JP2001510442A - 哺乳動物の血糖値低下のためのジペプチジルペプチダーゼ▲ｉｖ▼エフェクターの使用 - Google Patents
哺乳動物の血糖値低下のためのジペプチジルペプチダーゼ▲ｉｖ▼エフェクターの使用Info
- Publication number
- JP2001510442A JP2001510442A JP53845397A JP53845397A JP2001510442A JP 2001510442 A JP2001510442 A JP 2001510442A JP 53845397 A JP53845397 A JP 53845397A JP 53845397 A JP53845397 A JP 53845397A JP 2001510442 A JP2001510442 A JP 2001510442A
- Authority
- JP
- Japan
- Prior art keywords
- dpiv
- dipeptidyl peptidase
- effector
- glucose
- enzyme activity
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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Classifications
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- A—HUMAN NECESSITIES
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
-
- 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
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
(57)【要約】
本発明は、哺乳動物血中において、特異的酵素エフェクターがジペプチジルペプチダーゼ（ＤＰIVないしＣＤ２６）又はＤＰIV様酵素活性を抑制することで、内因性若しくは投与された向インスリン性((insulinotropic))ペプチド（インクレチン）、胃抑制性ポリペプチド／グルコース依存性向インスリン性ポリペプチド １−４２（ＧＩＰ1-42）及びグルカゴン様ペプチド−１ ７−３６アミド（ＧＬＰ−１7-36）（若しくはこれらのペプチドの類縁体）の分解が抑制をされるという新規な方法に関するものである。このように、ＤＰIV及びＤＰIV様酵素の分解に起因する上記ペプチド及び類縁体濃度の低下が、抑制若しくは遅延される。ＤＰIV活性が低下したことで、内因性若しくは投与されたインクレチン又はその類縁体の安定性が増した結果、向インスリン効果が持続し、膵臓ランゲルハンス島からのインスリン分泌に対する強力な刺激となり、グルコースは血中からより迅速に除去される。そのため、耐糖能が向上する。その結果として、長時間の高血糖((elebvted circulating glucose))によって引き起こされる炭水化物及び脂質代謝の異常、糖尿及び重篤な代謝性アシドーシスを含む真性糖尿病に関連する代謝異常や微小血管及び巨大血管((macrovascular))疾患及び多発性神経障害のような慢性変性((chronic alterations))が若しくは緩和される。本発明は高い血中グルコース濃度を低下させる新規な方法である。本発明は簡便で商業上有用であり、高い若しくは異常な血糖レベルに起因する、特にヒトの疾患の治療での使用に適している。
Description
【発明の詳細な説明】
哺乳動物の血糖値低下のためのジペプチジルペプチダーゼIVエフェクターの使用
本発明は、酵素ジペプチジルペプチダーゼIVの酵素活性と類似又は同一の活性
を持つ酵素群の活性抑制エフェクター（基質、擬基質、阻害剤、結合蛋白質、抗
体及び同様のもの）を投与することで血糖濃度を下げることを目的とした新規な
方法に関するものである。
非特異的蛋白質分解に含まれる蛋白質分解酵素の他に、内因性ペプチドの機能
制御（活性化、失活化又は調節）に伴う蛋白質の特異的分解を起こす蛋白質分解
酵素が知られている［KIRSCHKE,H.,LANGNER,J.,RIEMANN,S.,WIEDERANDERS,B.,AN
