JP2020530853A - トリメチルアミン及び/又はトリメチルアミン−n−オキシドに関連する標的薬 - Google Patents
トリメチルアミン及び/又はトリメチルアミン−n−オキシドに関連する標的薬 Download PDFInfo
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- JP2020530853A JP2020530853A JP2020508997A JP2020508997A JP2020530853A JP 2020530853 A JP2020530853 A JP 2020530853A JP 2020508997 A JP2020508997 A JP 2020508997A JP 2020508997 A JP2020508997 A JP 2020508997A JP 2020530853 A JP2020530853 A JP 2020530853A
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- UYPYRKYUKCHHIB-UHFFFAOYSA-N trimethylamine N-oxide Chemical compound C[N+](C)(C)[O-] UYPYRKYUKCHHIB-UHFFFAOYSA-N 0.000 title claims abstract description 60
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 title claims description 166
- 150000001875 compounds Chemical class 0.000 claims abstract description 275
- 108090000790 Enzymes Proteins 0.000 claims abstract description 199
- 102000004190 Enzymes Human genes 0.000 claims abstract description 199
- 230000005856 abnormality Effects 0.000 claims abstract description 146
- 244000005700 microbiome Species 0.000 claims abstract description 90
- 238000000034 method Methods 0.000 claims abstract description 84
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 38
- 230000000813 microbial effect Effects 0.000 claims abstract description 17
- 230000027455 binding Effects 0.000 claims description 81
- 241000192142 Proteobacteria Species 0.000 claims description 61
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical class C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 claims description 38
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims description 35
- 229960001231 choline Drugs 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 35
- -1 methyl (2R) -hydroxy (phenyl) acetate Chemical compound 0.000 claims description 23
- 108090000623 proteins and genes Proteins 0.000 claims description 19
- 102000004169 proteins and genes Human genes 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- HFACYLZERDEVSX-UHFFFAOYSA-N benzidine Chemical compound C1=CC(N)=CC=C1C1=CC=C(N)C=C1 HFACYLZERDEVSX-UHFFFAOYSA-N 0.000 claims description 15
- 238000004088 simulation Methods 0.000 claims description 15
- 238000003032 molecular docking Methods 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- WTARULDDTDQWMU-IUCAKERBSA-N (-)-β-pinene Chemical compound C1[C@@H]2C(C)(C)[C@H]1CCC2=C WTARULDDTDQWMU-IUCAKERBSA-N 0.000 claims description 10
