JP2018524577A - 作用機構 - Google Patents
作用機構 Download PDFInfo
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- JP2018524577A JP2018524577A JP2017565173A JP2017565173A JP2018524577A JP 2018524577 A JP2018524577 A JP 2018524577A JP 2017565173 A JP2017565173 A JP 2017565173A JP 2017565173 A JP2017565173 A JP 2017565173A JP 2018524577 A JP2018524577 A JP 2018524577A
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Abstract
Description
− TNFスーパーファミリーメンバーであるトリマータンパク質に結合し、必要な受容体を介するTNFスーパーファミリーメンバーのシグナル伝達を調節することができる化合物であって、対照と比較して、トリマー−化合物複合体あたりに結合した受容体の同等の平均数、又はトリマー−化合物複合体あたりに結合した受容体の平均数の変化をもたらす、上記化合物;
− 式(5)の化合物、又はその薬学的に許容される塩若しくは溶媒和物;
− TNFスーパーファミリーメンバーであるトリマータンパク質と、上記で定義された化合物とを含む複合体;
− ヒト又は動物の身体の治療方法における使用のための、上記で定義された化合物又は複合体;及び
− 上記で定義された化合物又は複合体と、薬学的に許容される担体とを含む医薬組成物
も提供する。
配列番号1及び2は、実施例で使用した配列を示す。
配列番号3は、C185_01974.0のHCVRを示す。
配列番号4は、C185_01974.0のLCVRを示す。
配列番号5は、C185_01974.0のmIgG1重鎖のアミノ酸配列を示す。
配列番号6は、C185_01974.0のカッパ軽鎖のアミノ酸配列を示す。
配列番号7は、C185_01979.0のHCVRを示す。
配列番号8は、C185_01979.0のLCVRを示す。
配列番号9は、C185_01979.0のmIgG1重鎖のアミノ酸配列を示す。
配列番号10は、C185_01979.0のカッパ軽鎖のアミノ酸配列を示す。
本発明は、TNFスーパーファミリーメンバーであるトリマータンパク質に結合し、必要なTNFスーパーファミリー受容体を介するトリマータンパク質のシグナル伝達を調節することができる化合物を同定する方法(アッセイ)に関する。本発明の方法によって同定される化合物は、したがって、モジュレータとして公知でもある。
本発明はまた、TNFスーパーファミリーメンバーであるトリマータンパク質に結合し、必要な受容体を介するTNFスーパーファミリーメンバーのシグナル伝達を調節することができる化合物にも関する。化合物は、対照と比較して、トリマー−化合物複合体あたりに結合した受容体の対応する平均数、又は平均数の変化をもたらす。そのような化合物を、上記の方法によって同定することができる。
本発明者らは、本発明の化合物と、トリマーTNFスーパーファミリーメンバーとを含む複合体に選択的に結合する抗体を開発した。これらの抗体を使用して、TNFを阻害することができるさらなる化合物を同定することができる。