SORGE.S.and BOHLEY,P.Lysosomal cysteine proteases.Excerpta Medica(Ciba
Proteinases.Ann.Rev.Biochem.57,701(1987)］。
このような転化酵素、シグナルペプチダーゼ若しくはエンケファリナーゼは神
経ペプチド研究の成果として免疫系に発見された［GOMEZ,S.,GLUSCHANKOF,P.,LE
PAGE,A.,MARRAKCHI,N．and COHEN,P.,Proc.Natl.Acad.Sci.USA 85,5468
多数のペプチドホルモンに豊富に存在するアミノ酸プロリンは、ペプチドの構
造上の特性を決定することから、プロリン特異的ペプチダーゼが、生理活性ペプ
チドの制御においてシグナルペプチダーゼと類似の機能を持つと論じられている
［YARON,A.,The Role of Proline in the Proteolytic Regulation of Biologic
ally Active Peptides.Biopolymers 26,215(1987):WALTER,R.,SIMMONS,W.H.and
YOSHIMOTO,T.,Proline Specific Endo-and Exopeptidases.Mol.Cell.Biochem.30
,111(1980);VANHOOF G.,GOOSSENS,F.,DE MEESTER,I.,HENDRIKS,D.and SCHARPE'S
.,Proline motifs and their biological processing.FASEB Journal 9,736(199
5)］。プロリンは、例外的な構造をとるため、非特異的蛋白質分解酵素による分
解を避けるような立体構造と安定性の両方をこのようなペプチドに付与している
［KESSLER,H.,Conformation and biological
activity.Angew.Chem.94,509(1982)］。一方で、プロリンを含んでいる配列（Ｈ
ＩＶプロテアーゼ，サイクロフィリンなどを含む）に非常に特異的に作用する酵
素群は医薬品化学における重要な標的である。特に、プロリンエンドペプチダー
ゼ（ＰＥＰ）やジペプチジルペプチダーゼIV（ＤＰIV）のようなプロリン下流で
切断するペプチダーゼ活性は、酵素による選択的分解や天然ペプチド基質の生理
活性の調節と結び付けられてきた。ＰＥＰは記憶と学習活動に関与し、ＤＰIVは
免疫応答における情報伝達に関与しているということが示された［ISHIURA,S.,T
SUKAHARA.T.,TABIRA.,SHIMIZU.T.,ARAHATA K.and SUGITA.H.,FEBS-Letters 260.
131(1990);HEGEN.M.,NIEDOBITEK.G.,KLEIN,C.E.,STEIN,H.and FLEISCHER,B.,J.o
f Immunology 144,2908(1990)］。
これらの酵素は、高いプロリン特異性に加え、典型的基質に含まれるアミノ酸
アラニンを含むペプチド結合を選択的に認識して切断することができる。現在の
ところ、アラニン含有ペプチドは、構造的に相関のあるプロリン含有ペプチドと
類似の立体構造をとるかどうかは議論中である。最近、このような特性が、蛋白
質中のプロリンとアラニンを交換した点突然変異実験にて述べられた［DODGE.R.
W.and SCHERAGA,H.A.,Folding and unfolding kinetics of the proline-to-ala
nine mutants of bovine pancreatic ribonuclease A.Biochemistry 35(5)1548(
1996)］。
血液中に存在するＤＰIV又はＤＰIV様活性（すなわち細胞質ゾルＤＰIIにはＤ
ＰIVとほとんど同一の基質特異性がある。）は、非常に特異的に、Ｎ末端から２
番目の位置にプロリン又はアラニンを持つ生理活性ペプチドのＮ末端からジペプ
チドを遊離する。以上のことから、本酵素は、体内においてポリペプチドの活性
制御に関与していると結論づけられた［VANHOOF,G.,GOOSSENS,F.,DE MEESTER,I.
