JP2022511234A - 新規なp62リガンド化合物、これを含むタンパク質異常疾患の予防、改善または治療用組成物 - Google Patents
新規なp62リガンド化合物、これを含むタンパク質異常疾患の予防、改善または治療用組成物 Download PDFInfo
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Abstract
Description
Wは炭素数6~10のアリールであり;
mは0~2の整数であり;
RaはR1または-OR1であり、
この時、R1は水素、または-(CH2)n1-R’1であり、
R’1は非置換;またはヒドロキシ、ハロゲン、炭素数1~4のアルキル、炭素数1~4のアルコキシ、ニトロ、アミノ、(炭素数1~4のアルキル)アミノ、またはジ(炭素数1~4のアルキル)アミノで置換されたフェニルであり、
n1は1~6の整数であり;
Rbは-OR2であり、
この時、R2は水素、または-(CH2)n2-R’2であり、
R’2は非置換;またはヒドロキシ、ハロゲン、炭素数1~4のアルキル、炭素数1~4のアルコキシ、ニトロ、アミノ、(炭素数1~4のアルキル)アミノ、またはジ(炭素数1~4のアルキル)アミノで置換されたフェニルであり、
n2は1~6の整数であり;
Rcは-(CH2)n3-OH、-(CH2)n3-NH-C(=NH)NH2、-C(=NH)NH2、炭素数1~6のアルキル、-CH(R3)-COO-R4、または-CH(COO-R4)-CH2CH2CH2-NH-C(=NH)NH2、-(CH2)n3-O-(CH2)n3-OR4、-CONH(CH2)n3-OR4、-CO(CH2)n4-OR4、-(CH2)n4-CH(NH2)-COOR4、-(CH2)n4-CONHR4であり、
n3は2~4の整数であり、
n4は1~4の整数であり、
R3は水素、または炭素数1~4のアルキルであり、
R4は水素、または炭素数1~4のアルキルであり、
Rdは水素、ハロゲン、炭素数1~4のアルコキシまたは炭素数1~4のアルキルであり、
この時、前記化学式1の化合物は、また好ましくは、下記化合物からなる群の中から選択される化合物でない:
1)2-((3,4-ビス(ベンジルオキシ)ベンジル)アミノ)エタン-1-オール(YTK-1105)
2)2-(3,4-ジフェネトキシベンジルアミノ)エタノール(YTK-2205)
3)2-(3,4-ビス(3-フェニルプロポキシ)ベンジルアミノ)エタノール(YTK-3305)
4)2-(3,4-ビス(4-フェニルブトキシ)ベンジルアミノ)エタノール(YTK-4405)
5)2-(ベンジルオキシ)-5-((2-ヒドロキシエチルアミノ)メチル)フェノール(YTK-1005)
6)2-(4-(ベンジルオキシ)-3-フェネトキシベンジルアミノ)エタノール(YTK-1205)
7)2-(4-(ベンジルオキシ)-3-(3-フェニルプロポキシ)ベンジルアミノ)エタノール(YTK-1305)
8)2-(4-(ベンジルオキシ)-3-(4-フェニルブトキシ)ベンジルアミノ)エタノール(YTK-1405)
9)2-((3-(フェネトキシ)ベンジル)アミノ)エタン-1-オール(YTK-205)
10)2-((3-(3-フェニルプロポキシ)ベンジル)アミノ)エタン-1-オール(YTK-305)
11)2-(3,4-ビス((4-クロロフェニル)メトキシ)ベンジルアミノ)エタノール(YT-5-1)
12)2-(3,4-ビス((4-フルオロフェニル)メトキシ)ベンジルアミノ)エタノール(YT-5-2)
13)2-(3,4-ビス((4-ジメチルアミノフェニル)メトキシ)ベンジルアミノ)エタノール(YT-5-3)
14)2-(3,4-ビス(4-ニトロフェニル)メトキシ)ベンジルアミノ)エタノール(YT-5-4)
15)2-(3,4-ビス(4-メトキシフェニル)メトキシ)ベンジルアミノ)エタノール(YT-5-5)
16)2-(3,4-ビス(4-ヒドロキシフェニル)メトキシ)ベンジルアミノ)エタノール(YT-5-6)
17)2-((3-((4-クロロベンジル)オキシ)ベンジル)アミノ)エタン-1-オール(YT-5-7)
18)2-((3-((4-フルオロベンジル)オキシ)ベンジル)アミノ)エタン-1-オール(YT-5-8)
19)2-((3-((4-ニトロベンジル)オキシ)ベンジル)アミノ)エタン-1-オール(YT-5-10)
20)2-(3,4-ジベンジルオキシ)ベンジルアミノ)プロパノール(YtK-11-A54)
21)2-((2-((3-(ベンジルオキシ)ベンジル)アミノ)エチル)アミノ)エタン-1-オール(YTK-108)
22)2-((2-((3-((4-クロロベンジル)オキシ)ベンジル)アミノ)エチル)アミノ)エタン-1-オール(YT-8-7);および
23)2-((2-((3-((4-フルオロベンジル)オキシ)ベンジル)アミノ)エチル)アミノ)エタン-1-オール(YT-8-8)。
1)2-((3-(ベンジルオキシ)ベンジル)アミノ)エタン-1-オール(YTK-105);
2)2-((2-((3,4-ビス(ベンジルオキシ)ベンジル)アミノ)エチル)アミノ)エタン-1-オール(YTK-1108);
3)1-(2-((3-(ベンジルオキシ)ベンジル)アミノ)エチル)グアニジン(YtK-107);
4)1-(2-((3-(フェネトキシベンジル)アミノ)エチル)グアニジン(YtK-207);
5)2-(2-((3,4-ビス(ベンジルオキシ)ベンジル)アミノ)エトキシ)エタン-1-オール(YtK-11-A76);
6)1-(3,4-ビス(ベンジルオキシ)ベンジル)-3-(2-ヒドロキシエチル)ウレア(ATB10041);
7)N-(3,4-ビス(ベンジルオキシ)ベンジル)-2-ヒドロキシアセトアミド(ATB10042);
8)(R)-2-アミノ-3-((3,4-ビス(ベンジルオキシ)ベンジル)アミノ)プロパン酸(ATB10043);
9)2-((3,4-ビス(ベンジルオキシ)ベンジル)アミノ)アセトアミド(ATB10044);
10)2-((3,4-ビス(ベンジルオキシ)-5-メトキシベンジル)アミノ)エタン-1-オール(ATB10045);および
11)2-((3,4-ビス(ベンジルオキシ)-5-クロロベンジル)アミノ)エタン-1-オール(ATB10046)。
したがって、さらに他の態様として、本発明は、下記化学式1aのp62リガンド化合物、その薬学的に許容可能な塩、立体異性体、水和物、溶媒和物またはプロドラッグを含む変形蛋白疾患の予防または治療用薬学的組成物を提供する。
Wは炭素数6~10のアリールであり;
mは0~2の整数であり;
RaはR1または-OR1であり、
この時、R1は水素、または-(CH2)n1-R’1であり、
R’1は非置換;またはヒドロキシ、ハロゲン、炭素数1~4のアルキル、炭素数1~4のアルコキシ、ニトロ、アミノ、(炭素数1~4のアルキル)アミノ、またはジ(炭素数1~4のアルキル)アミノで置換されたフェニルであり
n1は1~6の整数であり;
Rbは-OR2であり、
この時、R2は水素、または-(CH2)n2-R’2であり、
R’2は非置換;またはヒドロキシ、ハロゲン、炭素数1~4のアルキル、炭素数1~4のアルコキシ、ニトロ、アミノ、(炭素数1~4のアルキル)アミノ、またはジ(炭素数1~4のアルキル)アミノで置換されたフェニルであり、