- VAJVDSVGBWFCLW-UHFFFAOYSA-N 3-Phenyl-1-propanol Chemical compound OCCCC1=CC=CC=C1 VAJVDSVGBWFCLW-UHFFFAOYSA-N 0.000 claims description 10
- LUJMEECXHPYQOF-UHFFFAOYSA-N 3-hydroxyacetophenone Chemical compound CC(=O)C1=CC=CC(O)=C1 LUJMEECXHPYQOF-UHFFFAOYSA-N 0.000 claims description 10
- IJFXRHURBJZNAO-UHFFFAOYSA-N 3-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC(O)=C1 IJFXRHURBJZNAO-UHFFFAOYSA-N 0.000 claims description 10
- FNYDIAAMUCQQDE-UHFFFAOYSA-N 4-methylbenzene-1,3-diol Chemical compound CC1=CC=C(O)C=C1O FNYDIAAMUCQQDE-UHFFFAOYSA-N 0.000 claims description 10
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 claims description 10
- 208000004652 Cardiovascular Abnormalities Diseases 0.000 claims description 9
- 206010068233 Trimethylaminuria Diseases 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- 230000004060 metabolic process Effects 0.000 claims description 8
- ODLMAHJVESYWTB-UHFFFAOYSA-N propylbenzene Chemical compound CCCC1=CC=CC=C1 ODLMAHJVESYWTB-UHFFFAOYSA-N 0.000 claims description 8
- LHXDLQBQYFFVNW-XCBNKYQSSA-N (+)-fenchone Chemical compound C1C[C@]2(C)C(=O)C(C)(C)[C@H]1C2 LHXDLQBQYFFVNW-XCBNKYQSSA-N 0.000 claims description 7
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 7
- 235000016709 nutrition Nutrition 0.000 claims description 7
- DUXCSEISVMREAX-UHFFFAOYSA-N 3,3-dimethylbutan-1-ol Chemical compound CC(C)(C)CCO DUXCSEISVMREAX-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- XRAMJHXWXCMGJM-UHFFFAOYSA-N methyl 3-(4-hydroxyphenyl)propionate Chemical compound COC(=O)CCC1=CC=C(O)C=C1 XRAMJHXWXCMGJM-UHFFFAOYSA-N 0.000 claims description 6
- 230000035764 nutrition Effects 0.000 claims description 6
- 229930006715 (-)-beta-pinene Natural products 0.000 claims description 5
- GYUSHSKDGRZQOB-SSDOTTSWSA-N (1r)-2-methylcyclohexa-2,5-diene-1-carboxylic acid Chemical compound CC1=CCC=C[C@H]1C(O)=O GYUSHSKDGRZQOB-SSDOTTSWSA-N 0.000 claims description 5
- YVHAOWGRHCPODY-YFKPBYRVSA-N (2r)-3,3-dimethylbutane-1,2-diol Chemical compound CC(C)(C)[C@@H](O)CO YVHAOWGRHCPODY-YFKPBYRVSA-N 0.000 claims description 5
- MXLMTQWGSQIYOW-RXMQYKEDSA-N (2r)-3-methylbutan-2-ol Chemical compound CC(C)[C@@H](C)O MXLMTQWGSQIYOW-RXMQYKEDSA-N 0.000 claims description 5
- WVYWICLMDOOCFB-ZCFIWIBFSA-N (2r)-4-methylpentan-2-ol Chemical compound CC(C)C[C@@H](C)O WVYWICLMDOOCFB-ZCFIWIBFSA-N 0.000 claims description 5
