0.1 μM, 0.02 to 0.2 μM,. 05-0.5 μM, 0.1-1 μM, 0.2-2 μM, 0.3-3 μM, 0.4-4 μM, 0.5-5 μM, 0.6-6 μM, 0.7-7 μM,. 8-8 μM, 0.9-9 μM, 1-10 μM, 2-20 μM, 3-30 μM, 4-40 μM, 5-50 μM, 6-60 μM, 7-70 μM, 8-80 μM, 9-90 μM, 10-100 μM, 20-200 μM, 30-300 μM, 40-400 μ , 50~500μM, 60~600μM, 70~700μM, 80~800μM, 90~900μM, 100~1000μM, 200~2000μM, or may be 500～5000MyuM.

[4-3. Formulation and prescription]
The preventive or therapeutic agent for cataract according to one embodiment of the present invention can be formulated by a known technique using the above-described inhibitor and ingredients other than the above-described inhibitor as raw materials.

  When a prophylactic or therapeutic agent for cataract according to one embodiment of the present invention is administered (for example, when administered as an eye drop), the administration interval is not limited as long as a desired effect is obtained. The administration interval is, for example, once every 1 to 6 months, preferably once per hour, once every 2 hours, once every 3 hours, once every 6 hours, once every 12 hours. Once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, 3 Once a week, once a month, once every two months, once every three months, once every four months, once every five months, once every six months, and more Preferably at least once a day, at least once every two days, at least once every three days, at least once every four days, at least once every five days, at least once every six days, at least once a week It is.

  The preventive or therapeutic agent for cataract according to one embodiment of the present invention may be prescribed in combination with an agent for preventing or treating cataract and / or other diseases.

  Another embodiment of the present invention is a method for preventing or treating cataract using a prophylactic or therapeutic agent for cataract that contains an inhibitor that inhibits a signal transduction pathway that responds to DNA damage as an active ingredient. One embodiment of the present invention is a method for preventing cataract, which comprises a step of administering to a subject a prophylactic or therapeutic agent for cataract containing an inhibitor that inhibits a signal transduction pathway that responds to DNA damage as an active ingredient. Method or treatment method.

  In the following examples, the effect of each drug was tested using an ex vivo diabetic cataract model using a galactose-added medium.

<Example 1>
The lens was extracted from the left and right eyeballs of 6-week-old SD rats (Sankyo Lab Service Co., Ltd.). The lens extracted from the right eye was cultured using a medium obtained by adding 30 mM galactose to M199 medium (manufactured by SIGMA). On the other hand, the lens extracted from the left eye was cultured using a medium in which 30 mM galactose and 1 μM PLK3 inhibitor (specifically, GW843682X) were added to M199 medium.

  An incubator was used to culture each lens, and the temperature in the incubator was kept at 37 ° C. Four days after the start of the culture, each lens was taken out from the medium and observed with a microscope using SZX12 (Olympas).

  The test described above was performed a total of three times.

  FIG. 2 shows the test results of the microscope observation. As is clear from FIG. 2, in the lens extracted from the right eye cultured using a medium not added with a PLK3 inhibitor, the whitening of the cortex progressed from 4 days after the start of the culture. . On the other hand, in the lens extracted from the left eye that was cultured using a medium to which a PLK3 inhibitor was added, the whitening of the cortex was suppressed as compared with the lens extracted from the right eye.

<Example 2>
The lens was extracted from the left and right eyeballs of 6-week-old SD rats (Sankyo Lab Service Co., Ltd.). The lens extracted from the right eye was cultured using a medium obtained by adding 30 mM galactose to M199 medium (manufactured by SIGMA). On the other hand, the lens removed from the left eye was cultured using a medium in which 30 mM galactose and 10 μM ATM and ATR inhibitors (specifically, CGK733) were added to M199 medium.

  An incubator was used to culture each lens, and the temperature in the incubator was kept at 37 ° C. Four days after the start of the culture, each lens was taken out from the medium and observed with a microscope using SZX12 (Olympas).

  The test described above was performed a total of three times.

  FIG. 3 shows the test results of the microscope observation. As is clear from FIG. 3, in the lens extracted from the right eye cultured using a medium not added with an inhibitor of ATM and ATR, whitening of the cortex was observed from the start of culture to 4 days after the culture. It was progressing. On the other hand, in the lens extracted from the left eye cultured using a medium supplemented with an inhibitor of ATM and ATR, whitening of the cortex is suppressed as compared with the lens extracted from the right eye. It was.