n2は1~6の整数であり;
Rcは-(CH2)n3-OH、-(CH2)n3-NH-C(=NH)NH2、-C(=NH)NH2、炭素数1~6のアルキル、-CH(R3)-COO-R4、-CH(COO-R4)-CH2CH2CH2-NH-C(=NH)NH2、-(CH2)n3-O-(CH2)n3-OR4、-CONH(CH2)n3-OR4、-CO(CH2)n4-OR4、-(CH2)n4-CH(NH2)-COOR4、または-(CH2)n4-CONHR4であり、
n3は2~4の整数であり、
n4は1~4の整数であり、
R3は水素、または炭素数1~4のアルキルであり、
R4は水素、または炭素数1~4のアルキルであり、
Rdは水素、ハロゲン、炭素数1~4のアルコキシまたは炭素数1~4のアルキルである。
下記反応式1に開示された方法により、実施例1、2、3、4、10、11、14および19の化合物を合成した。
(段階1)3,4-ビス(ベンジルオキシ)ベンズアルデヒド(1101)の製造
3,4-ジヒドロキシベンズアルデヒド(0.50g、3.62mmol)を無水DMF(5ml)に溶解した後、K2CO3(1.50g、10.86mmol)を入れて、次いで、ベンジルブロミド(0.92mL、7.96mmol)を反応物に徐々に添加し60℃で4時間攪拌した。反応が終了すると、反応物を室温で冷却した後、精製水で希釈してジエチルエーテル(50ml)で2回抽出した。有機層を精製水(50ml)で2回洗浄した後、飽和塩化ナトリウム水溶液(50ml)でもう一度洗浄した。次いで、有機層に無水硫酸ナトリウムを入れて攪拌した後、減圧ろ過した。ろ過した溶液を濃縮した後、カラムクロマトグラフィーにより精製して、3,4-ビス(ベンジルオキシ)ベンズアルデヒド(1101、1.04g、収率90%)を得た。
3,4-ビス(ベンジルオキシ)ベンズアルデヒド(1101、33mg、0.1mmol)に無水エタノール(5ml)を入れて希釈した後、エタノールアミン(30μL、0.5mmol)を入れて、60~70℃で4時間攪拌した。反応物を室温で冷却してイミンが生成されたことをTLCで確認した後、NaBH4(7.6mg、0.2mmol)を徐々に反応物に入れて、さらに4時間攪拌した。反応溶媒を減圧して濃縮した後、水と酢酸エチルで抽出した。抽出した有機層を塩水で1回洗浄した後、有機層を取り、無水硫酸ナトリウムで脱水および減圧ろ過した。ろ過された有機層を濃縮した後、カラムクロマトグラフィー(ジクロロメタン:メタノール=19:1)で精製して、純粋な白い固体の2-((3,4-ビス(ベンジルオキシ)ベンジル)アミノ)エタン-1-オール(YTK-1105、32mg、収率85%)を得た。
段階1でベンジルブロミドの代わりに(2-ブロモエチル)ベンゼンを使用して実施例1と同様の方法で製造した。
段階1でベンジルブロミドの代わりに(3-ブロモプロピル)ベンゼンを使用して実施例1と同様の方法で製造した。
段階1でベンジルブロミドの代わりに(4-ブロモブチル)ベンゼンを使用して実施例1と同様の方法で製造した。
段階1でベンジルブロミドの代わりに1-(ブロモメチル)-4-クロロベンゼンを使用し、実施例1と同様の方法で製造した。
段階1でベンジルブロミドの代わりに1-(ブロモメチル)-4-フルオロベンゼンを使用し、実施例1と同様の方法で製造した。
3,4-ビス(ベンジルオキシ)ベンズアルデヒド(1101、33mg、0.1mmol)を無水エタノール(5ml)に溶解した後、2-((2-アミノエチル)アミノ)エタン-1-オール(50μL、0.5mmol)を入れて、4時間還流攪拌した。室温で冷却した後、TLCでイミンが生成されたことを確認した後、NaBH4(7.6mg、0.2mmol)を入れて、さらに4時間攪拌した。反応溶媒を減圧して濃縮した後、水を入れて酢酸エチルで抽出した。分離された有機層を塩水でもう一度洗浄した後、分液して無水硫酸ナトリウムで脱水した後、ろ過して濾液を減圧濃縮した。濃縮された混合物をカラムクロマトグラフィーにより精製して、白い固体の2-((2-((3,4-ビス(ベンジルオキシ)ベンジル)アミノ)エチル)アミノ)エタン-1-オール(YTK-1108、収率84%)を得た。
前記実施例14の製造方法で、2-((2-アミノエチル)アミノ)エタン-1-オールの代わりに2-(2-アミノエトキシ)エタン-1-オールを使用し、同様の製造方法で合成して、2-(2-((3,4-ビス(ベンジルオキシ)ベンジル)アミノ)エトキシ)エタン-1-オール(YTK-11-A76、収率78%)を得た。
(段階1)3,4-ジヒドロキシベンズアルデヒド(2.5g、18.1mmol)を無水アセトニトリル(30ml)に溶解した後、K2CO3(2.5g、18.1mmol)を添加し、次いで、ベンジルブロミド(3.44mL、29.0mmol)を徐々に添加した。反応物を2時間還流攪拌した後、反応溶媒を減圧濃縮した。冷たい10%NaOH水溶液を添加して10分間攪拌した後、酢酸エチル(100ml)で抽出した。水層を4N HClで酸性化した後、ジクロロメタン(300ml)で3回抽出した。有機層を塩水でもう一度洗浄した後、無水硫酸ナトリウムで脱水およびろ過した。ろ過された有機層を減圧濃縮した後、酢酸エチルで結晶化して精製することにより、白い粉末の4-ベンジルオキシ-3-ヒドロキシベンズアルデヒド(1001、2.90g、収率70%)を製造した。
(段階1)4-ベンジルオキシ-3-ヒドロキシベンズアルデヒド(1001、0.50g、2.19mmol)をDMF(10ml)で希釈し、無水K2CO3(604mg、4.38mmol)および(2-ブロモエチル)ベンゼン(0.36mL、2.63mmol)を順次に徐々に添加した。混合物を70℃で2時間加熱した後、室温で冷却した。混合物を水で希釈した後、エーテルで抽出して有機層を分離し、水層を再びエーテルで3回抽出した。抽出された有機層を水(2×20mL)で洗浄し、NaCl水溶液(20mL)でもう一度洗浄した。薄い淡黄色の抽出物を無水硫酸ナトリウムで脱水しろ過した後、減圧して濃縮した。濃縮液をエタノールアセテート:ヘキサン(1:9)を用いてカラムクロマトグラフィーで精製して、クリーム色固体の4-(ベンジルオキシ)-3-フェネトキシベンズアルデヒド(1201、0.66g、収率90%)を製造した。
(段階1)1301の製造:(2-ブロモエチル)ベンゼンの代わりに(3-ブロモプロピル)ベンゼンを使用して実施例6の段階1と同様の製造方法で合成した。
(段階1)3-ヒドロキシベンズアルデヒド(0.44g、3.62mmol)を無水DMF(5ml)に溶かした後、K2CO3を入れて、次いで、ベンジルブロミド(0.50ml、4.34mmol)を添加した後、60℃で4時間攪拌した。反応が終了すると、室温で冷却した後、水を添加した後、ジエチルエーテルで抽出した。水層をジエチルエーテルで2回さらで抽出した後、有機層を水と塩水でもう一度洗浄した。有機層に無水硫酸ナトリウムを入れて脱水した後、減圧ろ過した。ろ過された有機層を減圧濃縮した後、カラムクロマトグラフィーで精製(ヘキサン:酢酸エチル=9:1)して、純粋な3-(ベンジルオキシ)ベンズアルデヒド(101、0.70g、収率92%)を得た。