,HENDRIKS,D.,and SCHARPE,S.,Proline motifs and their biological processi
ng,FASEB Journal 9,736(1995)］。
グルコース依存性向インスリン性ポリペプチド：胃抑制性ポリペプチド１−４
２（ＧＩＰ1-42）及びグルカゴン様ペプチドアミド−１７−３６（ＧＬＰ−１7- 36
）は、膵臓からのグルコースによって誘導されるインスリン分泌を増加させる
ホルモン（インクレチン）であり、ＤＰIVの基質である。本酵素は、生体内
及び試験管内でこれらのペプチドのＮ末端からジペプチドであるチロシルアラニ
ン及びヒスチジルアラニンをそれぞれ遊離する［MENTLEIN,R.,GALLWITZ,B.,and
SCHMIDT,W.E.,Dipeptidyl Peptidase IV hydrolyzes gastric inhibitory polyp
eptide，glucagon-like peptide-1(7-36)amide,peptide histidine methionine
and is responsible for their degradation in human serum.Eur.J.Biochem.21
4,829(1993)］。
体内でＤＰIV若しくはＤＰIV様酵素活性による基質の分解が減少すれば、実験
室条件下でも哺乳類の病理学的な状態下でも、望ましくない酵素活性を効果的に
抑制することに寄与することができる［DEMUTH,H.-U.,Recent developments in
the irreversible inhibition of serine and cysteine proteases.J.Enzyme In
hibition 3,249-278(1990);DEMUTH,H.-U.and HEINS,J.,On the catalytic Mecha
nism of Dipeptidyl Peptidase IV.in Dipeptidyl Peptidase IV(CD 26)in Meta
bolism and the Immune Response(B.Fleischer,Ed.)R.G.Landes,Biomedical Pub
lishers,Georgetown,1-35(1995)］。手短に言えば、非インスリン依存性真性糖
尿病は、インスリン抵抗性とインスリン分泌とに関連するが、この時のインスリ
ン分泌は正常なグルコース濃度に対しては不適切な状態にあり、蛋白質分解酵素
の関与している血中インクレチン濃度の以上と関わっている可能性がある［BROW
N,J.C.,DAHL,M.,KWAWK,S.,MCINTOSH,C.H.S.,OTTE,S.C.and PEDERSON,R.A.Peptid
es 2,241(1981);SCHMIDT,W.E.,SIEGEL,E.G.,GALLWITZ,B.KUMMEL,H.,EBERT,R.and
CREUTZFELDT,W.,Characterization of the insulinotropic activity of fragm
ents derived from gastric inhibitory polypeptide.Diabetologia 29,591A(19
86);ADELHORST,K.,HEDEGAARD,B.B.,KNUDSEN,L.B.and KIRK,O.,Structure-activi
ty studies of glucagon-like peptide.J.Biol.Chem.296,6275(1994)］。
現在ではインスリン依存症真性糖尿病（ＩＤＤＭ）は、インスリン（子牛胎児
又は豚の膵臓から単離されたものか若しくは組換え分子として生産されたもの）
がさまざまな形態で患者へ投与され、治療されている。非インスリン依存性真性
