JP7397491B2 - PPARδ活性化剤 - Google Patents
PPARδ活性化剤 Download PDFInfo
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- JP7397491B2 JP7397491B2 JP2020553434A JP2020553434A JP7397491B2 JP 7397491 B2 JP7397491 B2 JP 7397491B2 JP 2020553434 A JP2020553434 A JP 2020553434A JP 2020553434 A JP2020553434 A JP 2020553434A JP 7397491 B2 JP7397491 B2 JP 7397491B2
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- pparδ
- metformin
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- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/08—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by singly-bound oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/26—Radicals substituted by sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
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- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
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Description
本願は、2018年10月23日に、日本に出願された特願2018-199523号に基づき優先権を主張し、その内容をここに援用する。
[1] グアニジン誘導体又はビグアニジン誘導体を有効成分とし、PPARδ(Peroxisome proliferator-activated receptor δ)の転写活性を活性化する、PPARδ活性化剤。
[2] 前記グアニジン誘導体及び前記ビグアニジン誘導体は、グアニジノ基又はビグアニジノ基が、PPARδのリガンド結合ポケットの内部表面を構成するアミノ酸残基のうち、hPPARδの413番目のヒスチジン、287番目のヒスチジン、253番目のスレオニン、及び437番目のチロシンにそれぞれ相当するアミノ酸残基と水素結合をした状態で、前記リガンド結合ポケットの内部に嵌まり込み得る、前記[1]のPPARδ活性化剤。
[3] 前記グアニジン誘導体が、下記一般式(1)
[式(1)中、R1は1価の有機基を表す。]
で表される化合物(但し、ビグアニジン誘導体を除く)である、前記[1]又は[2]のPPARδ活性化剤。
[式(1-1-1)及び(1-1-2)中、Z11は酸素原子又は硫黄原子を表し、n1は0又は1を表し、R12は、炭素数1~6の脂肪族炭化水素基を表し、n12は0~2の整数を表し、R13は水素原子又は炭素数1~6の脂肪族炭化水素基を表し、R14は置換基を有していてもよい芳香族炭化水素基を表し、p1は1以上の整数を表す。
式(1-1-3)及び(1-1-4)中、Z11は酸素原子又は硫黄原子を表し、n1は0又は1を表し、R15は炭素数1~6の脂肪族炭化水素基又はアルコキシ基を表し、n15は0~2の整数を表し、Z2は2価の連結基を表し、R5は置換基を有していてもよい芳香族炭化水素基、又は置換基を有していてもよい環式炭化水素基を表し、p2は1以上の整数を表す。]
のいずれかで表される化合物である、前記[3]のPPARδ活性化剤。
[式(2)中、R2及びR3は、それぞれ独立して、水素原子又は1価の有機基を表す。R2及びR3がいずれも1価の有機基の場合、両者が連結して環構造を形成していてもよい。]
で表される化合物である、前記[1]~[3]のいずれかのPPARδ活性化剤。
[8] 前記[1]~[7]のいずれかのPPARδ活性化剤を有効成分とする、運動耐性改善剤。
一般式(1-1)中、R11は、置換基を有していてもよい炭素数1~6の脂肪族炭化水素基、置換基を有していてもよい芳香族炭化水素基、又は置換基を有していてもよい複数環連結基を表す。置換基を有していてもよい炭素数1~6の脂肪族炭化水素基、及び置換基を有していてもよい芳香族炭化水素基としては、それぞれ、前記のR4として取り得る基と同様のものが挙げられる。置換基を有していてもよい複数環連結基としては、前記の1価の有機基として取り得る複数環連結基と同様のものが挙げられる。
一般式(1-1-2)中、p1は、1以上の整数であり、1~6の整数であることが好ましく、1~3の整数であることがより好ましく、1が特に好ましい。