ベンジルブロミドの代わりにフェネチルブロミドを使用して実施例8の段階1と同様の製造方法により3-フェネトキシベンズアルデヒド(201)を製造し、これを出発物質として使用して実施例8の段階2と同様の製造方法により、純粋な2-((3-(フェネトキシ)ベンジル)アミノ)エタン-1-オール(YTK-205、収率80%)を合成した。
ベンジルブロミドの代わりに1-(ブロモメチル)-4-クロロベンゼンを使用して実施例8の段階1と同様の製造方法により3-((4-クロロベンジル)オキシ)ベンズアルデヒド(101-1)を製造し、これを出発物質として使用して実施例8の段階2と同様の製造方法により、純粋な2-((3-((4-クロロベンジル)オキシ)ベンジル)アミノ)エタン-1-オール(YT-5-7)を合成した。
ベンジルブロミドの代わりに1-(ブロモメチル)-4-フルオロベンゼンを使用して実施例8の段階1と同様の製造方法により3-((4-フルオロベンジル)オキシ)ベンズアルデヒド(101-2)を製造し、これを出発物質として使用して実施例8の段階2と同様の製造方法により、純粋な2-((3-((4-フルオロベンジル)オキシ)ベンジル)アミノ)エタン-1-オール(YT-5-8)を合成した。
3-((4-クロロベンジル)オキシ)ベンズアルデヒド(101-1、300mg、1.2mmol)をメタノール(5ml)に溶解した後、2-(2-アミノエチルアミノ)エタノール(133mg、1.3mmol)を添加し、65℃で6時間攪拌した。イミンが生成されると反応物を0℃に冷却した後、NaBH4を添加し、1時間室温でさらに攪拌した。反応後、反応溶媒を減圧して除去した後、再び水で希釈して酢酸エチルで抽出した。抽出した有機層を無水硫酸ナトリウムで脱水した後、減圧ろ過した。ろ過された有機層を減圧濃縮した後、高分解能液体クロマトグラフィーにより精製して、白い固体の2-((2-((3,4-ビス(4-クロロベンジル)オキシ)ベンジル)アミノ)エチル)アミノ)エタン-1-オール(YT-8-7、25mg)を合成した。
3-((4-クロロベンジル)オキシ)ベンズアルデヒドの代わりに3-((4-フルオロベンジル)オキシ)ベンズアルデヒド(101-2)を出発物質として使用して実施例15の製造方法と同様の方法で製造した。
(段階1)3-(ベンジルオキシ)ベンズアルデヒド(101、1.0g、4.7mmol)をメタノール(20ml)に溶解した後、tert-ブチル-2-アミノエチルカルバメート(0.79g、4.9mmol)を反応物に入れて、65℃で6時間攪拌した。0℃に冷却した後、NaBH4を反応物に徐々に入れた後、1時間さらに室温で攪拌した。反応溶媒を減圧して除去した後、再び水で希釈して酢酸エチルで抽出した。抽出した有機層を無水硫酸ナトリウムで脱水した後、減圧ろ過した。ろ過された有機層を減圧濃縮した後、高分解能液体クロマトグラフィーにより精製して、明るい黄色の固体(111、1.3g)を得た。
3-(ベンジルオキシ)ベンズアルデヒド(101)の代わりに3-フェネトキシベンズアルデヒド(201)を出発物質として使用して実施例17の製造方法と同様の方法で、1-(2-((3-(フェネトキシベンジル)アミノ)エチル)グアニジン(YTK-207、22mg)を合成した。
(段階1)3,4-ビス(ベンジルオキシ)ベンズアルデヒド(1101、4g、12.5mmol)をテトラヒドロフラン(THF、40ml)に溶解した後、チタンイソプロポキシド((Ti(OiPr)4、7.15g、25.1mmol)を20℃で添加した。約5分間20℃で攪拌した後、2-メチルプロパン-2-スルフィンアミド(3.71g、30.7mmol)を徐々に反応物に添加した。反応物を20℃で5時間攪拌した後、aq.NH4Cl(100ml)を反応物に徐々に添加した。反応溶液を酢酸エチル(50ml)で3回抽出した後、有機層を無水硫酸ナトリウムで脱水および減圧した。ろ過された液を減圧濃縮して、N-(3,4-ビス(ベンジルオキシ)ベンジリデン)-2-メチルプロパン-2-スルフィンアミド(1108、4g)を得た。ESIMS m/z:422.5[M+H]+。
(3,4-ビス(ベンジルオキシ)フェニル)メタンアミン(1110、250mg、0.8mmol)をジクロロメタン(5ml)に溶解した後、反応容器を0℃に冷却した後、ヒドロキシベンゾトリアゾール(HOBT、160mg、1.1mmol)、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド(EDCI、225mg、1.1mmol)、トリエチルアミン(TEA、240mg、2.3mmol)および2-ヒドロキシ酢酸(72mg、0.9mmol)を順次に添加した。室温に加温した後、12時間攪拌した。反応物に精製水(20ml)を入れて、酢酸エチル(20ml)で2回抽出した後、抽出した有機層を再び水と塩水で順次に洗浄した後、無水硫酸ナトリウムで脱水および減圧した。ろ過液を減圧濃縮して高分解能液体クロマトグラフィーで精製して、白い固体のN-(3,4-ビス(ベンジルオキシ)ベンジル)-2-ヒドロキシアセトアミド(ATB10042、14mg)を製造した。
3,4-ビス(ベンジルオキシ)ベンズアルデヒド(1101、0.5g、1.5mmol)をメタノール(5ml)に溶解した後、(R)-3-アミノ-2-(tert-ブトキシカルボニルアミノ)プロパン酸(384mg、1.8mmol)を添加した後、65℃で6時間攪拌した。室温で冷却した後、NaBH4(60mg、1.6mmol)を反応物に徐々に添加した後、30℃で12時間攪拌した。反応物に精製水(50ml)を入れて、ジクロロメタン(20ml)で3回抽出した後、抽出した有機層を無水硫酸ナトリウムで脱水および減圧した。ろ過液を減圧濃縮した。濃縮された反応生成物を酢酸エチル(5ml)に溶解した後、酢酸エチル/塩酸溶液(3ml、2N)を添加した後、室温で5時間攪拌した後、溶媒を減圧濃縮して高分解能液体クロマトグラフィーで精製して、明るい灰色固体の(R)-2-アミノ-3-((3,4-ビス(ベンジルオキシ)ベンジル)アミノ)プロパン酸(ATB10043,40mg)を製造した。
3,4-ビス(ベンジルオキシ)ベンズアルデヒド(1101、0.5g、1.5mmol)をメタノール(5ml)に溶解した後、グリシンアミド(207mg、1.8mmol)およびトリエチルアミン(TEA、30mg、3.0mmol)を順次に反応物に添加した。反応物を65℃で2時間攪拌した後、室温で冷却した。室温でNaBH4(60mg、1.6mmol)を反応物に添加した後、30℃で12時間攪拌した。反応が終了すると、反応物に精製水(50ml)を入れて、ジクロロメタン(20ml)で3回抽出した後、抽出した有機層を無水硫酸ナトリウムで脱水および減圧した。ろ過液を減圧濃縮して高分解能液体クロマトグラフィーで精製して、白い固体の(R)-2-アミノ-3-((3,4-ビス(ベンジルオキシ)ベンジル)アミノ)プロパン酸(ATB10044、14mg)を製造した。
(段階1)3,4-ジヒドロキシ-5-メトキシベンズアルデヒド(0.5mg、2.9mmol)をアセトニトリル(ACN、50ml)に溶解した後、K2CO3(1.6g、11.8mmol)およびベンジルブロミド(1.09g、6.4mmol)を添加した。反応物を60℃で12時間攪拌した後、室温で冷却した。反応物に精製水(50ml)を入れて酢酸エチル(100ml)で抽出した後、抽出した有機層を無水硫酸ナトリウムで脱水および減圧ろ過した。ろ過された液を減圧濃縮して、黄色液体の3,4-ビス(ベンジルオキシ)-5-メトキシベンズアルデヒド(1111、0.5g)を得た。ESIMS m/z:349.2[M+H]+。