糖尿病（ＮＩＤＤＭ）は、節食若しくはスルホニル尿素を投与することでインス
リン分泌を刺激するか又は、ビグアニドと共に使用してグルコースの摂取を増大
させることで治療されている。近代的治療方法同様、ＩＤＤＭの伝統的治療方法
には、患者側の多大な努力、高額医療費、患者の生活の質の大幅な低下といった
特徴がある。標準的治療法（毎日のインスリンの静脈注射）は、１９３０年代か
ら実施されており、急性症状を治療するように指導されているが、投与が長期間
になると血管疾患や神経損傷をもたらす［LACY,P.,Status of Islet Cell Trans
plantation,Diabetes Care 16(3)76(1993)］。皮下デポー剤の点滴注入−インプ
ラント（毎日の注射を必要とせず、投与量が少なく、蛋白質分解作用のないイン
スリン放出）のような最近の方法も、ランゲルハンス島の完全移植（又は移植）
同様、試行中である。しかし、このような移植は高額である。その上、危険な外
科的処置があり、移植の場合は免疫抑制又は免疫反応を回避することが必要とな
る［LACY,P.,Treating Diabetes with Transplanted Cells.Sci.Americ.273(1)4
0-46(1995)］。還元グルコースを除去する試みは未だ成功していない。ＮＩＤＤ
Ｍの場合、スルホニル尿素で内因性インスリンの分泌を刺激する治療を受けてい
る患者の多くは、これらの薬剤に耐性を持つようになる。更に、ビグアニドを用
いてグルコース除去を増加させた成功例は少ない。
上記の治療方法とは対象的に、ここに提案する非常に効果的な低分子酵素阻害
剤の投与は、対費用効果の高い代替手段である。このような、種々の蛋白分解酵
素に対する阻害剤は、既に抗高血圧薬、免疫抑制剤そして抗ウイルス薬として用
いられている。安定性、輸送、清掃値特性を考慮して分子を化学的に設計するこ
とで、薬効を変え、そしてまた、臓器間の個々の違いに化合物を適応さえさせて
きた［SANDLER.M.and SMITH,H.J.,eds.,Design of Enzyme Inhibitors as Drugs
.Oxford University Press,Oxford(1989);MUNROE,J.E.,SHEPHERD,T.A.,JUNGHEIM
,L.N.,HORNBACK,W．J.,HATCH,S.D.,MUESING,M.A.,WISKERCHEN,M.A.,SU,K.S.,CAM
PANALE,K.M.,BAXTER,A.J.，and COLACINO,J.M.,Potent,orally biovailable HIV
-1 protease inhibitors containing noncoded D-aminoacids.Bioorg.Medicinal
Chem.Letters 5(23)2897(1995)］。
酵素のエフェクターによって哺乳動物血中のジペプチジルペプチダーゼ（ＤＰ
IV又はＣＤ２６）又はＤＰIV様酵素活性の抑制を誘導し、内因性向インスリン性
ペプチド（若しくは対外から投与されたもの）である胃抑制性ポリペプチド１−
４２（ＧＩＰ1-42）及びグルカゴン様ペプチドアミド−１ ７−３６（ＧＬＰ−17-36
）（若しくはこれらのペプチドの類縁体）の分解を抑制することで血糖値
を下げるという簡便で新規な方法が本発明のねらいである。通常はＤＰIV及びＤ
ＰIV様酵素に分解されて、これらのペプチド又はその類縁体濃度が低下するが、
これが抑制されるか若しくは遅延されることが期待される。
本発明は、哺乳動物血液中のジペプチジルペプチダーゼ（ＤＰIV又はＣＤ２６
）の酵素活性若しくはＤＰIV様酵素活性が抑制されることで耐糖能が改善される
、という発見に基づくものである。
本発明者は次のようなことを観察した。
