JP5461197B2 - 代謝障害を処置するための組成物および方法 - Google Patents
代謝障害を処置するための組成物および方法 Download PDFInfo
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- JP5461197B2 JP5461197B2 JP2009548468A JP2009548468A JP5461197B2 JP 5461197 B2 JP5461197 B2 JP 5461197B2 JP 2009548468 A JP2009548468 A JP 2009548468A JP 2009548468 A JP2009548468 A JP 2009548468A JP 5461197 B2 JP5461197 B2 JP 5461197B2
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- thiazol
- propylpyridin
- srebp
- fatostatin
- thiazole
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- RTZRUVMEWWPNRR-UHFFFAOYSA-N tert-butyl n-(3-iodo-1h-pyrrolo[2,3-b]pyridin-5-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CN=C2NC=C(I)C2=C1 RTZRUVMEWWPNRR-UHFFFAOYSA-N 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- GGNIKGLUPSHSBV-UHFFFAOYSA-N thiazole-5-carboxamide Chemical compound NC(=O)C1=CN=CS1 GGNIKGLUPSHSBV-UHFFFAOYSA-N 0.000 description 1
- WHLUQAYNVOGZST-UHFFFAOYSA-N tifenamil Chemical compound C=1C=CC=CC=1C(C(=O)SCCN(CC)CC)C1=CC=CC=C1 WHLUQAYNVOGZST-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 230000007723 transport mechanism Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000012130 whole-cell lysate Substances 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- 229940002552 xenical Drugs 0.000 description 1
Classifications
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- 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
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- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/10—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- 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
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- 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
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- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Description
本発明は、一般に、例えば、医学、細胞生物学、分子生物学、および生化学の分野に関する。特定の態様では、発明の分野は、肥満などの代謝障害の治療のための特定の組成物に関する。ある態様では、組成物は、例えば、ファトスタチンAおよびその類似体または誘導体を含む。
代謝症候群は、多数の心血管危険因子(高血圧症、脂質異常症(dyslipidaemia)、肥満、2型糖尿病、膵臓β細胞機能障害、およびアテローム性動脈硬化症が含まれる)を対象とする。脂肪または炭水化物の含有量が様々な食事は、動物(ヒトが含まれる)のエネルギー代謝に寄与する。長鎖脂肪酸は、主なエネルギー供給源であり、細胞膜を含む脂質の重要な成分である。長鎖脂肪酸は、食品に由来し、de novoで複雑な一連の反応を介してアセチル−CoAから合成される。コレステロールも食品に由来し、同様に複雑な反応を介してアセチル−CoAから合成される。de novo脂肪酸およびコレステロール合成を介した炭水化物のアシルグリセリドへの変換は、それぞれ、少なくとも12および23の酵素反応を含む。これらの酵素をコードする遺伝子の発現レベルは、ステロール調節エレメント結合タンパク質(SREBP)と呼ばれる3つの転写因子(SREBP−1a、SREBP−1c、およびSREBP−2)によって調節される(非特許文献1;非特許文献2)。これらの膜結合タンパク質は、ベーシック・ヘリックス・ループ・ヘリックス・ロイシンジッパー転写因子ファミリークラスのメンバーである(非特許文献1;非特許文献2;非特許文献3)。他のロイシンジッパー転写因子メンバーと異なり、SREBPは、小胞体膜結合前駆体として合成され、小胞体膜結合前駆体は核内の標的遺伝子の転写を活性化するためにゴルジ膜に結合する2つのプロテアーゼ(サイト−1およびサイト−2プロテアーゼ)によってタンパク質分解的に放出される必要がある(非特許文献1;非特許文献4)。
本発明は、個体(特に、例えば、ヒト、イヌ、ネコ、ウマ、ウシ、ヤギ、またはヒツジなどの哺乳動物)の1つまたは複数の代謝障害の治療および/または予防に関する。特に、本発明は、治療のための個体への1つまたは複数の組成物の送達に関し、特定の実施形態では、組成物は、ファトスタチンAおよび/またはその類似体および/または誘導体である。有効量の本発明の化合物を使用して障害由来の少なくとも1つの症状が治療および/または予防される限り、代謝障害は、任意の種類であり得る。
本発明は、例えば、以下を提供する。
(項目1)