(段階1)3-(ベンジルオキシ)-4-ヒドロキシベンズアルデヒド(0.5g、2.1mmol)をTHF(5ml)に溶解した後、NaH(0.1g、2.6mmol)を0℃で添加して30分間攪拌した。N-クロロコハク酸イミド(NCS、0.3g、2.3mmol)を反応物に0℃で添加した後、室温で12時間攪拌した。反応液を酢酸エチル(15ml)で希釈した後、アンモニウムクロリド水溶液(10ml)で洗浄した。分液した有機層を無水硫酸ナトリウムで脱水およびろ過した後、濾液を減圧濃縮して、3-(ベンジルオキシ)-5-クロロ-4-ヒドロキシベンズアルデヒド(1112、0.2g)を得た。ESIMS m/z:263.5[M+H]+。
実施例19の製造方法で、段階3で2-アミノエタン-1-オールの代わりにグリシンメチルエステルを使用したことを除いては、実施例19の製造方法と同様の方法で、メチル(R)-(3-(3,4-ビス(ベンジルオキシ)フェノキシ)-2-ヒドロキシプロピル)グリシネート(YOK-G-1104)を合成した。
実施例19の製造方法で、段階3で2-アミノエタン-1-オールの代わりにアラニンエチルエステルを使用したことを除いては、実施例19の製造方法と同様の方法で、エチル(R)-(3-(3,4-ビス(ベンジルオキシ)フェノキシ)-2-ヒドロキシプロピル)アラニネート(YOK-A-1104)を合成した。
前記化合物(実施例1-25)のp62タンパク質のオリゴマー化活性効能を評価するために、ヒト胚腎臓由来細胞のHEK293細胞株を収集した。本化合物中の代表化合物として実施例1、2、3、5、6、7、8、9、12および13の化合物(実施例10(YT-5-1)、実施例11(YT-5-2)、実施例12(YT5-7)、実施例13(YT5-8)、実施例15(YT-8-7)、実施例16(YT-8-8)、実施例17(YTK-107)、実施例18(YTK-107)、実施例20(ATB10041)、実施例21(ATB10042)、実施例22(ATB10043)、実施例23(ATB10044)、実施例24(ATB10045)、実施例25(ATB10046)を選択し、これらの選択された代表化合物の処理による細胞内p62タンパク質の活性化およびオリゴマー化を測定するために、100パイのディッシュにそれぞれの細胞を分注した。細胞がプレートの表面に完全に付着するように24時間さらに培養した後、細胞を収集し、各サンプルに100ulの溶解バッファー(20mM Tris(pH7.4)、150mM NaCl、1% Triton X-100、2mM NaF、2mM EDTA、2mM beta-glycerophosphate、5mM sodium orthovanadate、1mM PMSF、leupeptin、aproteinin)を注入し、細胞を溶解させた。測定された総タンパク質の濃度に基づいて各サンプルに常温で2時間試験化合物を処理した後、サンプルバッファーを追加して、95℃で10分間反応させた。反応済みのサンプルから25ulを取ってアクリルアミドゲルの各ウェルに分注した後、免疫ブロッティング法を実施した。免疫ブロッティング法は、3回以上の独立した実験から代表的なものを図式化した。結果は図2に示す。
図2から確認できるように、本発明によるp62リガンド化合物を処理した場合、化合物の処理により、p62タンパク質の単位体(monomer)の減少とともに、オリゴマー(oligomer)と高分子量凝集体(high-molecular aggregates)の増加を確認することができた。
前記化合物(実施例1-25)のオートファジー活性効能を評価するために、子宮頸癌患者由来細胞のHela細胞株を5%二酸化炭素が維持される培養器内で10%FBSと1%ストレプトマイシン/ペニシリンを含むDMEM培地を用いて培養した。本化合物中の代表化合物として実施例1、2、3、5、6、7、8、9、12および13の化合物(実施例5(YTK-1005)、実施例1(YTK-1105)、実施例6(YTK-1205)、実施例7(YTK-1305)、実施例2(YTK-2205)、実施例3(YTK-3305)、実施例8(YTK-105)、実施例9(YTK-205)、実施例14(YTK-1108)、実施例12(YT5-7)、実施例13(YT5-8))、実施例20(ATB10041)、実施例21(ATB10042)、実施例22(ATB10043)、実施例23(ATB10044)、実施例24(ATB10045)、実施例25(ATB10046)を選択し、これらの選択された代表化合物の処理によるオートファジー活性度を測定するために、6ウェルプレートにそれぞれの細胞を分注した。細胞がプレートの表面に完全に付着するように24時間さらに培養した。それぞれの化合物がオートファジー現象を増加させることができる濃度を見出すために、試験化合物を1、2、5、10、20μMに希釈して処理した。各化合物の処理後、細胞を再び細胞培養器で24時間培養した後、細胞を収集した。収集された細胞からタンパク質を抽出するために、各サンプルに100ulの溶解バッファー(20mM Tris(pH7.4)、150mM NaCl、1% Triton X-100、2mM NaF、2mM EDTA、2mM beta-glycerophosphate、5mM sodium orthovanadate、1mM PMSF、leupeptin、aproteinin)を注入して細胞を溶解させた。測定された総タンパク質の濃度に基づいて各サンプルにサンプルバッファーを追加して、100℃で5分間反応させた。反応済みのサンプルから5ulを取ってアクリルアミドゲルの各ウェルに分注した後、免疫ブロッティング法を実施した。免疫ブロッティング法は、3回以上の独立した実験から代表的なものを図式化した。結果は図2に示す。
前記化合物(実施例1-25)のオートファジー活性効能を調べるために、LC3をマーカーとして用いて実験例2と同様の方法で免疫ブロッティング法を行った。相違点としては、活性化に要求される処理時間および活性維持時間を評価するために、1、3、6、12、24、48時間、5μMの本化合物の中から選択された代表化合物(実施例5(YTK-1005)、実施例6(YTK-1205)、実施例7(YTK-1305)、実施例2(YTK-2205)、実施例3(YTK-3305)、実施例14(YTK-1108)、実施例8(YTK-105)、実施例9(YTK-205))を処理した。他方では、24時間、10μMの本化合物の中から選択された代表化合物(実施例10(YT5-1)、実施例11(YT5-2)、実施例16(YT8-8)、実施例15(YT8-7)、実施例17(YTK-107)、実施例18(YTK-207)、実施例20(ATB10041)、実施例21(ATB10042)、実施例22(ATB10043)、実施例23(ATB10044)、実施例24(ATB10045)、実施例25(ATB10046)を処理した。免疫ブロッティング法は、3回以上の独立した実験から代表的なものを図式化し、その結果は図3に示す。図4から分かるように、本発明によるp62リガンド化合物を処理した場合、化合物の処理によって漸増的にマクロオートファジー活性の標識子であるLC3の水準が増加することを確認することができた。