一般式(1-1-1)及び一般式(1-1-2)中、R12は、炭素数1~6の脂肪族炭化水素基を表す。当該脂肪族炭化水素基としては、前記のR4として取り得る基と同様のものが挙げられる。
一般式(1-1-1)及び一般式(1-1-2)中、R13は、水素原子又は炭素数1~6の脂肪族炭化水素基を表す。当該脂肪族炭化水素基としては、前記のR4として取り得る基と同様のものが挙げられる。
一般式(1-1-1)及び一般式(1-1-2)中、R14は、置換基を有していてもよい芳香族炭化水素基を表す。当該芳香族炭化水素基としては、前記のR4として取り得る基と同様のものが挙げられる。
一般式(1-1-4)中、p2は、1以上の整数であり、1~6の整数であることが好ましく、1~3の整数であることがより好ましく、1が特に好ましい。
一般式(1-1-3)及び一般式(1-1-4)中、R15は、炭素数1~6の脂肪族炭化水素基又はアルコキシ基を表す。当該脂肪族炭化水素基としては、前記のR4として取り得る基と同様のものが挙げられる。アルコキシ基としては、前記の脂肪族炭化水素基の置換基として挙げられた基と同様のものが挙げられる。
メトホルミンを固定したFG beads(登録商標)を用いたアフィニティ精製法により、メトホルミンの生体内での標的分子を探索した。メトホルミンの標的の探索には、ヒト肝臓癌由来細胞株HepG2細胞の細胞抽出液を用いた。
メトホルミンを固定化したFG beads(以下、「Met-ビーズ」と称する。)を作製した。固定化の方法は、COOH FGビーズの製造元から供与されたプロトコールに従った。具体的には、まず、N,N’-ジメチルホルムアミドで平衡化したCOOH FGビーズ(多摩川精機製社製)のリンカー末端のカルボン酸とN-ヒドロキシスクシンイミド(NHS)とを脱水縮合させることでNHS体を得た。次いで、得られたNHS体にメトホルミンを添加し、メトホルミンのNH2基とNHSエステルとを反応させてCOOH FGビーズのCOOH基とメトホルミンのNH2基とをアミド結合させて固定化した。COOH FGビーズへのメトホルミンの固定化反応の模式図を図3に示す。COOH FGビーズのうち、メトホルミンに未結合のCOOH基は、アミノエタノールによりマスキングした。マスキング後のMet-ビーズは、洗浄した後に50容量%メタノール水に懸濁して、以降の実験に用いた。
作製したMet-ビーズを、KClバッファー(100mM KCl、0.126g/mL グリセロール、20mM HEPES(pH7.9)、1mM MgCl2、200μM CaCl2、0.2mM EDTA、 0.1% NP-40)に懸濁した後、磁気分離を行って上清を廃棄した。次いで、このMet-ビーズに、200μLのKClバッファーを加えて超音波分散装置でビーズを分散させた後に磁気分離により上清を廃棄するという洗浄処理を3回繰り返した。
PPARδとメトホルミンの結合を共免疫沈降法により確認した。ヒト胎児腎臓由来細胞株HEK293細胞にMycタグ付きhPPARδ(Myc-hPPARδ)を強発現させたPPARδ強発現細胞の細胞抽出液から抗Myc抗体(sc-40、SantaCruz社製)を用いた免疫沈降により精製したMyc-hPPARδと、マウスの肝臓抽出液に対して、Met-ビーズを用いた免疫沈降を行った。
PPARδは核内受容体スーパーファミリーの一つであり、他にα、γというファミリーメンバーがある。Met-ビーズとHepG2細胞抽出液を用いてアフィニティ精製を行い、内在性のPPARαとの結合を検証した。この結果、メトホルミンとPPARαとの結合は確認できなかった。
メトホルミンは、AMPK(5’ AMP-activated protein kinase)を活性化することで、骨格筋での糖取り込みの亢進や肝臓での脂肪酸β酸化を制御していることが知られている。そこで、Met-ビーズとHepG2細胞抽出液を用いてアフィニティ精製を行い、内在性のAMPKとメトホルミンとの結合を検証した。この結果、メトホルミンとAMPKとの結合は確認できなかった。
メトホルミンとPPARδの親和性を、分子間相互作用測定装置(製品名:BLItz(登録商標)、Pall ForteBio社製)を用いて測定した。メトホルミンを固定化したバイオセンサーと精製Myc-hPPARδを用いて、メトホルミンとMyc-hPPARδの分子間相互作用を計測した。分子間相互作用測定装置のバイオセンサーへのメトホルミンの固定化は、メトホルミンのNH2基を介して行った。定に際しては、Myc-PPARδの濃度を6段階に希釈して、global fittingにより各濃度から算出された平均の分子間相互作用を算出した。バイオセンサーに固定化されたメトホルミンと段階希釈した精製Myc-hPPARδとの結合解離曲線を図7に示す。図中、縦軸は、メトホルミンを固定化したセンサー先端からのMyc-hPPARδタンパク質の距離(nm)であり、Myc-hPPARδタンパク質のセンサー先端への結合量の指標となる。この結果、結合速度定数(ka)は3.40×104M-1S-1解離速度定数(kd)は1.03×10-6S-1解離定数(KD)3.30×10-10Mと算出され、PPARδはメトホルミンへ強固に結合することが確認された。
