JP2009510130A - 薬物設計の方法 - Google Patents
薬物設計の方法 Download PDFInfo
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- JP2009510130A JP2009510130A JP2008533820A JP2008533820A JP2009510130A JP 2009510130 A JP2009510130 A JP 2009510130A JP 2008533820 A JP2008533820 A JP 2008533820A JP 2008533820 A JP2008533820 A JP 2008533820A JP 2009510130 A JP2009510130 A JP 2009510130A
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 21
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- 238000009739 binding Methods 0.000 description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 description 9
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 9
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- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 125000000628 margaroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000004001 molecular interaction Effects 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000001419 myristoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000005146 naphthylsulfonyl group Chemical group C1(=CC=CC2=CC=CC=C12)S(=O)(=O)* 0.000 description 1
- 125000001402 nonanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000008039 phosphoramides Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 230000024351 regulation of hormone secretion Effects 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 108010052231 seglitide Proteins 0.000 description 1
- 229950002758 seglitide Drugs 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 108090000680 somatostatin receptor 5 Proteins 0.000 description 1
- 102000004115 somatostatin receptor 5 Human genes 0.000 description 1
- 108010082379 somatostatin receptor type 1 Proteins 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WGYONVRJGWHMKV-UHFFFAOYSA-M tetrabutylazanium;benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1.CCCC[N+](CCCC)(CCCC)CCCC WGYONVRJGWHMKV-UHFFFAOYSA-M 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 125000000297 undecanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
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- C07H3/02—Monosaccharides
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- G01N33/566—Immunoassay; Biospecific binding assay; Materials therefor using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
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- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
- G01N2333/72—Assays involving receptors, cell surface antigens or cell surface determinants for hormones