TNFαは、TNFスーパーファミリーの典型的なメンバーである。TNFαは、免疫調節及び炎症応答を媒介する多面的なサイトカインである。in vivoでは、TNFαは細菌、寄生虫及びウイルス感染に対する応答に関与することも知られている。特に、TNFαは、関節リウマチ(RA)、炎症性腸疾患(クローン病を含む)、乾癬、アルツハイマー病(AD)、パーキンソン病(PD)、疼痛、てんかん、骨粗鬆症、喘息、敗血症、発熱、全身性エリテマトーデス(SLE)及び多発性硬化症(MS)並びにがんにおいて役割を有することが知られている。TNFαはまた、筋萎縮性側索硬化症(ALS)、虚血性脳卒中、免疫複合体媒介性糸球体腎炎、ループス腎炎(LN)、抗好中球細胞質抗体(ANCA−)関連糸球体腎炎、微小変化型疾患、糖尿病性腎症(DN)、急性腎傷害(AKI)、閉塞性尿路疾患、腎同種移植拒絶、シスプラチン誘導性AKI及び閉塞性尿路疾患における役割を有することが知られている。
本発明の方法を使用して同定される化合物及び化合物−トリマー複合体は、典型的には、薬学的に許容される担体と一緒に、医薬組成物中に製剤化される。
化合物(1)の合成は、WO2013/186229(例490)に開示されている。
化合物(2)の合成は、WO2013/186229(例2)に開示されている。
化合物(3)の合成は、WO2014/009295(例4)に開示されている。
化合物(4)の合成は、WO2013/186229(例89)に開示されている。
命名法
化合物は、ACD/Name Batch(Network)バージョン12.0又はAccelyrs Draw4.0を補助に用いて命名した。
DCM:ジクロロメタン EtOAc:酢酸エチル
DMF:N,N−ジメチルホルムアミド MeOH:メタノール
DMSO:ジメチルスルホキシド SiO2:シリカ
Et2O:ジエチルエーテル h:時間
THF:テトラヒドロフラン RT:保持時間
r.t.:室温 MeCN:アセトニトリル
br.:ブロード M:質量
ブライン:飽和塩化ナトリウム水溶液
HPLC:高速液体クロマトグラフィー
LCMS:液体クロマトグラフィー質量分析
ES+:エレクトロスプレーポジティブイオン化
TEA:トリエチルアミン
TLC:薄層クロマトグラフィー
全てのNMRは、300MHz又は400MHzのいずれかで取得した。
Waters Acquity−SQD、Waters Acquity UPLC BEH C18、2.1×50mm、1.7μmカラム
移動相A:10mMのギ酸アンモニウム+0.1%アンモニア
移動相B:95%MeCN+5%H2O+0.1%アンモニア
勾配プログラム(流量1.0mL/分、カラム温度40℃):
時間 A% B%
0.00 95 5
0.50 95 5
1.75 5 95
2.00 5 95
2.25 95 5
(6−ブロモ−7−フルオロ−2−メチルイミダゾ[1,2−a]ピリジン−3−イル)[2−(ジフルオロメトキシ)フェニル]−メタノール−エナンチオマーA
ラセミ体の標題化合物を、特許出願WO2014/009295に記載の以下の手順に従って調製した。そのように調製したラセミ体混合物を、以下に詳述するキラルクロマトグラフィーにより、エナンチオマー成分に分離した:
氷/ブライン浴で約−5℃に冷却した1−boc−3−アゼチジノン(11.3g、58.4mmol)及び(トリフルオロメチル)トリメチルシラン(9.22g、64.3mmol)のTHF溶液(100mL)に、フッ化セシウム(9.77g、64.3mmol)を少しずつ加えた。得られた混合物を室温で撹拌して、4時間後、TLC解析により、出発物質の完全消費とより極性の小さな成分とが示された。反応を飽和塩化アンモニウム水溶液(100mL)の添加によりクエンチし、水相をEtOAc(3×100mL)で抽出した。有機相を分離し、硫酸ナトリウムで乾燥させ、濾過し、揮発性物質を真空中で除去し、粗油状物を得た。そのように得られた油状物をDCM(100mL)に溶解し、トリフルオロ酢酸(40mL)を加えた。混合物を、周囲温度で4時間撹拌した。揮発物を真空中で除去し、残渣をトルエン(3×150mL)と共沸させて、標題化合物のトリフルオロ酢酸塩を褐色固体(15g)として得た。1H NMR (400 MHz, d6DMSO): δ/ppm 9.48 (s, 2 H), 7.95 (d, J 0.3 Hz, 1 H), 4.28 (d, J 13.1 Hz, 2 H), 4.06 (m, 2 H).
