JP6129360B2 - 肝細胞への改良された幹細胞分化のための化合物 - Google Patents
肝細胞への改良された幹細胞分化のための化合物 Download PDFInfo
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- JP6129360B2 JP6129360B2 JP2015562101A JP2015562101A JP6129360B2 JP 6129360 B2 JP6129360 B2 JP 6129360B2 JP 2015562101 A JP2015562101 A JP 2015562101A JP 2015562101 A JP2015562101 A JP 2015562101A JP 6129360 B2 JP6129360 B2 JP 6129360B2
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- hepatocytes
- pyridin
- carboxylic acid
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- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
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- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 238000011223 gene expression profiling Methods 0.000 description 1
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- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical class CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- CMCJLKKTKLLELA-UHFFFAOYSA-N methyl 2-(4-iodo-2-methoxypyridin-3-yl)-3-methylbenzimidazole-4-carboxylate Chemical compound CN1C=2C(C(=O)OC)=CC=CC=2N=C1C1=C(I)C=CN=C1OC CMCJLKKTKLLELA-UHFFFAOYSA-N 0.000 description 1
- ZUTLATZPACDTNV-UHFFFAOYSA-N methyl 2-[4-[2-(3-chlorophenyl)ethylamino]-2-oxo-1H-pyridin-3-yl]-1H-benzimidazole-4-carboxylate Chemical compound COC(=O)c1cccc2nc([nH]c12)-c1c(NCCc2cccc(Cl)c2)cc[nH]c1=O ZUTLATZPACDTNV-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 238000002493 microarray Methods 0.000 description 1
- 238000010208 microarray analysis Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229920000768 polyamine Chemical class 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- PNGLEYLFMHGIQO-UHFFFAOYSA-M sodium;3-(n-ethyl-3-methoxyanilino)-2-hydroxypropane-1-sulfonate;dihydrate Chemical compound O.O.[Na+].[O-]S(=O)(=O)CC(O)CN(CC)C1=CC=CC(OC)=C1 PNGLEYLFMHGIQO-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000034998 susceptibility to hepatitis B virus Diseases 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical class CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/067—Hepatocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2500/00—Specific components of cell culture medium
- C12N2500/30—Organic components
- C12N2500/46—Amines, e.g. putrescine
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2503/00—Use of cells in diagnostics
- C12N2503/02—Drug screening