4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;N−イソプロピル−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;N−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル)アセトアミド;N−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル)メタンスルホンアミド;N−ベンジル−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;N−(シクロプロピルメチル)−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;N−シクロヘキシル−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;tert−ブチル4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニルカルバメート;4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)−N−トシルベンゼンアミン;N−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル)−8−キノリンスルホンアミド;およびN−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル)−2−チオフェンスルホンアミド;またはその薬学的に許容可能な塩からなる群から選択される化合物。
(項目2)
項目1に記載の化合物の少なくとも1つ及び薬学的に許容可能なキャリアを含む薬学的組成物。
(項目3)
個体の代謝障害を治療するための薬学的組成物であって、2−プロピル−4−(4−p−トリルチアゾール−2−イル)ピリジン;4−(4−(4−ブロモフェニル)チアゾール−2−イル)−2−プロピルピリジン;4−(4−フェニルチアゾール−2−イル)−2−プロピルピリジン;4−(4−(4−クロロフェニル)チアゾール−2−イル)−2−プロピルピリジン;4−(4−(4−エチルフェニル)チアゾール−2−イル)ピリジン;4−(4−p−トリルチアゾール−2−イル)ピリジン;4−(4−(4−メトキシフェニル)チアゾール−2−イル)ピリジン;安息香酸4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル;4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェノール;メチル2−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェノキシ)アセテート;2−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェノキシ)酢酸;4−(4−(3,4−ジクロロフェニル)チアゾール−2−イル)−2−プロピルピリジン;4−(4−(4−フルオロフェニル)チアゾール−2−イル)−2−プロピルピリジン;4−(4−(2,4−ジフルオロフェニル)チアゾール−2−イル)−2−プロピルピリジン;4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;N−イソプロピル−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;N−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル)アセトアミド;N−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル)メタンスルホンアミド;N−ベンジル−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;N−(シクロプロピルメチル)−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;4−(4−ブロモフェニル)−2−(2−プロピルピリジン−4−イル)チアゾール−5−カルボン酸;メチル4−(4−ブロモフェニル)−2−(2−プロピルピリジン−4−イル)チアゾール−5−カルボキシレート;4−(4−(4−メトキシフェニル)チアゾール−2−イル)−2−プロピルピリジン;4−(4−(3−メトキシフェニル)チアゾール−2−イル)−2−プロピルピリジン;4−(4−(2−メトキシフェニル)チアゾール−2−イル)−2−プロピルピリジン;3−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェノール;2−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェノール;4−(4−ブロモフェニル)−N−イソプロピル−2−(2−プロピルピリジン−4−イル)チアゾール−5−カルボキシアミド;4−(4−(4−クロロフェニル)チアゾール−2−イル)ピリジン;4−(4−(4−クロロフェニル)チアゾール−2−イル)−2−エチルピリジン;2−プロピル−4−(4−(チオフェン−2−イル)チアゾール−2−イル)ピリジン;2−(2−プロピルピリジン−4−イル)−4−p−トリルチアゾール−5−カルボン酸;2−エチル−4−(4−p−トリルチアゾール−2−イル)ピリジン;4−フェニル−2−(2−プロピルピリジン−4−イル)チアゾール−5−カルボン酸;メチル2−(2−プロピルピリジン−4−イル)−4−p−トリルチアゾール−5−カルボキシレート;tert−ブチル4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニルカルバメート;N−シクロヘキシル−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)−N−トシルベンゼンアミン;N−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル)−8−キノリンスルホンアミド;およびN−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル)−2−チオフェンスルホンアミドから成る群から選択される少なくとも1つの化合物を含む、薬学的組成物。
(項目4)
前記少なくとも1つの化合物が、安息香酸4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル;4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェノール;メチル2−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェノキシ)アセテート;2−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェノキシ)酢酸;4−(4−(2,4−ジフルオロフェニル)チアゾール−2−イル)−2−プロピルピリジン;4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;N−イソプロピル−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;N−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル)アセトアミド;N−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル)メタンスルホンアミド;N−ベンジル−