1−[5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ピリミジン−2−イル]−3−(トリフルオロメチル)アゼチジン−3−オール
中間体2(12g)のアセトニトリル(150mL)中溶液に、TEA(30mL)及び2−クロロ−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ピリミジン(16g)を加え、反応液を65℃で18時間撹拌した。溶媒を真空中で除去し、固体残渣を粉砕し、蒸留水で洗浄してベージュ色固体を得て、高真空下で乾燥させて標題化合物をベージュ色固体(18.5g)として得た。1H NMR (300 MHz, d6 DMSO): δ/ppm 8.53 (2H, s), 7.46 (1H, s), 4.33-4.31 (2H, m), 4.10-4.08 (2H, m), 1.29 (12H, s). LCMS (ES+) RT 1.14分, 346.0 (M+H)+.
1−[5−[3−[(S)−[2−(ジフルオロメトキシ)フェニル]−ヒドロキシ−メチル]−7−フルオロ−2−メチル−イミダゾ[1,2−a]ピリジン−6−イル]ピリミジン−2−イル]−3−(トリフルオロメチル)アゼチジン−3−オール(エナンチオマーA)
中間体1(0.7g、2mmol)、中間体3(0.7g、2mmol)、1,1’−ビス(ジフェニルホスフィノ)フェロセン−パラジウム(II)ジクロリドジクロロメタン錯体(36mg、0.044mmol)及び2Mの炭酸ナトリウム(2mL)のジオキサン(12mL)中混合物を脱気し、3時間還流した。冷却した反応混合物をEtOAcで希釈し、ブラインで2回洗浄し、有機層を乾燥(MgSO4)し、真空中で濃縮した。残渣を、フラッシュカラムクロマトグラフィー(SiO2、0〜90%EtOAc/ヘプタン)に装填し、標題化合物をクリーム色固体(500mg、50%)として得た。1H NMR (300 MHz, DMSO-d6) : δ 8.51 (m, 3 H), 7.95 (dd, J1 2.3 Hz, J2 6.7 Hz, 1 H), 7.46 (m, 2 H), 7.36 (m, 2 H), 7.12 (m, 2 H), 6.42 (d, J 4.4 Hz, 1 H), 6.18 (d, J 4.4 Hz, 1 H), 4.35 (m, 2 H), 4.13 (d, J 10.2 Hz, 2 H), 2.12 (s, 3 H). LCMS (ES+) RT 1.34分, 540.0 (M+H)+. [α] + 39.7°.
サイズ排除クロマトグラフィーを使用して、様々な化合物の非存在下又は存在下における、TNFαに結合するTNFR1受容体の数を決定した。化合物(2)は、下記プロトコル1に記載の条件下で試験した。化合物(5)は、プロトコル2に記載されるように試験した。
化合物(2)を、300μMの融合TNFαトリマーに、化合物の最終濃度範囲90μM〜690μMで、DMSO濃度は1.0%で一定に保ちながら、加えた。TNFα及び化合物の試料を、4℃の温度で一晩インキュベートした。
化合物(5)を、20μMのTNFαトリマーに、最終濃度200μM(トリマー:化合物の比1:10)で、DMSO濃度は2.0%で一定に保ちながら、加えた。TNFα及び化合物の試料を、4℃の温度で一晩インキュベートした。受容体を最終濃度35μMで、10μMのトリマー−化合物複合体に加えた(トリマー−化合物複合体に対して3.5倍過剰の受容体)。DMSOの最終濃度は1.0%であった。混合物を22℃で1時間インキュベートした。
マウスTNFα(VC6535、UniProt P06804)の可溶性形態を融合タンパク質として大腸菌(E.Coli)で発現した。このタンパク質は、以下の最終配列を有する:
DKPVAHVVANHQVEEQLEWLSQRANALLANGMDLKDNQLVVPADGLYLVYSQVLFKGQGCPDYVLLTHTVSRFAISYQEKVNLLSAVKSPCPKDTPEGAELKPWYEPIYLGGVFQLEKGDQLSAEVNLPKYLDFAESGQVYFGVIAL(配列番号1)