対照群化合物のオートファジー活性効能を調べるために、LC3をマーカーとして用いて実験例2と同様の方法で免疫ブロッティングを行った。対照群化合物としては、下記の構造を有する化合物を用いた。
前記化合物(実施例1-25)のp62タンパク質活性およびオートファジー現象の活性程度を把握するために、p62とLC3をマーカーとして用いて免疫蛍光染色法を行った。培養された細胞内で新規p62リガンドとその異性体によるp62活性およびオートファジー現象の活性程度を把握するために、子宮頸癌患者由来細胞株のHela細胞株に新規p62リガンド化合物(YTK-1205、YTK-1305、YTK-2205、YTK-3305、YTK-105、YTK-205、YT5-1、YT9-1、YT5-2、YT9-2、YT8-2、YT8-1、YTK-107、YTK-207)を処理して培養した後、オートファジー現象の標識子としてLC3の斑点の発現程度と位置およびp62との斑点位置の共存性を観察した。
対照群化合物(YOK-A-1104、YOK-G-1104、YTK-1005、YTK-1105-1)のp62タンパク質の活性およびオートファジー現象の活性程度を把握するために、p62とLC3をマーカーとして用いて実験例4と同様の方法で免疫蛍光染色法を行った。YOK-A-1104、YOK-G-1104は、以下の化学式を有する化合物である。
前記化合物(実施例1-25)のユビキチン化されたタンパク質のp62媒介オートファジー伝達活性程度を把握するために、p62とFK2をマーカーとして用いて実験例4と同様の方法で免疫蛍光染色法を行った。化合物は実施例15(YT-8-7)、実施例16(YT-8-8)、実施例17(YTK-107)および実施例18(YTK-207)を処理した。化合物を処理した後、p62またはFK2の細胞内斑点、すなわち、p62とユビキチン化されたタンパク質がオートファゴソームに伝達される程度を共焦点顕微鏡で観察した。結果は図8に示す。免疫蛍光染色法は、3回以上の独立した実験から代表的なものを図式化した。
前記化合物(実施例1-25)の退行性脳疾患ハンチントン病の主要タンパク質である変性ハンチンチン(Htt-Q103)がp62媒介オートファジー伝達活性程度を把握するために、p62とHtt-Q103-GFPをマーカーとして用いて実験例4と同様の方法で免疫蛍光染色法を行った。化合物は実施例10(YT-5-1)、実施例15(YT-8-7)、実施例16(YT-8-8)、実施例17(YTK-105)、実施例18(YTK-207)および実施例2(YTK-2205)を用いた。化合物を処理した後、p62またはHtt-Q103-GFPの細胞内斑点、すなわち、p62と変性ハンチンチンタンパク質がオートファゴソームに伝達される程度を共焦点顕微鏡で観察した。結果は図9に示す。免疫蛍光染色法は、3回以上の独立した実験から代表的なものを図式化した。
Claims (19)
- 下記化学式1で表されるp62リガンド化合物、その薬学的に許容可能な塩、立体異性体、溶媒和物、水和物またはプロドラッグ。
Wは炭素数6~10のアリールであり、
mは0~2の整数であり、
RaはR1または-OR1であり、
この時、R1は水素、または-(CH2)n1-R’1であり、
R’1は非置換;またはヒドロキシ、ハロゲン、炭素数1~4のアルキル、炭素数1~4のアルコキシ、ニトロ、アミノ、(炭素数1~4のアルキル)アミノ、またはジ(炭素数1~4のアルキル)アミノで置換されたフェニルであり、
n1は1~6の整数であり、
Rbは-OR2であり、
この時、R2は水素、または-(CH2)n2-R’2であり、
R’2は非置換;またはヒドロキシ、ハロゲン、炭素数1~4のアルキル、炭素数1~4のアルコキシ、ニトロ、アミノ、(炭素数1~4のアルキル)アミノ、またはジ(炭素数1~4のアルキル)アミノで置換されたフェニルであり、
n2は1~6の整数であり、
Rcは-(CH2)n3-OH、-(CH2)n3-NH-C(=NH)NH2、-C(=NH)NH2、炭素数1~6のアルキル、-CH(R3)-COO-R4、または-CH(COO-R4)-CH2CH2CH2-NH-C(=NH)NH2、-(CH2)n3-O-(CH2)n3-OR4、-CONH(CH2)n3-OR4、-CO(CH2)n4-OR4、-(CH2)n4-CH(NH2)-COOR4、-(CH2)n4-CONHR4であり、
n3は2~4の整数であり、
n4は1~4の整数であり、
R3は水素、または炭素数1~4のアルキルであり、
R4は水素、または炭素数1~4のアルキルであり、
Rdは水素、ハロゲン、炭素数1~4のアルコキシまたは炭素数1~4のアルキルであり、
この時、前記化学式1の化合物は、下記化合物からなる群の中から選択される化合物でない。
1)2-((3,4-ビス(ベンジルオキシ)ベンジル)アミノ)エタン-1-オール(YTK-1105)
2)2-(3,4-ジフェネトキシベンジルアミノ)エタノール(YTK-2205)
3)2-(3,4-ビス(3-フェニルプロポキシ)ベンジルアミノ)エタノール(YTK-3305)
4)2-(3,4-ビス(4-フェニルブトキシ)ベンジルアミノ)エタノール(YTK-4405)
5)2-(ベンジルオキシ)-5-((2-ヒドロキシエチルアミノ)メチル)フェノール(YTK-1005)
6)2-(4-(ベンジルオキシ)-3-フェネトキシベンジルアミノ)エタノール(YTK-1205)
7)2-(4-(ベンジルオキシ)-3-(3-フェニルプロポキシ)ベンジルアミノ)エタノール(YTK-1305)
8)2-(4-(ベンジルオキシ)-3-(4-フェニルブトキシ)ベンジルアミノ)エタノール(YTK-1405)
9)2-((3-(フェネトキシ)ベンジル)アミノ)エタン-1-オール(YTK-205)
10)2-((3-(3-フェニルプロポキシ)ベンジル)アミノ)エタン-1-オール(YTK-305)
11)2-(3,4-ビス((4-クロロフェニル)メトキシ)ベンジルアミノ)エタノール(YT-5-1)
12)2-(3,4-ビス((4-フルオロフェニル)メトキシ)ベンジルアミノ)エタノール(YT-5-2)
13)2-(3,4-ビス((4-ジメチルアミノフェニル)メトキシ)ベンジルアミノ)エタノール(YT-5-3)
14)2-(3,4-ビス(4-ニトロフェニル)メトキシ)ベンジルアミノ)エタノール(YT-5-4)
15)2-(3,4-ビス(4-メトキシフェニル)メトキシ)ベンジルアミノ)エタノール(YT-5-5)
16)2-(3,4-ビス(4-ヒドロキシフェニル)メトキシ)ベンジルアミノ)エタノール(YT-5-6)
17)2-((3-((4-クロロベンジル)オキシ)ベンジル)アミノ)エタン-1-オール(YT-5-7)
18)2-((3-((4-フルオロベンジル)オキシ)ベンジル)アミノ)エタン-1-オール(YT-5-8)
19)2-((3-((4-ニトロベンジル)オキシ)ベンジル)アミノ)エタン-1-オール(YT-5-10)
20)2-(3,4-ジベンジルオキシ)ベンジルアミノ)プロパノール(YtK-11-A54)
21)2-((2-((3-(ベンジルオキシ)ベンジル)アミノ)エチル)アミノ)エタン-1-オール(YTK-108)