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;N−(シクロプロピルメチル)−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;4−(4−ブロモフェニル)−2−(2−プロピルピリジン−4−イル)チアゾール−5−カルボン酸;メチル4−(4−ブロモフェニル)−2−(2−プロピルピリジン−4−イル)チアゾール−5−カルボキシレート;4−(4−(3−メトキシフェニル)チアゾール−2−イル)−2−プロピルピリジン;4−(4−(2−メトキシフェニル)チアゾール−2−イル)−2−プロピルピリジン;3−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェノール;2−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェノール;および4−(4−ブロモフェニル)−N−イソプロピル−2−(2−プロピルピリジン−4−イル)チアゾール−5−カルボキシアミドからなる群から選択される、項目3に記載の薬学的組成物。
(項目5)
前記少なくとも1つの化合物が、2−プロピル−4−(4−p−トリルチアゾール−2−イル)ピリジン;4−(4−(4−ブロモフェニル)チアゾール−2−イル)−2−プロピルピリジン、N−イソプロピル−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン、およびN−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル)メタンスルホンアミドからなる群から選択される、項目3に記載の薬学的組成物。
(項目6)
前記代謝障害が、肥満、高脂質血症、糖尿病、脂肪肝、高血圧症、前立腺癌、および心血管疾患からなる群から選択される、項目3に記載の薬学的組成物。
(項目7)
前記代謝障害が肥満である、項目6に記載の薬学的組成物。
(項目8)
前記個体のSREBP経路のメンバーを阻害するのに効果的である、項目3記載の薬学的組成物。
(項目9)
前記SREBP経路のメンバーが、SREBP−1、SREBP−2、またはその両方である、項目8に記載の薬学的組成物。
(項目10)
化1の化合物であって、
本明細書中で使用される場合、「a」または「an」は、1つまたは複数を意味し得る。特許請求の範囲で用語「〜を含む」と併せて使用する場合、用語「a」または「an」は、1つ以上を意味し得る。本明細書中で使用される場合、「別の」は、少なくとも第2以上を意味し得る。特定の実施形態では、本発明の態様は、例えば、1つまたは複数の本発明の配列「から本質的になる」または「からなる」ことができる。本発明のいくつかの実施形態は、本発明の1つまたは複数の要素、方法工程、および/または方法からなるかから本質的になることができる。本明細書中に記載の任意の方法または組成物を本明細書中に記載の任意の他の方法または組成物に関連して実施することができる。
本発明の化合物を使用して、代謝障害を治療および/または予防する。例えば、脂肪酸およびコレステロールの無制御な合成および食物性脂肪の過剰摂取は、多数の医学的合併症(少なくとも肥満、糖尿病、高血圧症、および心血管疾患が含まれる)と相関する。ある態様では、これらの状態を、本発明の化合物を使用して治療および/または予防する。疫学的証拠により、代謝性疾患(肥満が含まれる)が浸潤型前立腺癌の発症も促進することを示している。
本発明は、代謝障害の少なくとも1つの症状の治療および/または予防に関する。代謝障害は、その症状が本発明の化合物を使用して改善または予防される限り、任意の種類の代謝障害であり得る。それにもかかわらず、特に、代謝性疾患は、欠損代謝酵素に起因する遺伝形質(例えば、調節タンパク質および輸送機構の変異に関与する1つまたは複数の変異または障害を有するもの)などの1つまたは複数の先天性代謝異常(遺伝障害ということもできる)に由来する。
1つの実施形態では、以下の一般式:
A−B−C
(式中、
A、B、およびCは同一であっても異なっていてもよく、それぞれ、5員環、6員環、または7員環であり得、環は、複素環もしくは非複素環、置換環、または非置換環である)を有する少なくとも1つの化合物またはその薬学的に許容可能な塩および立体異性体の投与を含む代謝障害の治療方法が存在する。
A−B−C
(式中、
A、B、およびCは同一または異なり、それぞれ、5員環、6員環、または7員環を含み、この環は、複素環もしくは非複素環、置換環、または非置換環であり、
A、B、およびCの任意の1つ、任意の2つ、または3つ全ては、非置換であるか、1つまたは複数の置換を有し、任意の置換は任意の他の置換と同一であっても異なっていてもよく、置換は、以下:
a)ヒドロキシ;
b)C1〜10アルキル;
c)C2〜10アルケニル;
d)C2〜10アルキニル;
e)C3〜6シクロアルキル;
f)アリール;
g)ヘテロアリール;
ここで、b)、c)、d)、e)、f)、および/またはg)中の置換は、以下:
1)ヒドロキシ;
2)−(C=O)Ra;
3)−(C=O)ORa;
4)−(C=O)H;
5)−(C=O)OH;
6)−O(CH2)nCOORa(式中、n=1〜10);
7)ハロ;
8)シアノ;
9)カルボキシ;
10)アミノ;
11)一置換アミノ;
12)二置換アミノ;
13)アミド;
14)一置換アミド;
15)二置換アミド;および
16)それらの任意の組み合わせからなる群から選択される1〜5個の基で任意選択的にさらに置換され、
ここで、2)、3)、または6)において、Raは、C1〜10アルキル、C2〜10アルケニル、C2〜10アルキニル、C3〜6シクロアルキル、アリール、またはヘテロアリールであり、
h)−(C=O)Ra;
i)−(C=O)ORa;
j)−(C=O)H;
k)−(C=O)OH;
l)−O(CH2)nCOORa(式中、n=1〜10)、
ここで、h)、i)、またはl)において、Raは、C1〜10アルキル、C2〜10アルケニル、C2〜10アルキニル、C3〜6シクロアルキル、アリール、またはヘテロアリールであり、
m)ハロ;
n)シアノ;
o)カルボキシ;
p)アミノ;
q)一置換アミノ;
r)二置換アミノ、
s)アミド;
t)一置換アミド;および
u)二置換アミドからなる群から選択され、
ここで、該一置換アミノ、二置換アミノ、一置換アミド、および二置換アミドの1つまたは複数は、C1〜10アルキル、C2〜10アルケニル、C2〜10アルキニル、C3〜6シクロアルキル、アリール、ヘテロアリール、スルホキシド、スルホン、スルホナート、アルキルスルホナート、スルホン酸、およびそれらの任意の組み合わせからなる群から選択される置換を有し、
ここで、u)において、該アルキル、アルケニル、アルキニル、シクロアルキル、アリール、またはヘテロアリールは、以下:
i)ヒドロキシ;
ii)−(C=O)Ra;
iii)−(C=O)ORa;
iv)−(C=O)H;
v)−(C=O)OH;
vi)−O(CH2)nCOORa(式中、n=1〜10)、
ここで、ii)、iii)、またはvi)において、Raは、C1〜10アルキル、C2〜10アルケニル、C2〜10アルキニル、C3〜6シクロアルキル、アリール、またはヘテロアリールであり、
vii)ハロ;
viii)シアノ;
ix)カルボキシ;