GSVCPQGKYIHPQDNSICCTKCHKGTYLYNDCPGPGQDTDCRECESGSFTASENHLRHCLSCSKCRKEMGQVEISSCTVDRDTVCGCRKNQYRHYWSENLFQCFNCSLCLNGTVHLSCQEKQNTVCTCHAGFFLRENECVSSSN(配列番号2)
均一性時間分解蛍光共鳴エネルギー移動(TR−FRET)アッセイを展開して、融合TNFαトリマーへのTNF受容体1(TNFR1細胞外ドメイン(ECD))結合の化合物媒介減少を測定した。
ヒトTNFαを、使用前に脱塩し、20mM酢酸アンモニウム、pH7.4にバッファー交換した。zebaスピンカラム(Thermo−Fisher、7kDa MWCO)と続くマイクロ透析(Thermo slide−a−lyzer mini透析ユニット、10kDa MWCO)との組み合わせにより、タンパク質の十分な脱塩とネイティブ質量分析による良好な分解能のシグナル生成を確実にした。TNFα(20μM)を小分子TNFα阻害剤(化合物(3))、200μM、2%DMSOと1:1(v:v)で加えた。化合物を、20mM酢酸アンモニウム、pH7.4を使用して、10mMのDMSOストックから希釈した。TNFα(20μM)をバッファー(20mM、酢酸アンモニウム、pH7.4、2%DMSO)と1:1(v:v)で加えて、DMSOのみの対照も調製した。両方の溶液を室温で一晩インキュベートし、その後、小分子含有試料を非共有結合性飛行時間型質量分析(Advion TriVersa NanoMateイオン源を備えたWaters LCT Premier)により解析し、TNFαが十分に結合されたことを確認した。
化合物ストック:
2μlの10mM DMSOストック、プラス2μlのDMSOを、96μlの20mM酢酸アンモニウムバッファーに加え、100μlの200μM化合物(3)、4%DMSOを得た。
TNFは、2×Zebaカラムを使用して脱塩し、続いて20mM酢酸アンモニウムpH7.4内へ透析した。TNFRは、2×zebaカラムを使用して脱塩し、続いて20mM酢酸アンモニウムpH7.4内へ透析した。A280測定を行い、タンパク質試料の最終濃度を確認した。
コーン=50V
イオン源温度=20℃
トラップ/移動衝突エネルギー=オフ
トラップガスフロー=0.4mL/分
ヘリウムセル=180mL/分
IMS(N2)=90mL/分
トラップDCバイアス=40V
モビリティトラッピング手動解除−利用不可
IMS波遅延=450us
IMS波速度=750m/s
IMS波高 40V
バッキング=6.21mbar
トラップ 2.05e−2mbar
IMS 3.47mbar
TOF 1.2e−6mbar
Quadプロファイル:
4000、5000、6000(ドウェル30、ランプ(ramp)30)
範囲 500〜8000
ここでT0は、TNFの初期量を表し、Rmin、R、Rmaxは、Rminから開始してRmaxで終了する、アッセイされる受容体Rの初期濃度を表す。分率fobsは、ネイティブ質量分析測定により平衡で観察されるTNF、TNF+1R、TNF+2R及びTNF+3R種のモル分率(例えば、fTNFobs)である。fcalcは、BioNetGen BNGLモデリングツール(Blinov, M. L., Faeder, J. R., Goldstein, B., and Hlavacek, W. S. (2004) BioNetGen: software for rule-based modeling of signal transduction based on the interactions of molecular domains. Bioinformatics 20, 3289-3291)を使用し、T0、R0並びにK1、K2及びK3の値を入力して、平衡方程式を解くことにより計算されるそれぞれの種についてのモル分率(例えば、fTNFcalc)である。誤差関数は、SciPy/NumPyフレームワーク(http://docs.scipy.org/doc/numpy/index.html)に実装されたbrute force最小化ユーティリティを使用して最小化した。全データ処理解析は、必要なときにBioNetGenルーチンを呼び出すPythonプログラミング言語(https://www.python.org/)で実施した。