- FCOUHTHQYOMLJT-MRVPVSSYSA-N (2r)-6-methylheptan-2-ol Chemical compound CC(C)CCC[C@@H](C)O FCOUHTHQYOMLJT-MRVPVSSYSA-N 0.000 claims description 5
- KJBPYIUAQLPHJG-VIFPVBQESA-N (2s)-1-phenylmethoxypropan-2-ol Chemical compound C[C@H](O)COCC1=CC=CC=C1 KJBPYIUAQLPHJG-VIFPVBQESA-N 0.000 claims description 5
- WTLNOANVTIKPEE-VKHMYHEASA-N (2s)-2-acetyloxypropanoic acid Chemical compound OC(=O)[C@H](C)OC(C)=O WTLNOANVTIKPEE-VKHMYHEASA-N 0.000 claims description 5
- MWCBGWLCXSUTHK-YFKPBYRVSA-N (2s)-2-methylbutane-1,4-diol Chemical compound OC[C@@H](C)CCO MWCBGWLCXSUTHK-YFKPBYRVSA-N 0.000 claims description 5
- JUTDHSGANMHVIC-JTQLQIEISA-N (2s)-2-phenylpyrrolidine Chemical compound C1CCN[C@@H]1C1=CC=CC=C1 JUTDHSGANMHVIC-JTQLQIEISA-N 0.000 claims description 5
- HMYXKHZCEYROAL-UHFFFAOYSA-N (4-chloro-2,3,5,6-tetrafluorophenyl)methanol Chemical compound OCC1=C(F)C(F)=C(Cl)C(F)=C1F HMYXKHZCEYROAL-UHFFFAOYSA-N 0.000 claims description 5
- VTWKXBJHBHYJBI-SOFGYWHQSA-N (ne)-n-benzylidenehydroxylamine Chemical compound O\N=C\C1=CC=CC=C1 VTWKXBJHBHYJBI-SOFGYWHQSA-N 0.000 claims description 5
- BPBNKCIVWFCMJY-UHFFFAOYSA-N 1-ethynyl-4-phenylbenzene Chemical group C1=CC(C#C)=CC=C1C1=CC=CC=C1 BPBNKCIVWFCMJY-UHFFFAOYSA-N 0.000 claims description 5
- YBVRFTBNIZWMSK-UHFFFAOYSA-N 2,2-dimethyl-1-phenylpropan-1-ol Chemical compound CC(C)(C)C(O)C1=CC=CC=C1 YBVRFTBNIZWMSK-UHFFFAOYSA-N 0.000 claims description 5
- 229940075142 2,5-diaminotoluene Drugs 0.000 claims description 5
- UYXWKABXDGYZSR-UHFFFAOYSA-N 2-(2,3-dihydro-1h-inden-5-yl)-2-oxoacetic acid Chemical compound OC(=O)C(=O)C1=CC=C2CCCC2=C1 UYXWKABXDGYZSR-UHFFFAOYSA-N 0.000 claims description 5
- JUNAPQMUUHSYOV-UHFFFAOYSA-N 2-(2h-tetrazol-5-yl)acetic acid Chemical compound OC(=O)CC=1N=NNN=1 JUNAPQMUUHSYOV-UHFFFAOYSA-N 0.000 claims description 5
- ZGQVZLSNEBEHFN-UHFFFAOYSA-N 2-(4-methylphenyl)benzonitrile Chemical compound C1=CC(C)=CC=C1C1=CC=CC=C1C#N ZGQVZLSNEBEHFN-UHFFFAOYSA-N 0.000 claims description 5
- OSSPZRHEHZZDSX-UHFFFAOYSA-N 2-methoxy-4-phenylbenzaldehyde Chemical compound C1=C(C=O)C(OC)=CC(C=2C=CC=CC=2)=C1 OSSPZRHEHZZDSX-UHFFFAOYSA-N 0.000 claims description 5
- IWTFOFMTUOBLHG-UHFFFAOYSA-N 2-methoxypyridine Chemical compound COC1=CC=CC=N1 IWTFOFMTUOBLHG-UHFFFAOYSA-N 0.000 claims description 5
- OBCSAIDCZQSFQH-UHFFFAOYSA-N 2-methyl-1,4-phenylenediamine Chemical compound CC1=CC(N)=CC=C1N OBCSAIDCZQSFQH-UHFFFAOYSA-N 0.000 claims description 5
- XSONSBDQIFBIOY-UHFFFAOYSA-N 2-phenoxyacetohydrazide Chemical compound NNC(=O)COC1=CC=CC=C1 XSONSBDQIFBIOY-UHFFFAOYSA-N 0.000 claims description 5