x)アミノ;
xi)一置換アミノ;
xii)二置換アミノ;
xiii)アミド;
xiv)一置換アミド;
xv)二置換アミド;および
xvi)それらの任意の組み合わせからなる群から選択される1〜5個の基で任意選択的にさらに置換される)を有する1つの化合物またはその薬学的に許容可能な塩もしくは立体異性体が存在する。
本発明の特定の実施形態では、本発明の組成物は、ステロール調節エレメント結合タンパク質(SREBP)経路の1つまたは複数のメンバーを対象とする。経路は、特定の態様で細胞質から核への輸送を容易にする膜結合転写因子(SREBP)のタンパク質分解性放出に関する。ここで、SREBPは、脂質産生に関連する酵素をコードする遺伝子の調節領域に存在するステロール調節エレメント(SRE)と呼ばれるエレメントに結合する。SREBPのDNAへの結合の際、標的遺伝子の転写は調整(例えば、上方制御など)される。
本発明の薬学的組成物は、薬学的に許容可能なキャリアに溶解または分散された有効量の1つまたは複数の本発明の組成物(およびさらなる薬剤(必要に応じる))を含む。句「薬学的または薬理学的に許容可能な」は、例えば、必要に応じて、ヒトなどの動物に投与した場合に副作用、アレルギー反応、または他の有害反応を引き起こさない分子的実体および組成物をいう。少なくとも1つのファトスタチンA類似体もしくは誘導体またはさらなる有効成分を含む薬学的組成物の調製は、Remington’s Pharmaceutical Sciences、18th Ed.Mack Printing Company、1990(本明細書中で参考として援用される)に例示されるように、本開示を考慮して当業者に公知であろう。さらに、動物(例えば、ヒト)投与のために、調製物は、FDAの生物学的基準に必要とされる無菌性、発熱性、一般的安全性、および純度の基準を満たすべきであると理解されるであろう。
本発明の好ましい実施形態では、消化管経路を介して投与されるようにファトスタチンA類似体または誘導体を処方する。消化管経路には、組成物が消化管に直接接触する全ての可能な投与経路が含まれる。具体的には、本明細書中に開示の薬学的組成物を、経口、口腔、直腸、または舌下に投与することができる。そのようなものとして、これらの組成物を、不活性希釈剤または吸収可能な食用キャリアを使用して処方することができるか、硬ゼラチンカプセルまたは軟ゼラチンカプセル中に封入することができるか、打錠することができるか、あるいは食物と直接組み込むことができる。
さらなる実施形態では、ファトスタチンA類似体または誘導体を、非経口経路を介して投与することができる。本明細書中で使用する場合、用語「非経口」には、消化管を回避する経路が含まれる。具体的には、本明細書中に開示の薬学的組成物を、例えば、静脈内、皮内、筋肉内、動脈内、髄腔内、皮下、または腹腔内(これらに限定されない)に投与することができる。米国特許第6,537,514号、同第6,613,308号、同第5,466,468号、同第5,543,158号、同第5,641,515号、および同第5,399,363号(それぞれ、その全体が本明細書中で参考として具体的に援用される)。
本発明の他の好ましい実施形態では、活性化合物ファトスタチンA類似体または誘導体を、種々の多岐にわたる経路(例えば、局所(すなわち、経皮)投与、粘膜投与(鼻腔内、膣など)および/または吸入)を介した投与のために処方することができる。
本発明の組成物の有効性を増加させるために、付加療法を代謝障害を有する個体に送達することができる。例えば、肥満個体に、肥満のための別の療法に加えて、本発明の組成物を投与することができる。さらなる肥満療法には、例えば、食事療法、理学療法(運動)、薬物療法、手術、および行動療法が含まれる。例示的薬物療法には、例えば、Xenical Orlistat(登録商標)、フェンテルミン、およびシブトラミン(Meridia(登録商標))が含まれる。例示的手術には、例えば、脂肪吸引および胃バイパスが含まれる。
本発明の特定の態様では、個体に、1つまたは複数の本発明の組成物を投与し、個体を、代謝障害の少なくとも1つの症状の改善について評価する。例えば、代謝障害が肥満である特定の実施形態では、肥満の改善を、1つまたは複数の本発明の組成物の治療中および/または治療後に決定することができる。肥満の改善を、任意の標準的手段によって測定することができるが、特定の態様では、肥満の改善を、例えば、体重測定、体型指数(BMI)測定、および/または体部位のサイズの測定(腰囲測定)によって測定する。例示的なBMI計算方法は、個体の体重(キログラム)をその身長(メートル)の2乗で割ること(体重[kg]身長[m]2)を含む。BMI30以上を肥満と見なし、BMI25〜29.9を過体重と見なす。
本明細書中に記載の任意の組成物を、キット中に含めることができる。非限定的な例では、キットは、1つまたは複数の代謝障害の治療および/または予防に適切な組成物を含む。
ファトスタチンAはSREBP応答性遺伝子の発現を減少させる
薬物処理細胞および非処理細胞の遺伝子発現プロフィールの比較により、ファトスタチンAによって影響を受ける特異的分子経路を明らかにすることができる。DU145細胞を、ファトスタチンAまたはDMSOのみで処理し、抽出mRNAサンプルを、33,000遺伝子をマッピングするAffimetrix DNAマイクロアレイによって分析した(表1)。
ファトスタチンAはSREBPのタンパク質分解活性を遮断する
SREBPはタンパク質分解的にプロセシングされて核に転位し、ここで、SREBPが脂質合成遺伝子の転写を活性化する(Brown and Goldstein、1997)。ファトスタチンAがSREBPのタンパク質分解活性に影響を及ぼすかどうかを試験するために、ファトスタチンAで処理したDU145細胞の全細胞溶解物を、SREBP−1のNH2末端に対する抗体を使用したウェスタンブロットによって分析した(図3A)。ファトスタチンAの処理により、用量依存様式でSREBP−1の68kDa成熟形態の量が減少した一方で、125KDa前駆体形態の量が増加した。そのCOOH末端に対する抗体を使用して、SREBP−2について類似の結果が得られた(図3B)。これらの結果は、ファトスタチンAが両SREBPイソ型のタンパク質分解活性を直接または間接的に妨害することを示す。
SREBP−1のノックダウンによるファトスタチン表現型の検証
ファトスタチンAにより、培養細胞中に以下の2つの表現型が生じる:(i)3T3−L1細胞のインスリン誘導性脂肪生成の阻害および(ii)DU145前立腺癌細胞の血清非依存性成長の抑制(Choiら、2003)。第1の表現型は、脂質合成におけるSREBP−1の公知の役割のために、ファトスタチンAがSREBP−1の遮断薬であるという本発明者らの結論と完全に一致する(Tontonozら、1993;Kim and Spiegelman、1996)。細胞培養条件下で3T3−L1細胞中のSREBP−1発現がSREBP−1に特異的な小さな干渉RNA(siRNA)の発現ベクターのトランスフェクションによってサイレンシングされたことを確認するために(図4G)、インスリン誘導性脂肪生成に及ぼすサイレンシングの影響を試験した。予想通り、SREBP−1発現のノックダウンによって3T3−L1細胞の油滴形成が完全に遮断されたのに対して(図4Dおよび4F、クローン1および2)、空のベクター(neo)でトランスフェクトしたコントロール細胞は、親3T3−L1細胞ほどの脂肪蓄積を示した(図4B)。これらの結果は、3T3−L1細胞におけるファトスタチンA誘導性表現型がSREBP−1阻害によって媒介されることを示す。