1. ジペプチジルペプチダーゼ（ＤＰIVまたはＣＤ２６）の酵素活性若しくはＤ
ＰIV様酵素活性が抑制されることで、グルコースに刺激され内因的に放出され
たか若しくは外部より投与されたインクレチン（又はそれらの類縁体）の安定
性を相対的に上昇させる。つまり、ＤＰIV若しくはＤＰIV様蛋白質のエフェク
ターを投与するということは、血液中のインクレチンの分解を制御することに
利用でき得る。
2. インクレチン（若しくはそれらの類縁体）の生物学的安定性が増すことで、
インスリン応答が変化する。
3. ジペプチジルペプチダーゼ（ＤＰIV又はＣＤ２６）若しくはＤＰIV様酵素が
減少することで、血液中のインクレチンの安定性が増し、それに続いてインス
リンによるグルコース除去に変化が生じる。つまり、耐糖機能はＤＰIVエフェ
クターの投与により改善され得ることを示している。
よって、本発明は臨床的に不適切な基礎食後高血糖の状態にある哺乳動物で見ら
れるような高血糖レベルを低下させることを目的としたジペプチジルペプチダー
ゼ（ＤＰIV）の若しくはＤＰIV様酵素活性のエフェクターの効用に関するもので
ある。本発明の特徴は、ＤＰIV又はＤＰIV様酵素活性のエフェクターを投与する
ことで、糖尿、高脂血症、代謝性アシドーシス及び真性糖尿病などの哺乳類の代
謝系の病理学的な機能不全を予防又は遅延させるということである。
より好ましい表現をするなら、本発明は、治療上有効な量のジペプチジルペプ
チダーゼ（ＤＰIV）の又はＤＰIV様酵素活性のエフェクターを投与することで、
臨床的に不適切な基礎食後高血糖を示している哺乳動物で見られるような高血糖
レベルを下げるという方法に関する。
別の表現をするなら、本発明は、臨床的に不適切な基礎食後高血糖を示してい
る哺乳動物で見られるような高血糖レベルを下げることに使用する、ジペプチジ
ルペプチダーゼ（ＤＰIV）の又はＤＰIV様酵素活性のエフェクターに関する。
本発明でいう、投与されるＤＰIV及びＤＰIV様酵素群のエフェクターは、酵素
阻害剤、基質、擬基質、ＤＰIV遺伝子発現阻害剤、結合蛋白質若しくは標的酵素
蛋白質の抗体という製剤学的処方又は、哺乳動物内でＤＰIV及びＤＰIV様蛋白質
濃度若しくは酵素活性を減少させるような別の化合物との組み合わせという製剤
学的処方をとる。本発明でいうエフェクターは、例えばアラニルピロリジドやイ
ソロイシルチアゾリジドのようなジペプチド誘導体若しくは模造ジペプチジドや
、擬基質Ｎ−バリルブロリル−Ｏ−ベンゾイルヒドロキシルアミンのようなＤＰ
IV阻害剤である。このような化合物は文献に記載されているか［DEMUTH,H.-U.,R
ecent developments in the irreversible inhibition of serine and cysteine
proteases.J.Enzyme Inhibition 3,249(1990)］、若しくはその文献中に記載さ
れている方法に従って合成される。
本発明でいう方法は、哺乳動物血液中の高い血糖濃度を下げる新規な方法であ
る。
本発明は、簡便で商業的に有用であり、不適切な高血糖血に起因するヒトの疾
病の治療用として適切である。
エフェクターは薬剤輸送用最先端素材と組み合わせた製剤の形で投与される。
エフェクターは非経口（生理食塩水での静脈内投与）若しくは経腸（経口、一般
的な抗体物質と処方されたもの）のどちらでも投与される。
エフェクターの体内安定性及び生物学的利用能のために、単回若しくは複数回
投与で期待される血糖濃度の正常化に達する。このようなエフェクターの投与量
は、例えば、ＤＰIV阻害剤としてのアミノアシルチアゾリジドの場合、キロ当た
り１．０ｍｇから１０．０ｍｇに変化する。
実施例
実施例１：生体内でＤＰIVの触媒する、インクレチンＧＩＰ1-42及びＧＬＰ
−１7-36の加水分解の阻害
試験管内では、精製酵素若しくはヒト血清を使用したＤＰIV及びＤＰIV様酵素