- VDULOAUXSMYUMG-UHFFFAOYSA-N 2-phenyl-1h-quinazolin-4-one Chemical compound N=1C2=CC=CC=C2C(O)=NC=1C1=CC=CC=C1 VDULOAUXSMYUMG-UHFFFAOYSA-N 0.000 claims description 5
- DKXHSOUZPMHNIZ-UHFFFAOYSA-N 2-pyridin-4-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one Chemical compound C=1C=2C(=O)NCCC=2NC=1C1=CC=NC=C1 DKXHSOUZPMHNIZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- DPDSFQSSCBFWBA-UHFFFAOYSA-N 2h-isoindole-1,3-diamine Chemical compound C1=CC=CC2=C(N)NC(N)=C21 DPDSFQSSCBFWBA-UHFFFAOYSA-N 0.000 claims description 5
- FLROJJGKUKLCAE-UHFFFAOYSA-N 3-amino-2-methylphenol Chemical compound CC1=C(N)C=CC=C1O FLROJJGKUKLCAE-UHFFFAOYSA-N 0.000 claims description 5
- KAWUBNUJMFOOOE-UHFFFAOYSA-N 3-amino-3-(3,5-dibromo-4-hydroxyphenyl)propanoic acid Chemical compound OC(=O)CC(N)C1=CC(Br)=C(O)C(Br)=C1 KAWUBNUJMFOOOE-UHFFFAOYSA-N 0.000 claims description 5
- IFSSSYDVRQSDSG-UHFFFAOYSA-N 3-ethenylaniline Chemical compound NC1=CC=CC(C=C)=C1 IFSSSYDVRQSDSG-UHFFFAOYSA-N 0.000 claims description 5
- XPFCZYUVICHKDS-UHFFFAOYSA-N 3-methylbutane-1,3-diol Chemical compound CC(C)(O)CCO XPFCZYUVICHKDS-UHFFFAOYSA-N 0.000 claims description 5
- MXDRPNGTQDRKQM-UHFFFAOYSA-N 3-methylpyridazine Chemical compound CC1=CC=CN=N1 MXDRPNGTQDRKQM-UHFFFAOYSA-N 0.000 claims description 5
- RGDQRXPEZUNWHX-UHFFFAOYSA-N 3-methylpyridin-2-amine Chemical compound CC1=CC=CN=C1N RGDQRXPEZUNWHX-UHFFFAOYSA-N 0.000 claims description 5
- PZNLKKRMQOCPGG-UHFFFAOYSA-N 3-phenyl-1h-pyrazole-5-carbohydrazide Chemical compound N1C(C(=O)NN)=CC(C=2C=CC=CC=2)=N1 PZNLKKRMQOCPGG-UHFFFAOYSA-N 0.000 claims description 5
- YLNMGMIEOWFPRX-UHFFFAOYSA-N 3-pyridin-2-ylaniline Chemical compound NC1=CC=CC(C=2N=CC=CC=2)=C1 YLNMGMIEOWFPRX-UHFFFAOYSA-N 0.000 claims description 5
- VPANVNSDJSUFEF-UHFFFAOYSA-N 4,5-dimethyl-1,2-oxazol-3-amine Chemical compound CC=1ON=C(N)C=1C VPANVNSDJSUFEF-UHFFFAOYSA-N 0.000 claims description 5
- BBCYWHMUTPKZKJ-UHFFFAOYSA-N 4-(5-methyl-1h-1,2,4-triazol-3-yl)aniline Chemical compound N1C(C)=NC(C=2C=CC(N)=CC=2)=N1 BBCYWHMUTPKZKJ-UHFFFAOYSA-N 0.000 claims description 5
- MASUVUIWOXJJKH-UHFFFAOYSA-N 4-methyl-3-phenyl-1,2-oxazol-5-amine Chemical compound CC1=C(N)ON=C1C1=CC=CC=C1 MASUVUIWOXJJKH-UHFFFAOYSA-N 0.000 claims description 5
- YORPCQSBLZIBKP-UHFFFAOYSA-N 4-methylpiperidin-1-ium-4-carboxylate Chemical compound OC(=O)C1(C)CCNCC1 YORPCQSBLZIBKP-UHFFFAOYSA-N 0.000 claims description 5