PPARδにおけるメトホルミンの結合部位を決定するために、PPARδのN-termドメインを欠損させた変異体(ΔN-term:1~70番目のアミノ酸領域を欠損させた変異体)と、LBDのα-ヘリックスを3個目までしか持たず、リガンド結合ポケットを完全に欠損させた変異体(ΔLBD:237~441番目のアミノ酸領域を欠損させた変異体)を作製した。PPARδの全長及び各変異体の構造の模式図を図8に示す。
PPARδは、核内で核内受容体RXR(Retinoid X receptor)とヘテロダイマーを形成し、PPARδのリガンド存在下で転写活性化因子PGC1α(peroxisome proliferative activated receptor gamma coactivator-1)と結合し、正の転写調節因子として働く。そこで、ルシフェラーゼアッセイを行い、メトホルミンがPPARδの転写制御に与える影響について検証した。
メトホルミンによるPPARδの転写活性化を調べるために、RXRα及びPGC1αと共に、ヒトPPARδを、ヒト胎児腎臓由来培養細胞株HEK293細胞に強発現させた。レポーターには、PPARδ/RXRα複合体が結合するDNA配列(PPAR-Response Element)を2つ持つチミジンキナーゼプロモーター(tk)/ルシフェラーゼ遺伝子レポータープラスミドを使用し、ルシフェラーゼアッセイを行った。PPARδ活性化のポジティブコントロールとして、PPARδのアゴニストであるGW501516(GlaxoSmithKline社製)を使用した。等量のDMSOを添加した反応液(コントロール)の発光量(Relative Light Unit;RLU)に対する反応液の発光量の割合を、相対活性値とした。
PPARδのアゴニストによる転写活性化は、アゴニストがPPARδのリガンド結合ポケットに結合し、転写共役因子であるPGC1αとの転写複合体の形成を誘導することによって起きていることが知られている。そこで、メトホルミン又はGW501516で処理した細胞のPPARδ/PGC1α転写複合体量を定量した。対照として、DMSO(ジメチルスルホキシド)処理を行った。
筋分化におけるPPARδによる転写活性化に対するメトホルミンの影響を調べた。
マウス骨格筋由来筋芽細胞株C2C12細胞を低血清刺激して筋分化を誘導し、分化6日目に、100μM メトホルミン、1μM GW501516、又はDMSOで処理した。処理後の細胞について、PPARδの標的遺伝子の発現をqPCRにより解析した。標的遺伝子は、angptl4遺伝子、pdk4遺伝子、plin遺伝子、及びucp3遺伝子の4種を測定した。
メトホルミン処理により転写因子PPARδが標的遺伝子のプロモーターにリクルートされるかを調べた。
まず、C2C12細胞にFLAGタグ付きのPPARδ(FLAG-PPARδ)を恒常的に発現させたC2C12-PPARδ細胞を作製した。C2C12-PPARδ細胞を低血清刺激して筋分化を誘導し、分化6日目に、100μM メトホルミン、1μM GW501516、又はDMSOで処理した。処理後の細胞について、FLAGタグを認識する抗体を用いてクロマチン免疫沈降(Conventional ChIP)を行った。
PPARδは脂質代謝関連遺伝子の発現を誘導し、特に骨格筋において脂肪酸のβ酸化を亢進することが知られている。PPARδアゴニストには、ミトコンドリア活性を上げる作用効果を有することが期待される。そこで、メトホルミンが代謝、特にミトコンドリア活性に及ぼす影響を調べた。具体的には、C2C12細胞を用いて、細胞代謝測定装置(Agilemt社製細胞外フラックスアナライザー)により細胞の酸素消費速度(OCR:Oxygen Consumption Rate)を測定した。
GW501516を代表とする従来開発されてきた一連のPPARδの合成アゴニスト(GW系薬剤)は、フェノキシ酢酸誘導体であり、カルボキシル基(-COOH)に非極性炭化水素等の長鎖状の疎水性基が結合した化学構造を基本骨格としている。これに対して、メトホルミンは、ビグアニド(biguanide, ビグアナイド)系薬剤の一つであり、従来のGW系薬剤と化学構造上の類似性はなく、GW系薬剤とPPARδのリガンド結合ポケットの特異的結合に必須であるカルボキシル基と長鎖状の疎水性基の両方とも持っていない。また、従来のGW系薬剤の物性は、酸性かつ非極性が特徴であるのに対して、メトホルミンは塩基性かつ水溶性である。加えて、従来のGW系薬剤の分子の大きさは、PPARδのリガンド結合ポケットの大きさに対応しているが、メトホルミンは著しく小さい。例えば、代表的な合成アゴニストGW501516やGW2331の分子量は453.5と490.3であるが、メトホルミンは169.2であり、約3分の1である。このように、メトホルミンは従来のPPARδを標的としたどの薬剤とも共通性がなく、どのようにPPARδに結合するのかを、複合体構造既知の従来のアゴニストから予測することは不可能である。そこで、PPARδのLBDとメトホルミンとの複合体の結晶を作製して、当該複合体の三次元構造をX線結晶解析で決定した。