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2506/00—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells
- C12N2506/45—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells from artificially induced pluripotent stem cells
Description
Gene_Symbol:遺伝子記号
Raw Est Fold Change:補正前推定倍数変化
Unadjusted p-value:未補正p-値
表1
用語“部分”は、一つの原子、或いは一つ又はそれより多い化学結合によってもう一つの原子又は分子に接続し、これによって分子の一部を形成する化学的に結合した原子の群を指す。例えば、式Iの可変基R1−R11は、共有結合によって式Iの核構造に接続された部分を指す。
他に示さない限り、用語“水素”又は“ヒドロ”は、水素原子(−H)の部分を指し、そしてH2ではない。
他に示さない限り、用語“その式の一つの化合物”又は“式の一つの化合物”又は“その式の化合物類”又は“式の化合物類”は、その式によって定義されるとおりの化合物の属から選択されるいずれもの化合物を指す(いずれものこのような化合物のいずれもの医薬的に受容可能な塩又はエステルを含む)。
もう一つの態様において、本発明は、以下の式:
もう一つの態様において、本発明は、以下の式:
もう一つの態様において、本発明は、以下の式:
もう一つの態様において、本発明は、以下の式:
もう一つの態様において、本発明は、以下の式:
もう一つの態様において、本発明は、以下の式:
一般的に、これらの化合物の調製において使用される出発物質及び試薬は、商業的供給業者、例えばAldrich Chemical Co.から入手可能であるか、又は当業者にとって既知の方法によって調製されるかのいずれかである。以下の合成反応スキームは、単に、それによって、本発明の化合物を合成することができる幾つかの方法の例示であり、そしてこれらの合成反応スキームに対する各種の改変を行うことができ、そして当業者に示唆するものである。更なる例示は、具体的な実施例中に見出すことができる。
2−[4−((S)−2−ヒドロキシ−2−フェニル−エチルアミノ)−2−オキソ−1,2−ジヒドロ−ピリジン−3−イル]−3H−ベンゾイミダゾール−4−カルボン酸3−フルオロ−ベンジルアミドの合成。
2−[4−((S)−2−ヒドロキシ−2−フェニル−エチルアミノ)−2−オキソ−1,2−ジヒドロ−ピリジン−3−イル]−3H−ベンゾイミダゾール−4−カルボン酸ベンジルアミドの合成
2−[4−((S)−2−ヒドロキシ−2−フェニル−エチルアミノ)−2−オキソ−1,2−ジヒドロ−ピリジン−3−イル]−3H−ベンゾイミダゾール−4−カルボン酸4−フルオロ−ベンジルアミドの合成
2−{4−[2−(3−クロロ−フェニル)−エチルアミノ]−2−オキソ−1,2−ジヒドロ−ピリジン−3−イル}−3H−ベンゾイミダゾール−4−カルボン酸ベンジルアミドの合成
2−{4−[2−(3−クロロ−フェニル)−エチルアミノ]−2−オキソ−1,2−ジヒドロ−ピリジン−3−イル}−3H−ベンゾイミダゾール−4−カルボン酸4−フルオロ−ベンジルアミドの合成
2−{4−[2−(3−クロロ−フェニル)−エチルアミノ]−2−オキソ−1,2−ジヒドロ−ピリジン−3−イル}−3H−ベンゾイミダゾール−4−カルボン酸3−フルオロ−ベンジルアミドの合成
2−{4−[2−(3−クロロ−フェニル)−エチルアミノ]−2−オキソ−1,2−ジヒドロ−ピリジン−3−イル}−3H−ベンゾイミダゾール−4−カルボン酸2−フルオロ−ベンジルアミドの合成
ヒトiPCS由来の肝細胞(iCell(登録商標)肝細胞)を、成人の器官をより良好にモデル化する、より大きい機能性のために好都合な条件を同定する目標で、式Iの化合物に暴露した。高処理量のマイクロ流体定量的RT−PCR(qRT−PCR)を使用して、成人の一次ヒト肝細胞と比較した場合、低いか又はhiPSC由来の肝細胞の未成熟な表現型を示すかのいずれかである、肝細胞機能のスペクトルを示す32個の遺伝子の発現を検討した。一次スクリーニング中に、多くの成熟関連遺伝子の数の有意な増加をもたらす多数の化合物が確認された。遺伝子発現の変化は、二次スクリーニングにおいて検証及び確認され、そして機能的配列を検索した。
新鮮なiCell(登録商標)肝細胞(20−23日目)を、iCell Hepatocytes Dissociation and Plating User’s Guideに従って、96ウェルのBIO Collagen IVで被覆されたプレート(BDカタログ番号354429)に、ウェル当たり60k細胞で播種し、そして培養した 播種から4時間後、培地Cを除去し、そして培地D中の1:50のMatrigel(カタログ番号354227)オーバーレイで置換えた。本出願人等は、播種後24時間に培地D中の5uMの細胞及び1%DMSOを投与した。3日目に、培地を除去し、そして本出願人等は、再び5uMを投与した。4日目に、本出願人等は、RNAを回収した。