ファトスタチンAは、マウスにおいて体重を減少させ、コレステロールレベルおよびグルコースレベルを低下させ、脂質合成酵素を下方制御する
ファトスタチンAの薬物様化学構造により、本発明者らは、全動物の肝臓中のSREBP−1を阻害する能力の調査に駆り立てられた。長期絶食(48時間)およびその後のさらなる48時間の無脂肪高炭水化物食の摂取による脂質合成条件下での肝臓SREBP−1に及ぼすファトスタチンAの影響を試験した。マウスに、30mg/kg/日のファトスタチンAを、48時間の絶食期間の1日前から開始して5日間腹腔内注射した。48時間の絶食後、処置群はコントロール群よりも多くの体重が減少した(4.9±0.3g/マウスと比較して6.12±0.6;p=0.01)(図6A)。処置中に摂食の減少や明らかな毒性は認められなかった(図6B)。興味深いことに、無脂肪高炭水化物食の再摂取48時間後、ファトスタチンA処置マウスの血清中のグルコースレベル(137±14mg/dlと比較して110±23;P=0.06)およびコレステロール(120±19mg/dlと比較して93±20;P=0.12)が低下する傾向があった(図6C)。HDLおよびLDLの両方は、処置マウス群で減少した。しかし、LDLレベルの減少がより有意なようであった(30±6mg/dlと比較して16±5)(図6C)。
本発明の有意性
生物活性小分子は、代謝経路が含まれる複雑な細胞過程を調査するための有益なツールであることが証明されている。脂質ホメオスタシスおよびインスリン作用の重要なレギュレーターは、SREBP転写因子のファミリーである(Brown and Goldstein、1997)。SREBP機能を調整する小分子は、代謝性疾患の治療で使用することができ、疾患のさらなる分子的理解のためのツールとしての機能を果たすことができる。本発明者らの細胞ベースのデータおよび動物データにより、ファトスタチンAが核内の成熟SREBP−1形態量の下方制御によって脂質合成遺伝子の発現を妨害することが示唆される。本発明者らの知る限り、ファトスタチンAは、培養細胞およびマウス肝臓の両方においてSREBPのタンパク質分解活性を阻害する第1の非ステロール様合成分子に相当する。
実施例1〜5についての例示的な材料と方法
本実施例では、例示的な材料と方法を示す。
ファトスタチンAは、肥満OB/OBマウスにおいて脂肪肝を予防し、高血糖を低下させ、体重減少を誘導する
創薬における遺伝子操作マウスモデルの重要性および役割は十分に報告されている(Zambrowicz and Sands、2003)。これらの動物モデルのうち、レプチン欠損マウスLepob/Lepobは、肥満およびその関連する症候群(インスリン抵抗性および脂肪肝疾患など)を研究するための特に有益なモデルと見なされている(Ktorzaら、1997)。ホモ接合体ob/ob肥満マウスは、体脂肪の蓄積、高血糖、高インスリン、および生殖障害が増加した(Ingalisら、1950)。肥満の結果の1つである代謝症候群は、多数の心血管危険因子(高血圧症、脂質異常症、2型糖尿病、膵臓β細胞機能障害、およびアテローム性動脈硬化症が含まれる)を伴う(Moller and Kaufman、2005)。
本研究は、平均体重が約23g/マウスの4〜5週齢の雄ob/obマウスを使用した。ファトスタチンA(30mg/kg/日)を毎日腹腔内に送達させ、体重および摂食を測定した。図8Aおよび8Bに示すように、処置したマウスの体重増加は、コントロールよりも有意に低かった。治療の最初の週の終了時に、DMSOを注射したobコントロールマウスは平均4.82g/マウス増加したのに対して(23.58±0.62から28.40±1.45への増加)、ファトスタチン処置群は約3.37g/マウス増加した(23.08±1.53から26.45±1.2g/マウスへの増加)(P=0.03)。処置28日後、ファトスタチンA処置群は、数週、コントロールよりも約12%軽かった(ファトスタチンについて36.2±2.2g/マウスと比較して32.1±1.4)(P=0.02)。累積摂食は両群で類似していた(図8C)。平均して、処置群では、摂食は、それぞれ、5.9±1.4g/マウス/日と比較してコントロールは5.4±1.5であり、有意に異ならなかった。
ob/obマウスにおける最も特徴的な表現型の1つは、インスリン抵抗性状態の結果としての高血糖である。血糖および脂質に及ぼすファトスタチンAの影響を決定するために、グルコース、トリグリセリド、およびコレステロールの血清レベルを、標準的な飼料を与えたob/obマウスで分析した。
無制御の摂食のために、ob/obマウスは病的に肥満になり、過剰レベルの脂肪が脂肪組織および異なる器官に蓄積する(肝臓に起因する非アルコール性脂肪肝およびインスリン抵抗性など)(Hookman and Barkin、2003)。約8〜9週齢のコントロール処置マウスは、ファトスタチンAで処置したマウスと比較して、淡色から明らかなように、肝臓サイズが拡大し、脂肪が蓄積した(図10A)。ファトスタチンA処置マウスの肝臓の平均重量は、コントロールより約32%軽かった(2.34±0.15と比較して1.59±0.2;P=0.06)(図10D)。オイルレッドで脂肪滴を染色したコントロールマウスの肝臓切片が脂肪滴を豊富に含んでいたのに対して、ファトスタチンA処置マウスの肝臓切片は脂肪滴を欠き、これは主にトリグリセリドである(図10B)。SREBP−1を過剰発現するトランスジェニックマウスが脂肪肝を発症することが示されている(Hortonら、2003)。しかし、SREBP−1を欠くob/obマウス(lepob/ob X Srebp 1−/−)では、脂肪肝状態は有意に改善され、SREBP−1がob/obマウスにおける脂肪肝発症の主な原因であることが示唆される(Yahagiら、2002)。
脂質合成経路中の酵素は、転写因子(PPARおよびSREBPなど)によって調節される。処置ob/obマウスにおける脂質合成酵素のレベルおよび活性に及ぼすファトスタチンAの影響を試験した。脂肪酸合成の律速段階を行うアセチル−CoAカルボキシラーゼ(ACC)活性を決定した。ACCは、アセチル−CoAのカルボキシル化を触媒してマロニルCoA(別の多官能酵素(脂肪酸シンターゼ(FAS))によって行われる脂肪酸合成の基礎単位)が得られる。脂肪酸合成におけるマロニルCoAの役割に加えて、これは、カルニチンパルミトイルトランスフェラーゼ1(CPT1)の阻害による脂肪酸酸化で重要な役割を果たす。脂質合成酵素はob/obマウスで有意に誘導され、これは、これらのマウスの病的な肥満表現型を部分的に説明している。ファトスタチンA処置マウスの肝臓抽出物中のACC活性は、約40%減少した(5.55±0.57nmol/min.mgと比較して3.44±0.44)(図12A)。脂肪酸シンターゼ活性も、ファトスタチンA処置ob/obマウスの肝臓抽出物中で有意に下方制御された。FAS活性は、処置マウスで70%超減少した(22.6±1.37nmol/min.mgと比較して8.64±1.91)(図12B)。両酵素についてウェスタンブロット分析で示すように、ACCおよびFAS活性の両方の減少は、両酵素の発現レベルの減少に起因する(図12C)。その生成物である脂肪酸(C14:0およびC16:0)は、非処置コントロールマウスの肝臓中よりファトスタチン処置ob/obマウスの肝臓中で有意に低下する(約50%)(表2を参照のこと)。