- G01N2333/726—G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
- G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
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Abstract
Description
(a)分子多様性をスキャンするために、式1の化合物の第1ライブラリーを設計すること(前記ライブラリーの各化合物が、以下に定義される少なくとも2つのファーマコフォア基R1〜R5を有し、かつ前記ライブラリーの化合物が、同数のファーマコフォア基を有する);
(b)1つまたは複数の生物学的アッセイにおいて、化合物の前記第1ライブラリーをアッセイすること;および
(c)第2ライブラリーを設計すること(前記第2ライブラリーの各化合物が、前記第1ライブラリーに対して1つまたは複数の更なるファーマコフォア基を含有する);
を含む、生物活性化合物を同定する方法であって、前記第1および第2ライブラリーの前記成分/各成分が、式1:
Zは、硫黄、酸素、CH2、C(O)、C(O)NRA、NH、NRAまたは水素であり、Zが水素である場合には、R1は存在せず、RAは、R1〜R5について定義されるセットから選択され、あるいはZおよびR1は一緒になって複素環を形成し、
Xは、式Iの少なくとも1つのXが窒素であるという条件で酸素または窒素であり、Xは、R1〜R5のうちの1つと独立して一緒になってアジドを形成することもでき、
R1〜R5は、以下の非ファーマコフォア基、H、メチルおよびアセチルから独立して選択され、並びにファーマコフォア基R1〜R5は、限定されないが、C2〜C20アルキルまたはアセチルを除外したアシル;C2〜C20アルケニル、アルキニル、ヘテロアルキル;C5〜C20アリール、ヘテロアリール、アリールアルキルまたはヘテロアリールアルキルを含む群から独立して選択され(任意に置換されかつ分岐状または直鎖状であることができる)、またはXおよび対応するR部分、R2〜R5がそれぞれ一緒になって複素環を形成する)
の化合物であるような方法を提供する。
Ac アセチル
DTPM 5−アシル−1,3−ジメチルバルビツレート
Ph フェニル
TBDMS t−ブチルジメチルシリル
TBDPS t−ブチルジフェニルシリル
Bn ベンジル
Bz ベンゾイル
Me メチル
DCE 1,2−ジクロロエタン
DCM ジクロロメタン,塩化メチレン
Tf トリフルオロメタンスルホニル
Ts 4−メチルフェニルスルホニル、p−トルエンスルホニル
DMF N,N−ジメチルホルムアミド
DMAP N,N−ジメチルアミノピリジン
α,α−DMT α,α−ジメトキシトルエン、ベンズアルデヒドジメチルアセタール
DMSO ジメチルスルホキシド
DTT ジチオスレイトール
DMTST ジメチル(メチルチオ)スルホニウムトリフルオロ−メタンスルホネート
TBAF テトラ−n−ブチルアンモニウムフルオライド
本発明を完全に可能にするために、本発明の化合物の製造で使用される特定のビルディングブロックを製造する方法が以下に記述される。記載のビルディングブロックは、本発明の化合物の液相合成および固相合成のどちらにも適している。
実施例C:2,6−二窒素置換グルコピラノシドビルディングブロックの合成
実施例G:二窒素含有アロピラノシドビルディングブロックの合成
(A)2P化合物の合成:R1=R2=OMe;
i)2−ナフタレンメタノール、DMTST、DCM;ii)TCA−Wang樹脂、BF3・Et2O、DCM;iii)NaOMe、メタノール;iv)a.KOtBu、DMF;b.MeI、DMF;v)HF‘プロトンスポンジ’、AcOH、DMF、65℃;vi)a.KOtBu、DMF;b.MeI、DMF;vii)1,4−ジチオ−DL−スレイトール、KOtBu、DMF;viii)HBTU、Fmoc−β−Ala−OH、DIPEA、DMF;ix)ピペリジン/DMF(1/4);x)TFA、Et3SiH、DCM
(B)3P化合物の合成:R1=メチル−2−ナフチル、R2=OMe;
i)2−ナフタレンメタノール、DMTST、DCM;ii)TCA−Wang樹脂、BF3・Et2O、DCM;iii)NaOMe、メタノール;iv)a.KOtBu、DMF;b.2−ブロモメチル−ナフタレン、DMF;v)HF‘プロトンスポンジ’、AcOH、DMF、65℃;vi)a.KOtBu、DMF;b.MeI、DMF;vii)1,4−ジチオ−DL−スレイトール、KOtBu、DMF;viii)HBTU、Fmoc−β−Ala−OH、DIPEA、DMF;ix)ピペリジン/DMF(1/4);x)TFA、Et3SiH、DCM
(C)4P化合物の合成:R1=メチル−2−ナフチル、R2=4−クロロベンジル
i)2−ナフタレンメタノール、DMTST、DCM;ii)TCA−Wang樹脂、BF3・Et2O、DCM;iii)NaOMe、メタノール;iv)a.KOtBu、DMF;b.2−ブロモメチル−ナフタレン、DMF;v)HF‘プロトンスポンジ’、AcOH、DMF、65℃;vi)a.KOtBu、DMF;b.4−クロロベンジルブロミド、DMF;vii)1,4−ジチオ−DL−スレイトール、KOtBu、DMF;viii)HBTU、Fmoc−β−Ala−OH、DIPEA、DMF;ix)ピペリジン/DMF(1/4);x)TFA、Et3SiH、DCM
アロース2,6Nビルディングブロックの合成がスキーム2に図示されている。反応条件は以下の通りである:
i)p−メトキシベンズアルデヒドジメチルアセタール、カンファースルホン酸、N,N−ジメチルホルムアミド(DMF);ii)Tf2O、ピリジン、ジクロロメタン(DCM);iii)テトラブチルアンモニウムベンゾエート、DMF、55℃;iv)BH3THF、Bu2BOTf、DCM;v)メタンスルホニルクロリド、ピリジン、DCM;vi)アジ化ナトリウム、DMF、85℃;vii)ナトリウムメタノラート(NaOMe)、メタノール;viii)n−ブタノール、エチレンジアミン、還流;ix)DTPM試薬、メタノール;x)安息香酸無水物、ピリジン;xi)トリフルオロ酢酸、トリエチルシラン、DCM
ライブラリーの設計:
ライブラリーの設計は、単糖足場上の異なる空間配列における正電荷および様々な数の芳香族置換基の提示に基づく。正電荷およびコア足場上に示される1つの芳香族で開始して、第1ライブラリーからの活性化合物(actives)は、高活性な分子を迅速に同定するために、より多くの芳香族置換基をさらに変化させ、加えることによって産生された。
1.式3による1,2アロース置換(および足場C/D)は、ライブラリーにおける分子の最も活性な配列を示し、式中、Zは酸素であり、R1はナフチルであり、R2はプロピルアミンまたはエチルアミンである。これらの化合物は、低いnM範囲にて最高の活性化合物(actives)を表し、更なる薬物の開発に適している候補である。
2.ナフチルとしてのR1は、対応するp−クロロベンジル置換基より活性である。
3.式3による1,2アロース(足場C/D)は、対応する1,2グルコースコンフォメーション(足場A/B)より活性である。
4.式3による1,2置換(足場C/D)は、対応する式4による2,6置換(足場G)より活性である。
5.プロピルアミンおよびエチルアミンとしてのR2は、メチルアミンより活性であり、Z、R1およびR2は上述のとおりである。
6.式3による2,3アロース置換(足場C/D)(R2はエチルアミンであり、R3はp−クロロベンジルである)は、プロピルアミンおよびエチルアミンとしての対応するR2と比較して、より活性な化合物(actives)を示す(式中、R3はp−クロロベンジル置換基であり、かつまた、R2はメチルアミン、エチルアミンまたはプロピルアミンであり、R3はナフチルである)。
7.式3による2,3グルコース置換(足場A/B)(R2はプロピルアミンであり、R3はナフチルである)は、メチルアミンまたはエチルアミンとしての対応するR2と比較して、より活性な化合物(actives)を示す(R2はメチルアミン、エチルアミンまたはプロピルアミンであり、R3はp−クロロベンジルである)。
8.式3による2,4および3,4置換(足場G)は、最も低い活性の化合物(actives)を示す。
実施例H.ソマトスタチンサブタイプSSTR−1〜SSTR−5に対する化合物のin vitroスクリーニング
一般法
所望のクローン化受容体(例えば、クローン化ヒトソマトスタチン受容体サブタイプ5,SSTR5)を含有する受容体膜調製物および放射標識化リガンドを試験に必要な濃度にて、受容体Bmax、リガンドKdおよび実験条件を最適化するのに必要な任意の他のパラメーターを含む選択された受容体−リガンドの組み合わせと関連する特定のパラメーターに従って希釈した。参照リガンドに対する競合活性について試験する場合、「化合物」を膜懸濁液、放射標識化参照リガンド(非特異的結合の測定のための、受容体に対する過剰量の未標識リガンドを含有する、または含有しない)と混合し、内部標準作業手順によって必要とされる温度でインキュベートした。インキュベートした後、氷冷洗浄バッファーを添加することによって、結合反応を止め、適切なフィルター上で濾過し、次いでそれをカウントした。データ分析および曲線フィッティングをXLfit(IDBS)で行った。
100%DMSO中の試験化合物の10mM溶液を調製した。約160μlを各希釈液に使用した(3組で20μl/ウェル)。10mM溶液の1:8希釈液を調製することによって、1.25mMアッセイストックを調製した。10mM溶液30μlにミリQ水210μLを添加した。次いで、ミリQ水中の1:5希釈液系列を調製した。
SST4アッセイ SST5アッセイ
A. 1.25mM溶液240μL 0.25mM 0.125mM
B. A48μL+ミリQ水192μL 0.05mM 0.025mM
C. B24μL+ミリQ水192μL 0.01mM 0.005mM
等
1:5希釈液系列内で各濃度:250μM、50μM、10μM、2mM、0.4μM、0.08μM、0.016μM、0.0032μM等(SST4アッセイに関して)および125μM、10μM、2μM、1μM、0.5μM等(SST5アッセイに関して)にて三重反復でアッセイを行った。
ヒトSST5ソマトスタチン受容体をHEK−293EBNA細胞内にトランスフェクトした。アッセイバッファー(50mMトリス−HCl,1mM EGTA,5mM MgCl2,10%ショ糖,pH7.5)に膜を懸濁した。受容体濃度(Bmax)は、[125I]SST−14結合0.31nM、体積0.4ml/バイアル(400ミクロアッセイ/バイアル)、タンパク質濃度1.03mg/mlに対して0.57pmol/mgタンパク質Kdであった。
実施例I:表1および2における化合物のHPLC法
表1および2における化合物HPLC分離は、以下に示す方法Aまたは方法Bで行った。
方法A
カラム:Agilent SB Zorbax C18 4.6×50mm(5μm、80Å)
LC移動相:
5%MeCN水溶液/1分
100%MeCN/7〜12分
方法B
カラム:Agilent SB Zorbax C18 4.6×50mm(5μm、80Å)
LC移動相:
5%MeCN水溶液/1分