Ma et al. (2014) JBC 289:12457-12466, C87の12458頁に記載されているように、C87は、TNFβの外部表面との相互作用において、TNFR1のループ2/ドメイン2由来の7アミノ酸ペプチドによって占められる空間に適応する分子を見つけることを試みるバーチャルスクリーニングを通じて発見された。MaらからのC87化合物、及びSilvian et al. (2011) ACS Chemical Biology 6:636-647からのBIO8898化合物を、本発明者によって試験した。
Maらで記載されたC87についてのBiacore観察結果は再現することができなかった。
細胞におけるTNF特異的阻害の証拠は観察されなかった。
さらにC87は、ミリモルの親和性に感受性である質量分析で結合が観察されなかった。
広範な結晶学的試みで、アポ−TNF(化合物なしのTNF)のみが製造された。
蛍光偏光(FP)アッセイにおいて、C87は、蛍光読出しを有する化合物の干渉レベルを超える有意な阻害を示さなかった。
TNFαの熱融解温度の安定化を測定するThermofluorで、C87についての小さな安定化が示された。
要約すると、トリマーの中心にC87が結合している証拠は見つからなかった。圧倒的多数のデータが、TNFαとの直接的相互作用がないことを示唆した。BIO8898もTNFαに結合しないことが分かった。
C87を、TNFαと1時間プレインキュベートしてから、NFκBの制御下にSEAPで安定的にトランスフェクトしたHEK−293細胞に加えた。適切なカウンタースクリーンも、非TNF関連(オフターゲット)活性を検出するために試験した。アッセイを一晩インキュベートした後、阻害を、対照化合物による100%ブロッキングと比較して測定した。最大C87濃度は10,000nMであり、3倍段階希釈した。
avi−タグリンカーを使用してTNFを固定化し、C87にチップを通過させた。一実験では、最高濃度の10μMからC87の用量応答を行った。結合は何ら観察されなかった。
400μMの濃度でC87のヒトTNFα(20μM)への結合の証拠はなかった。より低い分子量(約473Da)種が、5%未満の占有率で結合しているようである。C87は、503Daの分子量を有する。400μMの濃度での占有率に基づいて、低分子量種の1mMを超える親和性が予測される。
全体的に、TNFαとのC87の結晶化について、本出願に記載の化合物における通常的手段の試験条件を含め、多大な努力が注がれた。これには、様々リガンド濃度、様々なタンパク質濃度、及び様々な浸漬時間での多数の結晶化の試みの設定が含まれる。いくつかの結晶が観察され、解析によって、塩、つまり化合物を有しないTNFであることが分かった。
C87を、蛍光化合物(プローブ)に対するアッセイの前に1時間、TNFαと共にプレインキュベートした。蛍光化合物との直接的(同じ部位で結合する)又は間接的(TNFを妨害する)のいずれかの競合が、FPの減少により検出される。
Thermofluorは、タンパク質を安定化又は妨害のいずれかをする化合物によるTNFαの融解温度(Tm)の変化を測定する。3.8℃での安定化効果が500μMの濃度のC87で観察されることから、非特異的でありうる弱い結合の可能性が示唆される。
SEQ ID NO: 1
DKPVAHVVANHQVEEQLEWLSQRANALLANGMDLKDNQLVVPADGLYLVYSQVLFKGQGCPDYVLLTHTVSRFAISYQEKVNLLSAVKSPCPKDTPEGAELKPWYEPIYLGGVFQLEKGDQLSAEVNLPKYLDFAESGQVYFGVIAL
SEQ ID NO: 2
GSVCPQGKYIHPQDNSICCTKCHKGTYLYNDCPGPGQDTDCRECESGSFTASENHLRHCLSCSKCRKEMGQVEISSCTVDRDTVCGCRKNQYRHYWSENLFQCFNCSLCLNGTVHLSCQEKQNTVCTCHAGFFLRENECVSSSN
SEQ ID NO: 3 (HCVR of 1974)
DVQLVESGGGLVQPGRSLKLSCAASGFTFSAYYMAWVRQAPTKGLEWVASINYDGANTFYRDSVKGRFTVSRDNARSSLYLQMDSLRSEDTATYYCTTEAYGYNSNWFGYWGQGTLVTVSS