タンパク質レベルの減少は、転写および翻訳の調節に起因し得る。リアルタイムPCRを使用して、脂質合成転写因子PPARγに加えて、代表的な脂質合成遺伝子であるACC1、FAS、およびSCD1のmRNAレベルを決定した。ACC1、FAS、およびSCD1のmRNAレベルが約80%減少した(図13)。これらの結果は、より低い酵素のタンパク質レベルおよび活性レベルと一致し、SREBP−1の成熟の阻害によってファトスタチンAが脂質合成を低下させることを強く示す。脂質合成酵素の下方制御は、特定の実施形態では、その主な転写因子であるPPARγの1つを含む。この転写因子のmRNAレベルは、ファトスタチンA処置マウスの抽出物中で約40%減少した(図13)。ob/obマウスの肝臓由来のPPARγの欠失に関する研究により、脂肪肝も改善された(Matsusueら、2003)。しかし、PPARγを肝臓のみから欠失させ、これらのマウスにおいて糖尿病表現型が悪化した(Matsusueら、2003)。他の研究により、肝臓PPARγ−/−マウスの血中グルコースがより低く、機能的レプチン遺伝子を使用した高脂肪食において15週間後にインスリン抵抗性から防御されたことが示された(Kubotaら、1999)。ファトスタチンAで処置したob/obマウスの高血糖が減少し、脂肪肝が予防されるので、これは、特定の態様では、肝臓中のPPARγがこれらの病的状態に影響を及ぼし得るいくつかの要因のうちの1つであることを示す。さらに、白色脂肪などの他の組織は、抗高血糖効果で役割を果たすことができ、これは肝臓中で脂質合成が阻害される場合の脂質合成の減少によって相殺することができる。
動物研究手順
4〜5週齢のホモ接合体雄肥満(ob/ob)マウス(C57BL/6J、The Jackson Laboratory、Bar Harbor、ME)を、管理条件下(12時間の明暗サイクル;25℃)でAnimal Care Center at Baylor College of Medicineに収容した。動物実験を、米国国立衛生研究所によって公開されたGuide for the Care and Use of Laboratory Animals(NIH Publication No.85−23、1996改訂)にしたがって行った。1ケージあたり5匹の動物を収容し、標準的な実験動物用飼料(Purina Mills、Richmond IN)および水を到着後1週間自由に与えた。実験第1日目およびその後毎日、マウスの体重および飼料の消費量を測定した。マウスおよび飼料の残量を、ファトスタチンA(30mg/kg;150mL)注射前の午後3時〜5時に毎日測定した。
ファトスタチンAマウスへの28日間にわたる毎日の注射の28日後に、マウスを一晩絶食させ、採血し、全血糖およびβ−ヒドロキシブチラートを、Glucometer Precision Xtra(Abbott)を使用して測定した。血清成分の決定のために、Comparative Pathology Laboratory(Baylor College of Medicine)によってグルコース、トリグリセリド、およびコレステロールの測定を行った。血清非エステル化脂肪酸(NEFA)を、NEFA Cキット(Wako Chemicals、Richmond、VA)の使用によって測定した。
マウスを屠殺し、肝臓および精巣上体脂肪パッドを秤量した。以前に記載のように、各動物由来の肝臓スライスの凍結切片を、オイルレッドOで染色して、肝臓スライス中の脂肪滴(TG)を視覚化した(Abu−Elheigaら、2001)。残りの肝臓組織を、液体窒素中で凍結し、さらなる分析のために−80℃に保持した。
肝臓トリグリセリドおよびコレステロール含有量を、参考文献(Chandlerら、2003)に記載のように、96ウェルプレート形式での比色分析に適合したコレステロールEキット(Wako)およびInfinityトリグリセリドキット(Thermo Electron、Melbourne、Australia)を使用して測定した。
凍結肝臓の一部を、液体窒素中で粉砕した。粉末組織を、0.1mM PMSF、5mMベンズアミジン、および5mg/mLプロテアーゼインヒビターカクテル(Roche)を含む10mLのPBS中に懸濁し、Polytron(3×30秒、高速)を使用してホモジナイズし、短時間超音波処理してDNAを破壊した。抽出物を16,000×gで20分間の遠心分離によって清澄化した。上清中のタンパク質濃度を決定し、以下の酵素に対する市販の抗体を使用したウェスタンブロット分析に供した:FAS(BD Biosciences)、クエン酸リアーゼSCD1、FADS1、ACC、およびホスホロ−ACC抗体。タンパク質を、Amersham ECL Plus(商標)ウェスタンブロッティング検出試薬を使用して視覚化した。目的のタンパク質の特異的バンドの強度をスキャンし、定量のためにβ−アクチンに対して正規化した。
TRIzol試薬(Invitrogen)を使用して、マウス組織から総RNAを調製した。5匹のマウス由来の等量のRNAをプールし、DNアーゼI(Turbo DNA−free、Ambion,Inc.)で処理した。Superscript II RNアーゼH−逆転写酵素(Invitrogen)を使用したランダムな6マーのプライマーによって、第1のcDNA鎖を2μgのDNアーゼI処理総RNAから合成した。リアルタイムPCRは、最終体積20μLで、10ngの逆転写総RNA、0.5μMの順方向プライマーおよび逆方向プライマー、ならびに10μLのDyNAmo HS SYBR Green qPCRキット(Finnzymes)の2×マスターミックスを含んでいた。DNA Engine Opticon System(MJ Research,Inc)を使用して、96ウェルプレートでPCRを行った。全反応を三連で行い、mRNAの相対量を、比較C(t)法を使用して計算した。サイクル閾値C(t)を、Opticon Monitor software 2.02(MJ Research)を使用して計算した。マウスβ−アクチンのmRNAを内部コントロールとして使用した。
データを、平均±SDとして示す。2群間の相違を、対応のない両側(unpaired two−tailed)スチューデントt検定を使用して評価した。
ファトスタチンAおよびその類似体または誘導体の標的分子の同定
本発明のある態様では、ファトスタチンAまたはその類似体または誘導体の1つまたは複数の標的を同定する。かかる同定のために任意の適切な方法を使用することができるにも関わらず、特定の実施形態では、ファトスタチンAまたはその類似体または誘導体を標識する。例示的な標識には、例えば、ビオチンが含まれる。
例示的な化合物およびその修飾