30%MeCN水溶液/3分
40%MeCN水溶液/12分
100%MeCN/13〜15分
表1および2のビルディングブロックの特徴
表1:*化合物の2Pライブラリーに関してある濃度(μM)で置換されたSST5放射−リガンド結合%
表2:*化合物の3Pライブラリーに関してある濃度(μM)で置換されたSST5放射−リガンド結合%;R4=X30;化合物60〜63、119および156〜159は、2Pライブラリーからの比較用化合物である。
「+」:ある濃度(μM)で置換されたSST5放射リガンド% 60>+>40%
「−」:ある濃度(μM)で置換されたSST5放射リガンド%−<40%
ブランク:未決定
RT:保持時間/分
M+H:質量イオン+1
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Claims (20)
- (a)分子多様性をスキャンするために、式1の化合物の第1ライブラリーを設計すること(前記ライブラリーの各化合物が、以下に定義される少なくとも2つのファーマコフォア基R1〜R5を有し、かつ前記ライブラリーの化合物が、同数のファーマコフォア基を有する);
(b)1つまたは複数の生物学的アッセイにおいて、化合物の前記第1ライブラリーをアッセイすること;および
(c)第2ライブラリーを設計すること(前記第2ライブラリーの各化合物が、前記第1ライブラリーに対して1つまたは複数の更なるファーマコフォア基を含有する);
を含む、生物活性化合物を同定する方法であって、前記第1および第2ライブラリーの前記成分/各成分が、式1:
Zは、硫黄、酸素、CH2、C(O)、C(O)NRA、NH、NRAまたは水素であり、Zが水素である場合には、R1は存在せず、RAは、R1〜R5について定義されるセットから選択され、あるいはZおよびR1は一緒になって複素環を形成し、
Xは、式Iの少なくとも1つのXが窒素であるという条件で酸素または窒素であり、Xは、R1〜R5のうちの1つと独立して一緒になってアジドを形成することもでき、
R1〜R5は、以下の非ファーマコフォア基、H、メチルおよびアセチルから独立して選択され、並びにファーマコフォア基R1〜R5は、限定されないが、C2〜C20アルキルまたはアセチルを除外したアシル;C2〜C20アルケニル、アルキニル、ヘテロアルキル;C5〜C20アリール、ヘテロアリール、アリールアルキルまたはヘテロアリールアルキルを含む群から独立して選択され(任意に置換されかつ分岐状または直鎖状であることができる)、またはXおよび対応するR部分、R2〜R5がそれぞれ一緒になって複素環を形成する)
の化合物であるような、方法。 - 前記第1ライブラリーにおいて、置換基R1〜R5のうちの3つが、非ファーマコフォア基であり、かつ水素またはメチルまたはアセチルから選択される、請求項1に記載の方法。
- 前記第1ライブラリーにおいて、前記置換基R1〜R5のうちの2つが、非ファーマコフォア基であり、かつ水素またはメチルまたはアセチルから選択される、請求項1に記載の方法。
- Zが、硫黄または酸素である、請求項1に記載の方法。
- 前記ファーマコフォア基のうちの少なくとも1つが、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキルまたはアシルから選択される、請求項1〜4のいずれか一項に記載の方法。
- 請求項2に従って使用する場合に、式1の化合物から選択される化合物のライブラリー。
- 請求項3に従って使用する場合に、式1の化合物から選択される化合物のライブラリー。
- 前記化合物/各化合物が、グルコまたはガラクトまたはアロ立体配置をとる、請求項8に記載の方法。
- 前記化合物/各化合物が、グルコ立体配置をとる、請求項9に記載の方法。
- 前記化合物/各化合物が、アロ立体配置をとる、請求項9に記載の方法。
- 前記化合物/各化合物が、ガラクト立体配置をとる、請求項9に記載の方法。
- 前記ライブラリーの設計が、分子多様性を評価するための分子モデリングを含む、請求項1に記載の方法。
- R1〜R5の任意の置換基が、OH、NO、NO2、NH2、N3、ハロゲン、CF3、CHF2、CH2F、ニトリル、アルコキシ、アリールオキシ、アミジン、グアニジニウム、カルボン酸、カルボン酸エステル、カルボン酸アミド、アリール、シクロアルキル、ヘテロアルキル、ヘテロアリール、アミノアルキル、アミノジアルキル、アミノトリアルキル、アミノアシル、カルボニル、置換または非置換イミン、スルフェート、スルホンアミド、ホスフェート、ホスホルアミド、ヒドラジド、ヒドロキサメート、ヒドロキサム酸、ヘテロアリールオキシ、アミノアリール、アミノヘテロアリール、チオアルキル、チオアリールまたはチオヘテロアリールから選択され、任意にさらに置換されていてもよい、請求項1に記載の方法。
- 前記化合物が合成される、請求項1〜5のいずれか一項に記載の方法。
- 前記生物学的アッセイが、GPCRのペプチドリガンドクラスを含む、請求項1に記載の方法。
- 少なくとも1つのXが窒素であり、かつ前記Xが、対応するR2〜R5と一緒になって複素環を形成する、式1による化合物。
- XおよびR2が一緒になって複素環を形成する、請求項17に記載の化合物。
- 前記複素環がヘテロアリールである、請求項17または18に記載の化合物。
- 前記ヘテロアリールが、トリアゾール、ベンゾイミダゾール、ベンゾイミダゾロン、ベンゾイミダゾロチオン、イミダゾール、ヒダントイン、チオヒダントインおよびプリンから選択される、請求項17〜19のいずれか一項に記載の化合物。
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