活性による加水分解を抑制することができる（図１）。
本発明によれば、３０ｍＭ ＧＩＰ1-42若しくは３０ｍＭ ＧＬＰ−１7-36及
び可逆的ＤＰIV阻害剤である２０ｍＭイソロイシルチアゾリジド（１ａ）を含む
２０％血清画分をｐＨ７．６、３０℃、２４時間試験管で培養することで、酵素
の触媒する両ペプチドホルモンの加水分解は完全に抑制される（１ｂ及び１ｃ、
双方とも上段のスペクトル）。合成ＧＩＰ1-42（５ｍＭ）及び合成ＧＬＰ−１7- 36
（１５μＭ）を、ヒト血清（２０％）を含む０．１ｍＭトリシン緩衝液でｐＨ
７．６、３０℃で２４時間培養した。培養検定用サンプル（ＧＩＰ1-42の場合は
２．５ｐｍｏｌまた、ＧＬＰ−１7-36の場合は７．５ｐｍｏｌ）を経時的に抜き
取った。サンプルを２’，６’−ジヒドロキシアセトフェノンをマトリックスと
共結晶化((cocrystallize))し、ＭＡＬＤＩ−ＴＯＦ質量分析法にて分析した。
スペクトル（図１）は、１サンプル当たり２５０回の単一レーザー照射((single
laser shot))の累積値を示す。
（１ｂ）ｍ／ｚ４９８０±５．３のシグナルは、ＤＰIVの基質であるＧＩＰ1- 42
（分子量４９７５．６）を、ｍ／ｚ４７４５．２±５．５のシグナルはＤＰIV
から遊離した生産物ＧＩＰ3-42（分子量４７４０．４）を示す。
（１ｃ）ｍ／ｚ３３２５．０±１．２のシグナルは、ＤＰIVの基質であるＧＬ
Ｐ7-36（分子量３２９７．７）を、ｍ／ｚ３１１６．７±１．３のシグナルはＤ
ＰIVから遊離した生産物ＧＬＰ−１9-36（分子量３０８９．６）を示す。
阻害剤を含まない対照実験では、インクレチンはほとんど完全に消化された。
（図１ｂ及び１ｃ、双方とも下段のスペクトル）
実施例２：生体内でのＤＰIV阻害剤イソロイシルチアゾリジドによるＧＬＰ
−１7-36の分解の阻害
ラット循環系におけるＤＰIV阻害剤イソロイシルチアゾリジド（１．５Ｍ阻害
剤を含む０．９％食塩水の静脈注射）の存在又は非存在下及び対照実験での天然
インクレチン（この場合ＧＬＰ−１7-36）の代謝分析。
被験動物（ｎ＝５）における阻害剤イソロイシルチアゾリジドの体内濃度が０
．
１ｍｇ／ｋｇの時、向インスリン性ペプチドホルモンＧＬＰ−１7-36は実験中分
解されなかった（図２）。ＤＰIV阻害剤の存在若しくは被存在下のインクレチン
の代謝物を分析するために、被験及び対照動物に更に５０−１００ｐＭの125
Ｉ−ＧＬＰ−１7-36（比放射能、約１［Ｃｉ／ｐＭ］。初回の阻害剤若しくは食
塩又はその両方の静注後２０分）を投与した。血液サンプルを２−５分培養後に
回収し、２０％アセトニトリルで血漿を抽出した。その後、ペプチド抽出物を逆
相高速液体クロマトグラフィーで分離した。１２−１８分に溶出する画分を回収
し、放射能を測定した。データを、１分間当たりのカウント数［ｃｐｍ］で、最
大値に対する相対値として記載した。
実施例３：生体内におけるＤＰIV阻害剤イソロイシルチアゾリジドの静脈内投与
後のインスリン応答の変化と血糖値の低下
図は、イソロイシルチアゾリジド（０．１ｍｇ／ｋｇ）の存在または欠乏下に
おけるラット十二指腸内へのグルコース投与に対する血糖及びインスリン応答を
示す。ＤＰIVエフェクターを投与された動物群では、比投与対照群に比べて血中
グルコース濃度が急激に減少した。ここで認められた効果は容量依存性であり、
ラット１キログラム当たりＤＰIV阻害剤イソロイシルチアゾリジド０．０５ｍｇ
／ｍｉｎで輸液を終了した後でも可逆性である。十二指腸をグルコースで刺激さ
れた動物に対し、等量のグルコースを静注した阻害剤投与対照動物には効果が見
られなかった。図３に、前述の関係を示した。これは、血漿パラメーターの阻害
剤依存性変化を示している。Ａ：ＤＰIV活性、Ｂ：血漿インスリン値、Ｃ：血糖
値