図14は、本発明の例示的化合物を示し、その与えられた名称を表3に示す。図15〜17は、図2Aと同一の方法による20μMのこれらの例示的化合物についての例示的ルシフェラーゼレポーター遺伝子アッセイを示す。以前に記載のように脂肪生成アッセイを行った(Choiら、2003)。細胞中の油滴形成を完全に阻害した類似体を、脂肪生成阻害類似体と記録した。
SREBP活性化の阻害による脂肪合成の遮断
細胞中の脂肪枯渇の際、ステロール調節エレメント結合タンパク質(SREBP)が膜からタンパク質分解的に放出され、核に転位し、ここで、コレステロールおよび脂肪酸の生合成に関与する遺伝子の転写を活性化する。本発明では、脂肪生成を遮断する合成小分子がSREBP活性化の選択的インヒビターであることを示す。現在はファトスタチンと呼ばれるジアリールチアゾール誘導体はSREBPのタンパク質分解活性を妨害し、それにより、細胞中の脂質合成遺伝子の転写が減少する。ファトスタチンの分子標的は、SREBP切断活性化タンパク質(SCAP)のようである。ファトスタチンは、摂食の制御下でさえも、肥満ob/obマウスにおける体重、血糖、および肝臓脂肪蓄積の増加を遮断した。ファトスタチンは、SREBP調節についてのさらなる洞察を得るためのツールとしての機能を果たすことができ、代謝性疾患の新規の薬理学的介入のための出発点を得ることができる。
ルシフェラーゼレポーターアッセイ。0日目に、CHO−K1細胞を、培地A(5%ウシ胎児血清、100単位/mLペニシリン、および100μg/mL硫酸ストレプトマイシンを含むHamのF−12培地とダルベッコ改変イーグル培地との1:1混合物)を含む96ウェルプレートにプレートした。2日目に、細胞を、リポフェクタミン試薬(Invitrogen)を使用して、pSRE−Luc(SRE−1駆動ルシフェラーゼレポーター構築物)(Huaら、1995)およびpAc−β−gal(β−gal発現がアクチンプロモーターによって調節されるβ−galレポーター)で同時トランスフェクトした。5時間のインキュベーション後、細胞をリン酸緩衝化生理食塩水(PBS)で洗浄し、次いで、ファトスタチンの非存在下または存在下にて、培地B(5%脂質枯渇血清、100単位/mLペニシリン、100μg/mL硫酸ストレプトマイシン、50μMコンパクチン、および50μMメバロン酸ナトリウムを含むHamのF−12培地とダルベッコ改変イーグル培地との1:1混合物)中でインキュベートした。20時間のインキュベーション後、各ウェル中の細胞を溶解し、アリコートを使用してルシフェラーゼ活性およびβ−ガラクトシダーゼ活性を測定した。ルシフェラーゼ活性を、β−ガラクトシダーゼ活性によって正規化した。SREBP−1cのN末端成熟形態の過剰発現について、pCMV−SREBP−1c(1〜436)を、pSRE−LucおよびpAc−β−galで同時トランスフェクトした。
本明細書中で言及した全ての特許および刊行物は、本発明に属する当業者のレベルを示す。全ての特許および刊行物は、それぞれの刊行物が具体的且つ個別に参考として援用されると示されているのと同程度にその全体が本明細書中で参考として援用される。
Claims (10)
- 4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;N−イソプロピル−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;N−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル)アセトアミド;N−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル)メタンスルホンアミド;N−ベンジル−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;N−(シクロプロピルメチル)−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;N−シクロヘキシル−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;tert−ブチル4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニルカルバメート;4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)−N−トシルベンゼンアミン;N−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル)−8−キノリンスルホンアミド;およびN−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル)−2−チオフェンスルホンアミド;またはその薬学的に許容可能な塩からなる群から選択される化合物。
- 請求項1に記載の化合物の少なくとも1つ及び薬学的に許容可能なキャリアを含む薬学的組成物。
- 個体の代謝障害を治療するための薬学的組成物であって、2−プロピル−4−(4−p−トリルチアゾール−2−イル)ピリジン;4−(4−(4−ブロモフェニル)チアゾール−2−イル)−2−プロピルピリジン;4−(4−フェニルチアゾール−2−イル)−2−プロピルピリジン;4−(4−(4−クロロフェニル)チアゾール−2−イル)−2−プロピルピリジン;4−(4−(4−エチルフェニル)チアゾール−2−イル)ピリジン;4−(4−p−トリルチアゾール−2−イル)ピリジン;4−(4−(4−メトキシフェニル)チアゾール−2−イル)ピリジン;安息香酸4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル;4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェノール;メチル2−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェノキシ)アセテート;2−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェノキシ)酢酸;4−(4−(3,4−ジクロロフェニル)チアゾール−2−イル)−2−プロピルピリジン;4−(4−(4−フルオロフェニル)チアゾール−2−イル)−2−プロピルピリジン;4−(4−(2,4−ジフルオロフェニル)チアゾール−2−イル)−2−プロピルピリジン;4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;N−イソプロピル−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;N−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル)アセトアミド;N−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル)メタンスルホンアミド;N−ベンジル−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;N−(シクロプロピルメチル)−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;4−(4−ブロモフェニル)−2−(2−プロピルピリジン−4−イル)チアゾール