試料のRNAを、TaqMan(登録商標)Gene Expression Cells−to−CTTM Kit(Life Technologiesカタログ番号4387299)を使用して、化合物処理後の各種の時点で−80℃に冷凍して単離した。全ての試料を、マイクロ流体定量的PCRによって、Biomark Fluidigm 96.96チップ(BMK−M−96.96)及びABI Taqmanプローブを使用して加工した。正規化及びモデルベースの発現測定は、Biogazelle qBASE及びGenormソフトウェアを使用して計算した。三重の全ての試料のデータを平均し、そして相対的遺伝子発現値に対して、5個のハウスキーピング遺伝子に対して正規化した。発現値は、ベヒクル対照に対する倍数の変化によって計算した。図1及び2を参照されたい。
実施例1の化合物で処理されたiCell肝細胞は;インターフェロン活性化遺伝子(ISG)発現に対する動力学的影響を含む遺伝子の宿主の上方及び下方制御をもたらす。図7a、7b、7c、及び表1を参照されたい。
200マイクロリットルのHBVを含有する血清を、SW41試験管中で10−50%のOptiprepの勾配にかけた。試料を100,000×gで2時間4Cで遠心した。500マイクロリットルの画分を上部から収集し;それぞれの画分をHBsAg(ELISA)及びHBV DNA(TaqMan PCR)に対して分析した。ウイルスを含有する画分を、−80Cで保存した。図6bを参照されたい。
新鮮なiCell(登録商標)肝細胞(20−23日目)を、iCell Hepatocytes Dissociation and Plating User’s Guideに従って、96ウェルのBIO Collagen IVで被覆されたプレート(BDカタログ番号354429)のウェル当たり60k細胞で播種し、そして培養した 播種から4時間後、培地Cを除去し、そして培地D中の1:50のMatrigel(カタログ番号354227)オーバーレイで置換えた。播種後24時間に、細胞を、1%のDMSOを含有する培地D中の1uMの実施例1の化合物で処理した。新鮮な化合物を含有する培地を2日後に補充した。播種後4日目に、細胞を10のMOI(感染効率)でHBVで感染した。簡単には、精製したウイルスを、実施例1の化合物を含有する培地D中に希釈し、そして細胞と共に4−6時間又は一晩インキュベートした。ウイルスの接種菌液の除去後、1uMの実施例1の化合物を含有する新鮮な培地を加え、そして細胞を2日毎に培地を交換しながら14日間インキュベートした。培養培地を分泌されたウイルスの抗原(HBsAg、HBeAg)及びHBV DNAに対して分析した。図3、4、5、6aを参照されたい。
Claims (28)
- 以下の式I:
- R1、R2、R3、R4、及びR5が、全て水素である、請求項1に記載の化合物。
- R1、R2、R3、R4、又はR5の少なくとも一つがハロゲンである、請求項1に記載の化合物。
- R1、R2、R3、R4、又はR5の少なくとも一つがフルオロである、請求項1に記載の化合物。
- R1、R3、及びR5が全て水素であり、そしてR2又はR4の一つがフルオロであり、そして他方が水素である、請求項1に記載の化合物。
- R6、R7、R8、R9、及びR10が、全て水素である、請求項1に記載の化合物。
- R6、R7、R8、R9、及びR10の少なくとも一つがハロゲンである、請求項1に記載の化合物。
- R6、R7、R8、R9、及びR10の少なくとも一つがクロロである、請求項1に記載の化合物。
- R6、R8、及びR10が全て水素であり、そしてR7又はR9の一つがクロロであり、そして他方が水素である、請求項1に記載の化合物。
- R11が水素である、請求項1に記載の化合物。
- R1、R2、R3、R4、又はR5の一つがフルオロであり、そしてその他が水素であり;そしてR6、R7、R8、R9、R10及びR11が水素である、請求項1に記載の化合物。
- R11がヒドロキシである、請求項1に記載の化合物。
- R1、R2、R3、R4、又はR5がフルオロであり、そしてその他が水素であり;R6、R7、R8、R9、及びR10が水素であり、そしてR11がヒドロキシである、請求項1に記載の化合物。
- 以下の式:
- 以下の式:
- 以下の式:
- 以下の式:
- 以下の式:
- 以下の式:
- 以下の式:
- 以下の式IA:
- 以下の式IB:
- 請求項1に記載の化合物及び医薬的に受容可能な担体を含んでなる医薬組成物。
- 幹細胞を肝細胞に分化するための、請求項1に記載の化合物を前記幹細胞に投与することを含んでなる方法。
- 前記肝細胞が、B型肝炎ウイルスに感染させられる、請求項24に記載の方法。
- 前記感染させられる肝細胞が、B型肝炎ウイルスを治療するための化合物をスクリーニングするために使用される、請求項25に記載の方法。
- インターフェロン活性化遺伝子が、分化された肝細胞中で下方制御される、請求項24に記載の方法。
- 前記肝細胞が、B型肝炎ウイルスに感染させられる、請求項27に記載の方法。
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WO2014140058A1 (en) | 2014-09-18 |
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US20150158840A1 (en) | 2015-06-11 |
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