- LUQVCHRDAGWYMG-UHFFFAOYSA-N 4-phenylbenzamide Chemical compound C1=CC(C(=O)N)=CC=C1C1=CC=CC=C1 LUQVCHRDAGWYMG-UHFFFAOYSA-N 0.000 claims description 5
- NYSUFKYXLDNHQN-UHFFFAOYSA-N 4-pyrrolidin-1-ium-1-ylbutanoate Chemical compound OC(=O)CCCN1CCCC1 NYSUFKYXLDNHQN-UHFFFAOYSA-N 0.000 claims description 5
- OFNBXLBLUCECGY-UHFFFAOYSA-N 5-(4-methylphenyl)-1h-1,2,4-triazol-3-amine Chemical compound C1=CC(C)=CC=C1C1=NC(N)=NN1 OFNBXLBLUCECGY-UHFFFAOYSA-N 0.000 claims description 5
- GVPFRVKDBZWRCZ-UHFFFAOYSA-N 5-(4-methylphenyl)-1h-pyrazol-3-amine Chemical compound C1=CC(C)=CC=C1C1=CC(N)=NN1 GVPFRVKDBZWRCZ-UHFFFAOYSA-N 0.000 claims description 5
- UPPKQVVRCXNMAP-UHFFFAOYSA-N 8-methyl-4h-thieno[3,2-c]chromene-2-carboxylic acid Chemical compound C12=CC(C)=CC=C2OCC2=C1SC(C(O)=O)=C2 UPPKQVVRCXNMAP-UHFFFAOYSA-N 0.000 claims description 5
- MMNWSHJJPDXKCH-UHFFFAOYSA-N 9,10-dioxoanthracene-2-sulfonic acid Chemical compound C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 MMNWSHJJPDXKCH-UHFFFAOYSA-N 0.000 claims description 5
- 201000001320 Atherosclerosis Diseases 0.000 claims description 5
- XLBVNMSMFQMKEY-BYPYZUCNSA-N N-methyl-L-glutamic acid Chemical compound CN[C@H](C(O)=O)CCC(O)=O XLBVNMSMFQMKEY-BYPYZUCNSA-N 0.000 claims description 5
- WTARULDDTDQWMU-UHFFFAOYSA-N Pseudopinene Natural products C1C2C(C)(C)C1CCC2=C WTARULDDTDQWMU-UHFFFAOYSA-N 0.000 claims description 5
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 claims description 5
- 208000007536 Thrombosis Diseases 0.000 claims description 5
- ZJCCRDAZUWHFQH-UHFFFAOYSA-N Trimethylolpropane Chemical compound CCC(CO)(CO)CO ZJCCRDAZUWHFQH-UHFFFAOYSA-N 0.000 claims description 5
- JHNURUNMNRSGRO-SSDOTTSWSA-N [(3r)-2,3-dihydro-1,4-benzodioxin-3-yl]methanamine Chemical compound C1=CC=C2O[C@H](CN)COC2=C1 JHNURUNMNRSGRO-SSDOTTSWSA-N 0.000 claims description 5
- BAPJBEWLBFYGME-UHFFFAOYSA-N acrylic acid methyl ester Natural products COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 5
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- GGNQRNBDZQJCCN-UHFFFAOYSA-N benzene-1,2,4-triol Chemical compound OC1=CC=C(O)C(O)=C1 GGNQRNBDZQJCCN-UHFFFAOYSA-N 0.000 claims description 5
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- UBRCBHVOYDSGKZ-UHFFFAOYSA-N chembl1422046 Chemical compound NC1=CC=C(O)C(C=2SC3=CC=CC=C3N=2)=C1 UBRCBHVOYDSGKZ-UHFFFAOYSA-N 0.000 claims description 5