PPARδのアミノ酸配列の第170番目のグルタミンから第441番目のチロシン(カルボキシル末端、C-末端)までのポリペプチド(PPARδ-LBD)とメトホルミンの複合体の結晶構造解析を行った。
PPARδ-LBDは、下記の通りにして調製した。まず、His×6タグ付きポリペプチドとして大腸菌に発現させた後、溶菌して不溶性画分を分取した。分取した不溶性画分を、可溶化溶液(20mM Tris-Cl(pH7.5)、2M 尿素、2mM DTT、500mM NaCl、0.5% Tween20)で可溶化した後、遠心分離(25,000rpm、45分間)で上清を分取した。得られた上清は、透析して尿素とTween20を除去した後、Ni-アフィニティーカラム(Ni-NTA Agarose、QIAGEN社製)を用いて精製した後、His×6タグをHRV3Cで切断した。切断後のポリペプチドを、アミコン(Amicon Ultra tube カットオフ分子量10,000、Merk Millipore社製)を用いて濃縮した後、展開溶液(20mM TrisCl(pH7.5)、500mM NaCl、0.5mM Tris(2-carboxyethyl)phosphate(TCEP))で平衡化したSuperdex 75pgゲル濾過カラム(GE Healthcare社製)で精製した。PPARδ-LBDを含む分画は、アミコンで10mg/mLまで濃縮して結晶化の試料とした。精製試料は、質量分析(MALDI-TOF MS、Bruker Daltonics社製)でPPARδ-LBDであることを確認して、液体窒素で瞬間凍結して-80℃の低温で保存した。
PPARδ-LBDとメトホルミンとの複合体結晶は、ハンギングドロップ型の蒸気拡散平衡法で作製した。メトホルミン塩酸塩(LKT Laboratories社製)を蒸留精製水に溶かして100mMとしたメトホルミン水溶液を、精製したPPARδ-LBD試料と混合して結晶化用試料溶液(PPARδ-LBD濃度が0.3mM、PPARδ-LBD:メトホルミン=1:10(モル比)を調製した。結晶化は、結晶化用試料溶液1μLとリザーバ溶液(40mM Bis-Tris-Propandiol(pH6.8)、10mM DTT、2.5% EDTA(1,2-Propanediol,1 mM ethylenediaminetetraacetic acid)、0.5% HBDG(detergent n-Heptyl-β-D-thioglucoside)、200μM KCl、4% PEG8K)を混合して、リザーバ溶液に対して温度20℃で蒸気平衡して、4日程度で結晶を得た。
X線強度データは、大型放射光施設SPring-8のビームラインBL41XUで、温度100K℃でMX300HE検出器を用いて収集した。収集したX線強度データは、X線回折データ処理用ソフトウエア(DENZO/SCALPACK、HKL2000プログラム)で各種補正等を施して構造解析用のX線強度データセット(分解能:2.00Å)とした。構造解析は、RCSB Protein Data Bank(Rutgers, UCSD)に登録されているPPARδ-LBDの公開された構造(PDBコード5U3Q)を元にして、プログラム(PHASER)を用いて分子置換法によって初期位相を決定した。構造モデルの修正や再構築は、分子グラフィックスプログラム(COOT)を用いて行い、プログラム(PHENIX)により精密化した。これらのモデル修正と精密化を反復して行い、R-factor 18.4%、FreeR-factor 21.4%の複合体の原子モデルを得るに至った。
さらに、メトホルミン複合体のPPARδ-LBD構造を用いて構造解析を進めた。この結果、分解能2.29Å、R-factor19.3%、Free R-factor22.0%の複合体の原子モデルを得た。
PPARδ-LBDとメトホルミンとの複合体結晶の構造を図16に示す。結晶中には、構造がほぼ同じ2分子のPPARδ-LBD(図中、Molecule AとMoleculeB)が存在しており、メトホルミンはそれぞれのドメインの中にあるリガンド結合ポケットに結合している。それぞれのPPARδ-LBDの分子表面には、結晶化に用いた界面活性剤HBDGが結合していた。
メトホルミンが運動耐性を改善させることができるかを、マウスを用いて最終運動耐性テストを実施して検証した。
メトホルミン/PPARδの共結晶構造のデータを利用して、新たなPPARδ活性化剤を探索した。
化合物(1-1-4)のうち、化合物(B-1)、化合物(B-2)、及び化合物(B-3)が、PPARδの転写制御に与える影響について調べた。PPARδの転写活性に対する影響は、DMSOに溶解させた各化合物10μMで処理した細胞に対してルシフェラーゼアッセイを行うことによって測定した。
化合物(1-1-2)のうち、化合物(A-4)(1-{4-[({2-[3-フルオロ-4-(トリフルオロメチル)フェニル]4-メチルチアゾール-5-イル}メチル)チオ]-2-メチルベンジル}グアニジン)を合成し、そのPPARδの転写制御に与える影響について調べた。
(1)S-(4-シアノ-3-メチルフェニル)エタンチオエートの合成
MS-ESI(m/z)423.1[M+H]+.