SEQ ID NO: 4 (LCVR of 1974)
DIQMTQSPASLPASPEEIVTITCQASQDIGNWLSWYQQKPGKSPQLLIYGATSLADGVPSRFSASRSGTQYSLKISRLQVEDFGIFYCLQGQSTPYTFGAGTKLELK
SEQ ID NO: 5 (1974 HC mIgG1 full)
DVQLVESGGGLVQPGRSLKLSCAASGFTFSAYYMAWVRQAPTKGLEWVASINYDGANTFYRDSVKGRFTVSRDNARSSLYLQMDSLRSEDTATYYCTTEAYGYNSNWFGYWGQGTLVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK
SEQ ID NO: 6 (1974 LC kappa full)
DIQMTQSPASLPASPEEIVTITCQASQDIGNWLSWYQQKPGKSPQLLIYGATSLADGVPSRFSASRSGTQYSLKISRLQVEDFGIFYCLQGQSTPYTFGAGTKLELKRTDAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC
SEQ ID NO: 7 (HCVR of 1979)
EVHLVESGPGLVKPSQSLSLTCSVTGYSITNSYWDWIRKFPGNKMEWMGYINYSGSTGYNPSLKSRISISRDTSNNQFFLQLNSITTEDTATYYCARGTYGYNAYHFDYWGRGVMVTVSS
SEQ ID NO: 8 (LCVR of 1979)
DIQMTQSPASLSASLEEIVTITCQASQDIGNWLSWYQQKPGKSPHLLIYGTTSLADGVPSRFSGSRSGTQYSLKISGLQVADIGIYVCLQAYSTPFTFGSGTKLEIK
SEQ ID NO: 9 (1979 HC mIgG1 full)
EVHLVESGPGLVKPSQSLSLTCSVTGYSITNSYWDWIRKFPGNKMEWMGYINYSGSTGYNPSLKSRISISRDTSNNQFFLQLNSITTEDTATYYCARGTYGYNAYHFDYWGRGVMVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK
SEQ ID NO: 10 (1979 LC Kappa full)
DIQMTQSPASLSASLEEIVTITCQASQDIGNWLSWYQQKPGKSPHLLIYGTTSLADGVPSRFSGSRSGTQYSLKISGLQVADIGIYVCLQAYSTPFTFGSGTKLEIKRTDAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC
Claims (26)
- TNFスーパーファミリーメンバーであるトリマータンパク質に結合し、必要なTNFスーパーファミリー受容体を介するトリマータンパク質のシグナル伝達を調節することができる化合物を同定する方法であって、トリマー−化合物複合体あたりに結合した受容体の平均数を決定するステップ、それによって、化合物が受容体を介するシグナル伝達を調節することができるかどうかを同定するステップを含む、上記方法。
- 対照と比較して、トリマー−化合物複合体あたりに結合した受容体の平均数を決定するステップを含む、請求項1に記載の方法。
- 対照が、化合物の非存在下でTNFスーパーファミリーメンバーのトリマー及び必要な受容体を含む、請求項2に記載の方法。
- 対照と比較したトリマー−化合物複合体あたりに結合した受容体の平均数の減少が、化合物が受容体を介するシグナル伝達を調節することができることを同定する、請求項3に記載の方法。
- 対照が、TNFスーパーファミリーメンバーのトリマー、必要な受容体、及び受容体を介するトリマーのシグナル伝達を調節することが公知の化合物を含む、請求項2に記載の方法。
- 対照と比較したトリマー−化合物複合体あたりに結合した受容体の同等の平均数、又は対照と比較したトリマー−化合物複合体あたりに結合した受容体の平均数の減少が、化合物が受容体を介するシグナル伝達を調節することができることを同定する、請求項5に記載の方法。