- KYUUPPKLZSVGMG-UHFFFAOYSA-N cyclobutanecarbohydrazide Chemical compound NNC(=O)C1CCC1 KYUUPPKLZSVGMG-UHFFFAOYSA-N 0.000 claims description 5
- CTHCTLCNUREAJV-UHFFFAOYSA-N heptane-2,4,6-trione Chemical compound CC(=O)CC(=O)CC(C)=O CTHCTLCNUREAJV-UHFFFAOYSA-N 0.000 claims description 5
- 230000005764 inhibitory process Effects 0.000 claims description 5
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 claims description 5
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 5
- KMROKLMQVGAOMJ-UHFFFAOYSA-N methyl 4-methylpiperidine-4-carboxylate Chemical compound COC(=O)C1(C)CCNCC1 KMROKLMQVGAOMJ-UHFFFAOYSA-N 0.000 claims description 5
- CXGFWBPQQXZELI-UHFFFAOYSA-N n-ethylpyridin-2-amine Chemical compound CCNC1=CC=CC=N1 CXGFWBPQQXZELI-UHFFFAOYSA-N 0.000 claims description 5
- DBGFNLVRAFYZBI-UHFFFAOYSA-N n-methylpyridin-3-amine Chemical compound CNC1=CC=CN=C1 DBGFNLVRAFYZBI-UHFFFAOYSA-N 0.000 claims description 5
- DLRJIFUOBPOJNS-UHFFFAOYSA-N phenetole Chemical compound CCOC1=CC=CC=C1 DLRJIFUOBPOJNS-UHFFFAOYSA-N 0.000 claims description 5
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 claims description 5
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- VZRRCQOUNSHSGB-XSSZXYGBSA-N (1r,4s,5r)-4-hydroxy-4,6,6-trimethylbicyclo[3.1.1]heptan-3-one Chemical compound C1[C@@H]2C(C)(C)[C@H]1CC(=O)[C@]2(O)C VZRRCQOUNSHSGB-XSSZXYGBSA-N 0.000 claims description 4
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- PUEWSNLDTZQXLN-UHFFFAOYSA-N 1-pyridin-3-ylpropan-2-amine Chemical compound CC(N)CC1=CC=CN=C1 PUEWSNLDTZQXLN-UHFFFAOYSA-N 0.000 claims description 4
- HECLRDQVFMWTQS-RGOKHQFPSA-N 1755-01-7 Chemical compound C1[C@H]2[C@@H]3CC=C[C@@H]3[C@@H]1C=C2 HECLRDQVFMWTQS-RGOKHQFPSA-N 0.000 claims description 4
- AMCOCUDBDKVWRZ-UHFFFAOYSA-N 2-(2-hydroxyethoxy)phenol Chemical compound OCCOC1=CC=CC=C1O AMCOCUDBDKVWRZ-UHFFFAOYSA-N 0.000 claims description 4
- GHKSKVKCKMGRDU-UHFFFAOYSA-N 2-(3-aminopropylamino)ethanol Chemical compound NCCCNCCO GHKSKVKCKMGRDU-UHFFFAOYSA-N 0.000 claims description 4
- NGFPWHGISWUQOI-MRVPVSSYSA-N 2-[(2r)-butan-2-yl]phenol Chemical compound CC[C@@H](C)C1=CC=CC=C1O NGFPWHGISWUQOI-MRVPVSSYSA-N 0.000 claims description 4
- TZYRSLHNPKPEFV-UHFFFAOYSA-N 2-ethyl-1-butanol Chemical compound CCC(CC)CO TZYRSLHNPKPEFV-UHFFFAOYSA-N 0.000 claims description 4
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Abstract
Description