被験動物（ｎ＝５、雄ウェスターラット、２００−２２５ｇ）に、まず１．５
Ｍイソロイシルチアゾリジドを含む０．９％食塩水（▲）又は等量の０．９％食
塩水（■）を投与した（対照群ｎ＝５）。被験群には更に毎分０．７５Ｍの阻害
剤を３０分間輸液し（＊）、対照群には阻害剤を含まない０．９％食塩水を同一
時間輸液した。開始時間ｔ＝０に、全動物に４０％（ｗ／ｖ）グルコース溶液１
ｇ／ｋｇを十二指腸に投与した。１０分ごとに、全被験動物から採血した。全血
を用いてグルコースを分析（Lifescan One Touch II analyzer）し、ＤＰIV活性
及びインスリン濃度は血漿を用いて分析した。インスリン標識免疫定量は、１０
〜１６０ｍＵ／ｍｌの範囲で感度があった［REDERSON,R.A.,BUCHAN,A.M.J.,ZAHE
DI-ASH,S,.CHEN,C.B.& BROWN,J.C.Reg.Peptides.3,53-63(1982)］。ＤＰIV活性
を分光光度分析にて評価した［DEMUTH,H.-U.and HEINS,J.,On the catalytic Me
chanism of Dipeptidyl Peptidase IV.in Dipeptidyl Peptidase IV（CD 26）in
Metabolism and the Immune Response(B.Fleischer,Ed.)R.G.Landes,Biomedica
l Publishers.Georgetown.1-35(1995)］。全データを、平均±標準誤差で示した
。
【手続補正書】特許法第１８４条の８第１項
【提出日】平成１０年５月２５日（１９９８．５．２５）
【補正内容】
請求の範囲
1. 臨床的に不適切な基礎食後高血糖((basal and post-prandeial hyperglyc
emia))を呈している哺乳動物において見出されるような高血糖レベルを下げるた
めの、ジペプチジルペプチダーゼ（ＤＰIV）又はＤＰIV様酵素活性の活性抑制エ
フェクターの使用。
2. 糖尿、高脂血症、代謝性アシドーシス又は真性糖尿病などの哺乳動物の病
理学的代謝異常を予防若しくは緩和するために、ジペプチジルペプチダーゼ（Ｄ
ＰIV）又はＤＰIV類似酵素活性のエフェクターを投与することを特徴とする請求
項１の使用。
3. エフェクターとは、阻害剤、基質、擬基質、ＤＰIV遺伝子発現阻害剤、結
合蛋白質を含むジペプチジルペプチダーゼ（ＤＰIV）若しくはＤＰIV様酵素活性
のエフェクター、又は抗ジペプチジルペプチダーゼ若しくは抗ＤＰIV様酵素活性
抗体、又は指定されたエフェクターの組み合わせとして作用する物質を包含する
、請求項１の使用。
4. 臨床的に不適切な基礎食後高血糖を呈している哺乳動物において見出され
るような高血糖レベルを下げる過程で使用するための、ジペプチジルペプチダー
ゼ（ＤＰIV）若しくはＤＰIV様酵素活性のエフェクター。
─────────────────────────────────────────────────────
フロントページの続き
(51)Int.Cl.7 識別記号 ＦＩ テーマコート゛(参考）
Ａ６１Ｋ 45/00 Ｃ０７Ｄ 277/04
Ａ６１Ｐ 3/06 Ａ６１Ｋ 37/54
3/10 37/64
// Ｃ０７Ｄ 277/04 37/02
(72)発明者 シュミット，ヨルン
ドイツ連邦共和国 ディ―06114 ハレ,
アイヘンドルフシュトラーセ ２
(72)発明者 パウリイ，ロバート，ピー.
カナダ国 ブイ６ティ ２ビー８ ブリテ
ィッシュ コロンビア，バンクーバー，フ
ェアビュー クレセント 2631
(72)発明者 マッキントッシュ，クリストファー，エイ
チ．，エス.
カナダ国 ブイ６ティ １ティ７ ブリテ
ィッシュ コロンビア，バンクーバー，ア
リソン ロード 605―2233
(72)発明者 ペダーソン，レイ，エイ.