−5−カルボン酸;メチル4−(4−ブロモフェニル)−2−(2−プロピルピリジン−4−イル)チアゾール−5−カルボキシレート;4−(4−(4−メトキシフェニル)チアゾール−2−イル)−2−プロピルピリジン;4−(4−(3−メトキシフェニル)チアゾール−2−イル)−2−プロピルピリジン;4−(4−(2−メトキシフェニル)チアゾール−2−イル)−2−プロピルピリジン;3−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェノール;2−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェノール;4−(4−ブロモフェニル)−N−イソプロピル−2−(2−プロピルピリジン−4−イル)チアゾール−5−カルボキシアミド;4−(4−(4−クロロフェニル)チアゾール−2−イル)ピリジン;4−(4−(4−クロロフェニル)チアゾール−2−イル)−2−エチルピリジン;2−プロピル−4−(4−(チオフェン−2−イル)チアゾール−2−イル)ピリジン;2−(2−プロピルピリジン−4−イル)−4−p−トリルチアゾール−5−カルボン酸;2−エチル−4−(4−p−トリルチアゾール−2−イル)ピリジン;4−フェニル−2−(2−プロピルピリジン−4−イル)チアゾール−5−カルボン酸;メチル2−(2−プロピルピリジン−4−イル)−4−p−トリルチアゾール−5−カルボキシレート;tert−ブチル4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニルカルバメート;N−シクロヘキシル−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)−N−トシルベンゼンアミン;N−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル)−8−キノリンスルホンアミド;およびN−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル)−2−チオフェンスルホンアミドから成る群から選択される少なくとも1つの化合物を含む、薬学的組成物。
- 前記少なくとも1つの化合物が、安息香酸4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル;4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェノール;メチル2−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェノキシ)アセテート;2−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェノキシ)酢酸;4−(4−(2,4−ジフルオロフェニル)チアゾール−2−イル)−2−プロピルピリジン;4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;N−イソプロピル−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;N−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル)アセトアミド;N−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル)メタンスルホンアミド;N−ベンジル−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;N−(シクロプロピルメチル)−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン;4−(4−ブロモフェニル)−2−(2−プロピルピリジン−4−イル)チアゾール−5−カルボン酸;メチル4−(4−ブロモフェニル)−2−(2−プロピルピリジン−4−イル)チアゾール−5−カルボキシレート;4−(4−(3−メトキシフェニル)チアゾール−2−イル)−2−プロピルピリジン;4−(4−(2−メトキシフェニル)チアゾール−2−イル)−2−プロピルピリジン;3−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェノール;2−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェノール;および4−(4−ブロモフェニル)−N−イソプロピル−2−(2−プロピルピリジン−4−イル)チアゾール−5−カルボキシアミドからなる群から選択される、請求項3に記載の薬学的組成物。
- 前記少なくとも1つの化合物が、2−プロピル−4−(4−p−トリルチアゾール−2−イル)ピリジン;4−(4−(4−ブロモフェニル)チアゾール−2−イル)−2−プロピルピリジン、N−イソプロピル−4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)ベンゼンアミン、およびN−(4−(2−(2−プロピルピリジン−4−イル)チアゾール−4−イル)フェニル)メタンスルホンアミドからなる群から選択される、請求項3に記載の薬学的組成物。
- 前記代謝障害が、肥満、高脂質血症、糖尿病、脂肪肝、高血圧症、前立腺癌、および心血管疾患からなる群から選択される、請求項3に記載の薬学的組成物。
- 前記代謝障害が肥満である、請求項6に記載の薬学的組成物。
- 前記個体のSREBP経路のメンバーを阻害するのに効果的である、請求項3記載の薬学的組成物。
- 前記SREBP経路のメンバーが、SREBP−1、SREBP−2、またはその両方である、請求項8に記載の薬学的組成物。
- 化1の化合物であって、
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AU2008214095A1 (en) | 2008-08-14 |
WO2008097835A2 (en) | 2008-08-14 |
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EP2120580A4 (en) | 2011-09-28 |
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CN101674730B (zh) | 2014-09-10 |
EP2120580A2 (en) | 2009-11-25 |
US8207196B2 (en) | 2012-06-26 |
CA2677264C (en) | 2021-11-30 |
US20130005768A1 (en) | 2013-01-03 |
JP5878937B2 (ja) | 2016-03-08 |
CA2677264A1 (en) | 2008-08-14 |
CN101674730A (zh) | 2010-03-17 |
EP2120580B1 (en) | 2017-12-27 |
WO2008097835A3 (en) | 2008-10-30 |
JP2014088431A (ja) | 2014-05-15 |
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