22)2-((2-((3-((4-クロロベンジル)オキシ)ベンジル)アミノ)エチル)アミノ)エタン-1-オール(YT-8-7);および
23)2-((2-((3-((4-フルオロベンジル)オキシ)ベンジル)アミノ)エチル)アミノ)エタン-1-オール(YT-8-8)。 - 前記Wはフェニルである、請求項1に記載の化合物、その薬学的に許容可能な塩、立体異性体、溶媒和物、水和物またはプロドラッグ。
- 前記Raは水素、または-O-(CH2)n1-R’1であり、R’1は非置換;またはヒドロキシ、フルオロ、クロロ、ブロモ、メチル、エチル、メトキシ、エトキシ、ニトロ、アミノまたはジメチルアミノで置換されたフェニルであり、n1は1~4の整数である、請求項1に記載の化合物、その薬学的に許容可能な塩、立体異性体、溶媒和物、水和物またはプロドラッグ。
- 前記Rbはヒドロキシ、または-O-(CH2)n2-R’2であり、R’2は非置換;またはヒドロキシ、フルオロ、クロロ、ブロモ、メチル、エチル、メトキシ、エトキシ、ニトロ、アミノまたはジメチルアミノで置換されたフェニルであり、n2は1~4の整数である、請求項1に記載の化合物、その薬学的に許容可能な塩、立体異性体、溶媒和物、水和物またはプロドラッグ。
- 前記Rcは-(CH2)2-OH、-(CH2)2-NH-C(=NH)NH2、-C(=NH)NH2、メチル、エチル、イソプロピル、-(CH2)n3-O-(CH2)n3-OR3、-CONH(CH2)n3-OR3、-CO(CH2)n4-OR3、-(CH2)n4-CH(NH2)-COOR3、または-(CH2)n4-CONHR3であり、n3は2~3の整数であり、n4は1~2の整数であり、R3は水素または炭素数1~2のアルキルであり、Rdは水素、ハロゲン、炭素数1~2のアルコキシまたは炭素数1~2のアルキルである、請求項1に記載の化合物、その薬学的に許容可能な塩、立体異性体、溶媒和物、水和物またはプロドラッグ。
- 前記化学式1の化合物が下記化合物からなる群から選択される、請求項1に記載の化合物、その薬学的に許容可能な塩、立体異性体、溶媒和物、水和物またはプロドラッグ。
1)2-((3-(ベンジルオキシ)ベンジル)アミノ)エタン-1-オール(YTK-105);
2)2-((2-((3,4-ビス(ベンジルオキシ)ベンジル)アミノ)エチル)アミノ)エタン-1-オール(YTK-1108);
3)1-(2-((3-(ベンジルオキシ)ベンジル)アミノ)エチル)グアニジン(YtK-107);
4)1-(2-((3-(フェネトキシベンジル)アミノ)エチル)グアニジン(YtK-207);
5)2-(2-((3,4-ビス(ベンジルオキシ)ベンジル)アミノ)エトキシ)エタン-1-オール(YtK-11-A76);
6)1-(3,4-ビス(ベンジルオキシ)ベンジル)-3-(2-ヒドロキシエチル)ウレア(ATB10041);
7)N-(3,4-ビス(ベンジルオキシ)ベンジル)-2-ヒドロキシアセトアミド(ATB10042);
8)(R)-2-アミノ-3-((3,4-ビス(ベンジルオキシ)ベンジル)アミノ)プロパン酸(ATB10043);
9)2-((3,4-ビス(ベンジルオキシ)ベンジル)アミノ)アセトアミド(ATB10044);
10)2-((3,4-ビス(ベンジルオキシ)-5-メトキシベンジル)アミノ)エタン-1-オール(ATB10045);および
11)2-((3,4-ビス(ベンジルオキシ)-5-クロロベンジル)アミノ)エタン-1-オール(ATB10046)。 - 下記化学式1aの化合物、その薬学的に許容可能な塩、立体異性体、溶媒和物、水和物またはプロドラッグを含む、タンパク質異常疾患の予防、改善または治療用薬学的組成物。
Wは炭素数6~10のアリールであり、
mは0~2の整数であり、
RaはR1または-OR1であり、
この時、R1は水素、または-(CH2)n1-R’1であり、
R’1は非置換、またはヒドロキシ、ハロゲン、炭素数1~4のアルキル、炭素数1~4のアルコキシ、ニトロ、アミノ、(炭素数1~4のアルキル)アミノ、またはジ(炭素数1~4のアルキル)アミノで置換されたフェニルであり、
n1は1~6の整数であり、
Rbは-OR2であり、
この時、R2は水素、または-(CH2)n2-R’2であり、
R’2は非置換;またはヒドロキシ、ハロゲン、炭素数1~4のアルキル、炭素数1~4のアルコキシ、ニトロ、アミノ、(炭素数1~4のアルキル)アミノ、またはジ(炭素数1~4のアルキル)アミノで置換されたフェニルであり、
n2は1~6の整数であり、
Rcは-(CH2)n3-OH、-(CH2)n3-NH-C(=NH)NH2、-C(=NH)NH2、炭素数1~6のアルキル、-CH(R3)-COO-R4、または-CH(COO-R4)-CH2CH2CH2-NH-C(=NH)NH2、-(CH2)n3-O-(CH2)n3-OR4、-CONH(CH2)n3-OR4、-CO(CH2)n4-OR4、-(CH2)n4-CH(NH2)-COOR4、-(CH2)n4-CONHR4であり、
n3は2~4の整数であり、
n4は1~4の整数であり、
R3は水素、または炭素数1~4のアルキルであり、
R4は水素、または炭素数1~4のアルキルであり、
Rdは水素、ハロゲン、炭素数1~4のアルコキシまたは炭素数1~4のアルキルである。 - 前記タンパク質異常疾患は、神経変性疾患、アルファ1-アンチトリプシン欠乏症、角膜症、色素性網膜症、2型糖尿病および嚢胞性線維症である、請求項7に記載の薬学的組成物。
- 前記神経変性疾患は、ライム病(Lyme borreliosis)、致死性家族性不眠症(Fatal familial insomnia)、クロイツフェルト-ヤコブ病(Creutzfeldt-Jakob Disease;CJD)、多発性硬化症(multiple sclerosis;MS)、認知症(dementia)、アルツハイマー病(Alzheimer’s disease)、てんかん(epilepsy)、パーキンソン病(Parkinson’s disease)、脳卒中(stroke)、ハンチントン病(huntington’s disease)、ピック病(Picks disease)、筋萎縮性側索硬化症(amyotrophic lateral sclerosis、ALS)脊髄小脳失調症、その他ポリ-Q疾患、遺伝性脳アミロイド血管病症、家族性アミロイド多発神経病症、1次全身アミロイド症(ALアミロイド症)、反応性全身アミロイド症(AAアミロイド症)、アルファ1-アンチトリプシン欠乏症、アレキサンダー病、角膜症、色素性網膜症、2型糖尿病、嚢胞性線維症、注射-局所化アミロイド症、ベータ-2マイクログロブリンアミロイド症、遺伝性非-神経病アミロイド症、およびフィンランド遺伝性全身アミロイド症からなる群から選択される1種以上である、請求項8に記載の薬学的組成物。
- 下記化学式1aの化合物、その薬学的に許容可能な塩、立体異性体、溶媒和物、水和物またはプロドラッグを含む、変性タンパク質のオートファジー活性増加用の薬学的組成物。
Wは炭素数6~10のアリールであり、
mは0~2の整数であり、
RaはR1または-OR1であり、
この時、R1は水素、または-(CH2)n1-R’1であり、