カナダ国 ブイ６エス １ケイ９ ブリテ
ィッシュ コロンビア，バンクーバー，ウ
エスト トウェンティサード アベニュー
3876
Claims (1)
- 【特許請求の範囲】 1. 臨床的に不適切な基礎食後高血糖(basal and post-prandeial hyperglyce mia)を呈している哺乳動物において見出されるような高血糖レベルを下げるため の、ジペプチジルペプチダーゼ（ＤＰIV）又はＤＰIV様酵素活性のエフェクター の使用。 2. 糖尿、高脂血症、代謝性アシドーシス又は真性糖尿病などの哺乳動物の病 理学的代謝異常を予防若しくは緩和するために、ジペプチジルペプチダーゼ（Ｄ ＰIV）又はＤＰIV類似酵素活性のエフェクターを投与することを特徴とする請求 項１の使用。 3. エフェクターとは、阻害剤、基質、擬基質、ＤＰIV遺伝子発現阻害剤、結 合蛋白質を含むジペプチジルペプチダーゼ（ＤＰIV）若しくはＤＰIV様酵素活性 のエフェクター、又は抗ジペプチジルペプチダーゼ若しくは抗ＤＰIV様酵素活性 抗体、又は指定されたエフェクターの組み合わせとして作用する物質を包含する 、請求項１の使用。 4. 臨床的に不適切な基礎食後高血糖を呈している哺乳動物において見出され るような高血糖レベルを下げる過程で使用するための、ジペプチジルペプチダー ゼ（ＤＰIV）若しくはＤＰIV様酵素活性のエフェクター。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19616486.9A DE19616486C5 (de) | 1996-04-25 | 1996-04-25 | Verfahren zur Senkung des Blutglukosespiegels in Säugern |
| DE19616486.9 | 1996-04-25 | ||
| PCT/DE1997/000820 WO1997040832A1 (de) | 1996-04-25 | 1997-04-24 | Verwendung von dipeptidyl peptidase iv effektoren zur senkung des blutglukosespiegels in säugern |
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| JP2008320714A Division JP2009137973A (ja) | 1996-04-25 | 2008-12-17 | 哺乳動物の血糖値低下のためのジペプチジルペプチダーゼｉｖエフェクターの使用 |
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|---|---|
| JP2001510442A true JP2001510442A (ja) | 2001-07-31 |
Family
ID=7792391
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| JP2008320714A Withdrawn JP2009137973A (ja) | 1996-04-25 | 2008-12-17 | 哺乳動物の血糖値低下のためのジペプチジルペプチダーゼｉｖエフェクターの使用 |
| JP2011284809A Pending JP2012092136A (ja) | 1996-04-25 | 2011-12-27 | 哺乳動物の血糖値低下のためのジペプチジルペプチダーゼｉｖエフェクターの使用 |
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| JP2008320714A Withdrawn JP2009137973A (ja) | 1996-04-25 | 2008-12-17 | 哺乳動物の血糖値低下のためのジペプチジルペプチダーゼｉｖエフェクターの使用 |
| JP2011284809A Pending JP2012092136A (ja) | 1996-04-25 | 2011-12-27 | 哺乳動物の血糖値低下のためのジペプチジルペプチダーゼｉｖエフェクターの使用 |
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| EP (3) | EP1084705B1 (ja) |
| JP (3) | JP2001510442A (ja) |
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| CN (2) | CN1269528C (ja) |
| AT (1) | ATE202705T1 (ja) |
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| CA (1) | CA2252576C (ja) |
| DE (5) | DE19616486C5 (ja) |
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| AU3224997A (en) | 1996-05-29 | 1998-01-05 | Prototek, Inc | Prodrugs of thalidomide and methods for using same as modulators of t-cell function |
| US6006753A (en) | 1996-08-30 | 1999-12-28 | Eli Lilly And Company | Use of GLP-1 or analogs to abolish catabolic changes after surgery |
| AR016751A1 (es) | 1996-11-22 | 2001-08-01 | Athena Neurosciences Inc | Metodo para inhibir la liberacion del peptido beta-amiloide en una celula, composicion farmaceutica y compuestos utiles en dicho metodo |
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- 1997-04-24 DE DE59703959T patent/DE59703959D1/de not_active Revoked
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- 1997-04-24 PT PT119496T patent/PT1084705E/pt unknown
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- 1997-04-24 EP EP10184503.0A patent/EP2289513A3/de not_active Withdrawn
- 1997-04-24 DE DE122007000083C patent/DE122007000083I1/de active Pending
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