- トリマー−化合物複合体あたりに結合した受容体の平均数が、3:1〜10:1(受容体:トリマー)のモル比で決定される、請求項1から6までのいずれか一項に記載の方法。
- 化合物が、トリマー−化合物複合体あたりに平均3個未満の受容体が結合すると決定される場合、受容体を介するトリマータンパク質のシグナル伝達を調節することができると同定される、請求項1から7までのいずれか一項に記載の方法。
- 化合物が、トリマー−化合物複合体あたりに平均2個の受容体が結合すると決定される場合、受容体を介するトリマータンパク質のシグナル伝達を調節することができると同定される、請求項8に記載の方法。
- 化合物が、トリマー−化合物複合体あたりに平均1個の受容体が結合すると決定される場合、受容体を介するトリマータンパク質のシグナル伝達を調節することができると同定される、請求項8に記載の方法。
- トリマー−化合物複合体あたりに結合した受容体の数が、
(a)イオン移動度質量分析;及び/又は
(b)サイズ排除クロマトグラフィー;及び/又は
(c)凝集アッセイ;及び/又は
(d)Forster共鳴エネルギー移動;及び/又は
(e)結晶解析
によって決定される、請求項1から10までのいずれか一項に記載の方法。 - TNFスーパーファミリーメンバーがTNFαであり、受容体がTNF−Rである、請求項1から11までのいずれか一項に記載の方法。
- TNFスーパーファミリーメンバーであるトリマータンパク質に結合し、必要な受容体を介するTNFスーパーファミリーメンバーのシグナル伝達を調節することができる化合物であって、対照と比較して、トリマー−化合物複合体あたりに結合した受容体の同等の平均数、又はトリマー−化合物複合体あたりに結合した受容体の平均数の変化をもたらす、上記化合物。
- 化合物の非存在下でTNFスーパーファミリーメンバーのトリマーと必要な受容体とを含む対照と比較して、トリマー−化合物複合体あたりに結合した受容体の平均数の減少をもたらす、請求項13に記載の化合物。
- TNFスーパーファミリーメンバーのトリマー、必要な受容体、及び受容体を介するトリマーのシグナル伝達を調節することが公知の化合物を含む対照と比較して、トリマー−化合物複合体あたりに結合した受容体の同等の平均数、又はトリマー−化合物複合体あたりに結合した受容体の平均数の減少をもたらす、請求項13に記載の化合物。
- トリマー−化合物複合体あたりに結合する平均3個未満の受容体をもたらす、請求項13、14又は15に記載の化合物。
- トリマー−化合物複合体あたりに結合する平均2個の受容体をもたらす、請求項16に記載の化合物。
- トリマー−化合物複合体あたりに結合する平均1個の受容体をもたらす、請求項16に記載の化合物。
- 結合した受容体の平均数が3:1〜10:1(受容体:トリマー)のモル比で決定される、請求項13から18までのいずれか一項に記載の化合物。
- TNFスーパーファミリーメンバーがTNFαであり、受容体がTNF−Rである、請求項13から19までのいずれか一項に記載の化合物。
- 式(5)の化合物、又はその薬学的に許容される塩若しくは溶媒和物。
- TNFスーパーファミリーメンバーであるトリマータンパク質と、請求項13から21までのいずれか一項に記載の化合物とを含む複合体。
- ヒト又は動物の身体の治療方法における使用のための、請求項13から21までのいずれか一項に記載の化合物又は請求項22に記載の複合体。
- 化合物が受容体を介してトリマーによって誘導されるシグナル伝達に拮抗する、自己免疫障害及び炎症障害;神経障害及び神経変性障害;疼痛障害及び侵害障害;並びに心血管障害の処置及び/又は防止における使用のための、請求項23に記載の化合物又は複合体。
- 関節リウマチ、クローン病、乾癬、全身性エリテマトーデス、アルツハイマー病、パーキンソン病及びてんかんの処置及び/又は防止における使用のための、請求項24に記載の化合物又は複合体。
- 請求項13から21までのいずれか一項に記載の化合物、又は請求項22に記載の複合体と、薬学的に許容される担体とを含む医薬組成物。
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