R’1は非置換;またはヒドロキシ、ハロゲン、炭素数1~4のアルキル、炭素数1~4のアルコキシ、ニトロ、アミノ、(炭素数1~4のアルキル)アミノ、またはジ(炭素数1~4のアルキル)アミノで置換されたフェニルであり、
n1は1~6の整数であり、
Rbは-OR2であり、
この時、R2は水素、または-(CH2)n2-R’2であり、
R’2は非置換;またはヒドロキシ、ハロゲン、炭素数1~4のアルキル、炭素数1~4のアルコキシ、ニトロ、アミノ、(炭素数1~4のアルキル)アミノ、またはジ(炭素数1~4のアルキル)アミノで置換されたフェニルであり、
n2は1~6の整数であり、
Rcは-(CH2)n3-OH、-(CH2)n3-NH-C(=NH)NH2、-C(=NH)NH2、炭素数1~6のアルキル、-CH(R3)-COO-R4、または-CH(COO-R4)-CH2CH2CH2-NH-C(=NH)NH2、-(CH2)n3-O-(CH2)n3-OR4、-CONH(CH2)n3-OR4、-CO(CH2)n4-OR4、-(CH2)n4-CH(NH2)-COOR4、-(CH2)n4-CONHR4であり、
n3は2~4の整数であり、
n4は1~4の整数であり、
R3は水素、または炭素数1~4のアルキルであり、
R4は水素、または炭素数1~4のアルキルであり、
Rdは水素、ハロゲン、炭素数1~4のアルコキシまたは炭素数1~4のアルキルである。 - 前記タンパク質は、癌誘発タンパク質、プリオンタンパク質、アミロイド前駆体タンパク質(APP)、アルファ-シヌクレイン、スーパーオキシドディスムターゼ、タウ、免疫グロブリン、アミロイド-A、トランスサイレチン、ベータ2-マイクログロブリン、シスタチンC、アポリポタンパク質(Apolipoproteine)A1、TDP-43、島アミロイドポリペプチド(islet amyloid polypeptide)、ANF、ゲルゾリン(gelsolin)、インスリン、リゾチーム、フィブリノゲン、ハンチンチン(huntingtin)アルファ-1-アンチトリプシンZ、クリスタリン(crystallin)、c9オープンリーディングフレーム72(c9orf72)、グリア細胞繊維性酸性タンパク質(glial fibrillary acidic protein)、嚢胞性線維症膜コンダクタンス制御因子タンパク質(cystic fibrosis transmembrane conductance regulator protein)、ロドプシン(rhodopsin)およびアタキシンと、Poly-Q延伸を有するその他タンパク質からなる群から選択される1種以上である、請求項10に記載の薬学的組成物。
- 下記化学式1aの化合物、その薬学的に許容可能な塩、立体異性体、溶媒和物、水和物またはプロドラッグを含む、タンパク質異常疾患の予防または改善用食品組成物。
Wは炭素数6~10のアリールであり、
mは0~2の整数であり、
RaはR1または-OR1であり、
この時、R1は水素、または-(CH2)n1-R’1であり、
R’1は非置換;またはヒドロキシ、ハロゲン、炭素数1~4のアルキル、炭素数1~4のアルコキシ、ニトロ、アミノ、(炭素数1~4のアルキル)アミノ、またはジ(炭素数1~4のアルキル)アミノで置換されたフェニルであり、
n1は1~6の整数であり、
Rbは-OR2であり、
この時、R2は水素、または-(CH2)n2-R’2であり、
R’2は非置換、またはヒドロキシ、ハロゲン、炭素数1~4のアルキル、炭素数1~4のアルコキシ、ニトロ、アミノ、(炭素数1~4のアルキル)アミノ、またはジ(炭素数1~4のアルキル)アミノで置換されたフェニルであり、
n2は1~6の整数であり、
Rcは-(CH2)n3-OH、-(CH2)n3-NH-C(=NH)NH2、-C(=NH)NH2、炭素数1~6のアルキル、-CH(R3)-COO-R4、または-CH(COO-R4)-CH2CH2CH2-NH-C(=NH)NH2、-(CH2)n3-O-(CH2)n3-OR4、-CONH(CH2)n3-OR4、-CO(CH2)n4-OR4、-(CH2)n4-CH(NH2)-COOR4、-(CH2)n4-CONHR4であり、
n3は2~4の整数であり、
n4は1~4の整数であり、
R3は水素、または炭素数1~4のアルキルであり、
R4は水素、または炭素数1~4のアルキルであり、
Rdは水素、ハロゲン、炭素数1~4のアルコキシまたは炭素数1~4のアルキルである。 - 前記タンパク質異常疾患は、神経変性疾患、アルファ1-アンチトリプシン欠乏症、角膜症、色素性網膜症、2型糖尿病および嚢胞性線維症である、請求項12に記載の食品組成物。
- 前記神経変性疾患は、ライム病(Lyme borreliosis)、致死性家族性不眠症(Fatal familial insomnia)、クロイツフェルト-ヤコブ病(Creutzfeldt-Jakob Disease;CJD)、多発性硬化症(multiple sclerosis;MS)、認知症(dementia)、アルツハイマー病(Alzheimer’s disease)、てんかん(epilepsy)、パーキンソン病(Parkinson’s disease)、脳卒中(stroke)、ハンチントン病(huntington’s disease)、ピック病(Picks disease)、筋萎縮性側索硬化症(amyotrophic lateral sclerosis、ALS)脊髄小脳失調症、その他、ポリ-Q疾患、遺伝性脳アミロイド血管病症、家族性アミロイド多発神経病症、1次全身アミロイド症(ALアミロイド症)、反応性全身アミロイド症(AAアミロイド症)、アルファ1-アンチトリプシン欠乏症、アレキサンダー病、角膜症、色素性網膜症、2型糖尿病、嚢胞性線維症、注射-局所化アミロイド症、ベータ-2マイクログロブリンアミロイド症、遺伝性非-神経病アミロイド症、およびフィンランド遺伝性全身アミロイド症からなる群から選択される1種以上である、請求項13に記載の食品組成物。
- 請求項1~6のいずれか一項に記載のp62リガンド化合物を細胞またはp62タンパク質に処理する段階を含む、タンパク質凝集体の分解を増大させる方法。
- 請求項1~6のいずれか一項に記載のp62リガンド化合物を細胞またはp62タンパク質に処理する段階を含む、選択的オートファジーの活性化方法。
- 請求項1~6のいずれか一項に記載のp62リガンド化合物を個体に投与する段階を含む、細胞またはp62タンパク質に処理する段階を含む、タンパク質異常疾患を予防、改善または治療する方法。
- 前記タンパク質異常疾患は、神経変性疾患、アルファ1-アンチトリプシン欠乏症、角膜症、色素性網膜塩、2型糖尿病および嚢胞性線維症である、請求項17に記載の方法。