<Example 3>
The lens was extracted from the left and right eyeballs of 6-week-old SD rats (Sankyo Lab Service Co., Ltd.). The lens extracted from the right eye was cultured using a medium obtained by adding 30 mM galactose to M199 medium (manufactured by SIGMA). On the other hand, the lens extracted from the left eye was cultured using a medium in which 30 mM galactose and 20 μM ATR inhibitor (specifically, VE-821) were added to M199 medium.

  An incubator was used to culture each lens, and the temperature in the incubator was kept at 37 ° C. Four days after the start of the culture, each lens was taken out from the medium and observed with a microscope using SZX12 (Olympas).

  FIG. 4 shows the test results of microscopic observation. As is clear from FIG. 4, in the lens extracted from the right eye cultured using a medium not added with an ATR inhibitor, the whitening of the cortex progressed from the start of culture to 4 days after the culture. . On the other hand, in the lens extracted from the left eye that was cultured using a medium to which an ATR inhibitor was added, the whitening of the cortex was suppressed compared to the lens extracted from the right eye.

<Example 4>
The lens was extracted from the left and right eyeballs of 6-week-old SD rats (Sankyo Lab Service Co., Ltd.). The lens extracted from the right eye was cultured using a medium obtained by adding 30 mM galactose to M199 medium (manufactured by SIGMA). On the other hand, the lens extracted from the left eye was cultured using a medium in which 30 mM galactose and 10 μM ATM inhibitor (specifically, KU55933) were added to M199 medium.

  An incubator was used to culture each lens, and the temperature in the incubator was kept at 37 ° C. Four days after the start of the culture, each lens was taken out from the medium and observed with a microscope using SZX12 (Olympas).

  FIG. 5 shows the test results of microscopic observation. As is clear from FIG. 5, in the lens extracted from the right eye cultured using a medium not added with an ATM inhibitor, the whitening of the cortex progressed from the start of culture to 4 days after the culture. . On the other hand, in the lens extracted from the left eye that was cultured using a medium to which an ATM inhibitor was added, whitening of the cortex was suppressed as compared with the lens extracted from the right eye.

<Example 5>
The lens was extracted from the eyeball of a 6-week-old SD rat (Sankyo Lab Service Co., Ltd.). The extracted lens was cultured using a medium obtained by adding 30 mM galactose to M199 medium (manufactured by SIGMA).

  An incubator was used to culture each lens, and the temperature in the incubator was kept at 37 ° C. Two days after the start of the culture, each lens was taken out from the medium and observed with a microscope using SZX12 (manufactured by Olympus).

  Thereafter, the lens cultured in a medium obtained by adding 30 mM galactose to M199 medium is obtained by adding a medium obtained by adding 30 mM galactose and 10, 20, or 40 μM ATM inhibitor (specifically, AZD0156) to M199 medium. And cultured. Four days after the start of the first culture (two days after the start of the culture in the medium to which the inhibitor was added), each lens was taken out of the medium and observed with a microscope using SZX12 (Olympas).

  FIG. 6 shows the test results of microscopic observation. As is apparent from FIG. 6, the lens two days after the start of the first culture before the addition of the inhibitor showed a cloudiness of the cortex, but four days after the start of the first culture after the addition of the ATM inhibitor. In the lens, the disappearance and dilution of the cortical white turbidity were confirmed. This indicates that the drug of the present invention has not only a cataract preventing effect but also a cataract therapeutic effect.

  The present invention can be used as an agent for preventing or treating cataract.

Claims (6)

  A prophylactic or therapeutic agent for cataract, comprising as an active ingredient an inhibitor that inhibits a signal transduction pathway that responds to DNA damage.   The inhibitors include PLK3 inhibitor, ATM inhibitor, ATR inhibitor, p53 inhibitor, CHK1 inhibitor, CHK2 inhibitor, WEE1 inhibitor, Plk1 inhibitor, Aurora A kinase inhibitor, DNA replication inhibitor, DNA synthesis The prophylactic or therapeutic agent for cataract according to claim 1, which is one or more selected from the group consisting of an inhibitor, a mitosis inhibitor, a CDC25a inhibitor, a CDC25c inhibitor, and a DNA-PK inhibitor. .   The inhibitor includes a compound containing a monocyclic ring in the structure, a compound containing a heterocyclic ring in the structure, a compound containing both a monocyclic ring and a heterocyclic ring in the structure, and a structure containing The preventive or therapeutic agent for cataract according to claim 2, which is one or more selected from the group consisting of compounds containing an amide bond.   The preventive or therapeutic agent for cataract according to any one of claims 1 to 3, which is an eye drop.   The preventive or therapeutic agent for cataract according to any one of claims 1 to 4, wherein the cataract is diabetic cataract.   Use of an inhibitor that inhibits a signal transduction pathway in response to DNA damage, for producing a preventive or therapeutic agent for cataract.