MS-ESI(m/z) 426.1[M+H]+.
MS-ESI(m/z)428.1[M+H]+.
MS-ESI(m/z)446.0[M+H]+.
MS-ESI(m/z)669.3[M+H]+.
MS-ESI(m/z) 469.2[M+H]+.
PPARδにより発現誘導される遺伝子の発現に対する、化合物(A-4)の影響を調べた。具体的には、マウス骨格筋由来の筋芽細胞株であるC2C12細胞に化合物(A-4)を添加し、PPARδにより発現誘導される遺伝子のうち、angptl4遺伝子、pdk4遺伝子、及びcpt1a遺伝子(非特許文献12)の発現量を測定した。また、内在性コントロールとして、Hprt遺伝子を用い、PPARδ活性化のポジティブコントロールとして、GW0742を用いた。
得られた遺伝子発現データから、各遺伝子の発現量を、内在性コンロトール遺伝子の発現量で除算した相対発現量として算出した。
Claims (9)
- グアニジン誘導体を有効成分とし、PPARδ(Peroxisome proliferator-activated receptor δ)の転写活性を活性化し、
前記グアニジン誘導体が、下記一般式(1-1-1)~(1-1-4)
のいずれかで表される化合物である、PPARδ活性化剤。 - 前記グアニジン誘導体は、グアニジノ基が、PPARδのリガンド結合ポケットの内部表面を構成するアミノ酸残基のうち、ヒトPPARδの413番目のヒスチジン、287番目のヒスチジン、253番目のスレオニン、及び437番目のチロシンにそれぞれ相当するアミノ酸残基と水素結合をした状態で、前記リガンド結合ポケットの内部に嵌まり込み得る、請求項1又は2に記載のPPARδ活性化剤。
- グアニジン誘導体を有効成分とし、PPARδ(Peroxisome proliferator-activated receptor δ)の転写活性を活性化し、
前記グアニジン誘導体が、下記一般式(1-1-1)~(1-1-4)
のいずれかで表される化合物である、PPARδ活性化剤を有効成分とする、運動耐性改善剤。 - グアニジン誘導体又はビグアニジン誘導体を有効成分とし、PPARδ(Peroxisome proliferator-activated receptor δ)の転写活性を活性化し、
前記グアニジン誘導体が、下記一般式(1)
で表される化合物であり、
前記ビグアニジン誘導体が、下記一般式(2)
で表される化合物である、PPARδ活性化剤を有効成分とする、運動耐性改善剤。 - メトホルミン、フェンホルミン、及びブホルミンからなる群より選択される1種以上を有効成分とする、PPARδ活性化剤を有効成分とする、運動耐性改善剤。
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WO2003090783A1 (fr) | 2002-04-26 | 2003-11-06 | Ajinomoto Co., Inc. | Agent preventif/remede pour diabete |
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WO2003090783A1 (fr) | 2002-04-26 | 2003-11-06 | Ajinomoto Co., Inc. | Agent preventif/remede pour diabete |
JP2010514804A (ja) | 2006-12-29 | 2010-05-06 | ザ・ソーク・インスティチュート・フォー・バイオロジカル・スタディーズ | 運動能力を高めるための方法 |
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