- 前記神経変性疾患は、ライム病(Lyme borreliosis)、致死性家族性不眠症(Fatal familial insomnia)、クロイツフェルト-ヤコブ病(Creutzfeldt-Jakob Disease;CJD)、多発性硬化症(multiple sclerosis;MS)、認知症(dementia)、アルツハイマー病(Alzheimer’s disease)、てんかん(epilepsy)、パーキンソン病(Parkinson’s disease)、脳卒中(stroke)、ハンチントン病(huntington’s disease)、ピック病(Picks disease)、筋萎縮性側索硬化症(amyotrophic lateral sclerosis、ALS)脊髄小脳失調症、その他、ポリ-Q疾患、遺伝性脳アミロイド血管病症、家族性アミロイド多発神経病症、1次全身アミロイド症(ALアミロイド症)、反応性全身アミロイド症(AAアミロイド症)、アルファ1-アンチトリプシン欠乏症、アレキサンダー病、角膜症、色素性網膜症、2型糖尿病、嚢胞性線維症、注射-局所化アミロイド症、ベータ-2マイクログロブリンアミロイド症、遺伝性非-神経病アミロイド症およびフィンランド遺伝性全身アミロイド症からなる群から選択される1種以上である、請求項18に記載の方法。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20160031799A1 (en) * | 2011-08-08 | 2016-02-04 | Id4Pharma, Llc | P62-zz chemical inhibitor |
WO2016200827A1 (en) * | 2015-06-11 | 2016-12-15 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | P62-zz chemical inhibitor |
EP3338787A1 (en) * | 2015-08-18 | 2018-06-27 | Seoul National University R&DB Foundation | Prevention and treatment of neurodegenerative diseases through autophagy activity mediated by ligand or arginylated bip binding to p62 zz domain |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4167581A (en) * | 1972-12-15 | 1979-09-11 | Imperial Chemical Industries Limited | Alkanolamine derivatives and pharmaceutical compositions and uses thereof |
US4471116A (en) * | 1982-07-28 | 1984-09-11 | Hoffmann-La Roche Inc. | Substituted (10H-phenothiazin-10-L)-propyl-1-piperazines |
US4857522A (en) | 1988-03-21 | 1989-08-15 | E. R. Squibb & Sons, Inc. | Derivatives of pravastatin for inhibiting cholesterol biosynthesis |
US20040009932A1 (en) | 2002-04-26 | 2004-01-15 | Kathleen Phelan | Antibacterial compounds with activity against penicillin-resistant streptococcus pneumoniae |
CN102229602A (zh) | 2011-05-13 | 2011-11-02 | 中山大学 | 他克林杂合物与制备方法及其在治疗神经退行性疾病药物中的应用 |
US8890745B2 (en) * | 2011-10-27 | 2014-11-18 | Raytheon Company | RF gun barrel detection system |
EP3039022A4 (en) | 2013-08-29 | 2017-08-16 | Baylor College Of Medicine | Compositions and methods for the treatment of metabolic and body weight related disorders |
KR101594168B1 (ko) * | 2013-10-02 | 2016-02-15 | 서울대학교산학협력단 | p62의 ZZ 영역에 의해 매개되는 자가포식 조절 방법 및 그 용도 |
BR112018008918A8 (pt) * | 2015-11-02 | 2019-02-26 | Univ Yale | compostos de quimera proteólise dirigida e métodos para preparação e uso dos mesmos |
KR20170023045A (ko) * | 2017-02-20 | 2017-03-02 | 서울대학교산학협력단 | p62 ZZ 도메인에 결합하는 리간드 또는 아르기닌화된 BiP에 의해 매개되는 오토파지 활성을 통한 신경변성 질환 예방 및 치료 |
WO2019190172A1 (ko) | 2018-03-26 | 2019-10-03 | 주식회사 프로텍바이오 | 신규한 화합물 및 이를 포함하는 비만 또는 대사증후군의 예방 또는 치료용 약학적 조성물 |
TWI748212B (zh) | 2018-07-24 | 2021-12-01 | 南韓商普洛科技股份有限公司 | 新穎的p62配體化合物及包含其之用於預防、改善或治療蛋白質構象病(proteinopathies)的組成物 |
CN114641282A (zh) * | 2019-06-18 | 2022-06-17 | 普罗泰克株式会社 | p62配体化合物及其ER-自噬促进用途 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20160031799A1 (en) * | 2011-08-08 | 2016-02-04 | Id4Pharma, Llc | P62-zz chemical inhibitor |
WO2016200827A1 (en) * | 2015-06-11 | 2016-12-15 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | P62-zz chemical inhibitor |
EP3338787A1 (en) * | 2015-08-18 | 2018-06-27 | Seoul National University R&DB Foundation | Prevention and treatment of neurodegenerative diseases through autophagy activity mediated by ligand or arginylated bip binding to p62 zz domain |
Non-Patent Citations (1)
Title |
---|
LEUKEMIA, vol. 30, no. 2, JPN6022003036, 2016, pages 390 - 398, ISSN: 0004926494 * |
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