本出願は、2017年8月14日に出願された米国仮出願第62/545,056号の利益を主張し、その全体が参照により本明細書に組み込まれる。本出願はさらに、2017年8月14日に出願された米国仮出願第62/545,065号の利益を主張し、その全体が参照により本明細書に組み込まれる。
図1〜3に示すように、(たとえば、TMA、TMAO、及び/又はそれらの誘導体の少なくとも一つに関連する異常の患者を治療するためなどの)方法100の実施形態は、微生物分類群のセットからの少なくとも一つの分類群由来の微生物(例えば、ファーミキューテス(門)及びプロテオバクテリア(門)の少なくとも一つなど)に関連する1又は複数の標的(たとえば、CutC酵素、Rieske型オキシゲナーゼ(CntA)酵素、他の酵素、タンパク質、他の生物学的標的、非生物学的標的、TMA、TMAO、及び/又はその誘導体の少なくとも一つに関連する酵素など)に影響を及ぼす(たとえば、阻害するなど)ための化合物(たとえば、薬物など)の治療上有効な量を1又は複数の異常(たとえば、TMA、TMAO、及び/又はその誘導体の少なくとも一つに関連する1又は複数の異常など)を有する患者に投与することS110、を含み得る。
方法100の実施形態は、1又は複数の異常(たとえば、TMA、TMAO、及び/又はそれらの誘導体の少なくとも一つに関連する1又は複数の異常)を有する1人又は複数の患者に1又は複数の化合物(たとえば、治療上有効な量の1又は複数の化合物)を投与(及び/又は他の適切な提供、促進など)することS110を含むことができ、これは、1人又は複数の患者の治療を促進するように機能することができる。
追加的に又は代替的に、方法100の実施形態は、化合物決定を容易にするためのモデリング及び/又は実験で使用するための標的の代表特性を決定するように機能し得る1又は複数の標的(たとえば、CutC酵素;CntA酵素;他の酵素;タンパク質;他の生物学的標的;非生物学的標的;TMA、TMAO、及び/又はそれらの誘導体の少なくとも一つに関連する酵素)の1又は複数の代表的な配列を決定することS120を含み得る。
追加的に又は代替的に、方法100の実施形態は、1又は複数のモデル及び1又は複数の対照分子を用いた1又は複数の実験に基づいて前記1又は複数の標的に対する1又は複数の対照結合パラメータ(及び/又は他の適切な相互作用パラメータなど)を決定することS140を含むことができ、これは1又は複数の対照と1又は複数の標的との間の相互作用を記述する特性を決定するように機能することができる。
追加的に又は代替的に、前記方法100の実施形態は、1又は複数のモデルと化合物(たとえば、CutC酵素及び/又はCntA酵素を阻害する可能性など、1又は複数の標的に影響を与える可能性があるもの)のライブラリを使用した一連の実験に基づいて、1又は複数の標的に対する化合物結合パラメータ(及び/又は他の適切な相互作用パラメータ)のセットを決定することS150を含むことができ、これは、1又は複数の化合物(たとえば、可能な化合物)と1又は複数の標的との間の相互作用を記述する特性を決定するように機能し得る。
追加的に又は代替的に、前記方法100の実施形態は、前記1又は複数の対照結合パラメータと前記化合物結合パラメータのセットに基づいて少なくとも一つの(たとえば、化合物のライブラリからの)化合物を同定することS160を含むことができ、これは、トリメチルアミン(TMA)、トリメチルアミンN−オキシド(TMAO)、及びそれらの誘導体の少なくとも一つに関連する異常を有する患者の治療及び/又は任意の適切な異常を有する患者の治療をするための少なくとも一つの化合物を同定するように機能することができる。
追加的に又は代替的に、方法100の実施形態は、1又は複数の化合物を実験的に検証及び/又はそうでない場合試験するように機能することができる、1又は複数の化合物を検証することS170を含み得る。
本明細書に記載されている変形のいずれか(たとえば、実施形態、変形、実施例、具体例、図)及び/又は本明細書に記載されている変形の任意の部分は、追加的に又は代替的に、組み合わされ、集約され、除外され、使用され、連続的に実行され、並行して実行され、及び/又は別の方法で適用され得る。
Claims (23)
- トリメチルアミン(TMA)、トリメチルアミンN−オキシド(TMAO)、及びそれらの誘導体の少なくとも一つに関連する異常を有する患者を治療する方法であって、前記方法は、ファーミキューテス(門)及びプロテオバクテリア(門)の少なくとも一方由来の微生物のコリントリメチルアミン−リアーゼ(CutC)酵素を阻害するための化合物の治療上有効な量を、前記異常を有する前記患者に投与することを含み、ここで、前記化合物は、2−エチル−1−ブタノール;(2R)−3,3−ジメチル−1,2−ブタンジオール;(2S)−3,3−ジメチル−1,2−ブタンジオール;(2S)−4−メチル−2−ペンタノール;(2S)−3−メチル−2−ブタノール;(2R)−4−メチル−2−ペンタノール;(2R)−3−メチル−2−ブタノール;(2S)−2−ペンタノール;(2S)−2−メチル−1,4−ブタンジオール;2−メチル−2,4−ブタンジオール;トリメチロールプロパン;3−(4−メトキシフェニル)プロパナール;1−(3−ピリジニル)−2−プロパンアミン;2−[(2R)−2−ブタニル]フェノール;4−プロピル安息香酸;(2S)−1−(ベンジルオキシ)−2−プロパノール;3−(4−ヒドロキシフェニル)プロパン酸メチル;α−メチルフェニルアラニン;2,2−ジメチル−1−フェニル−1−プロパノール;メチル(2R)−ヒドロキシ(フェニル)アセテート;(2S)−2−フェニルピロリジニウム;4−メチル−3−フェニル−1,2−オキサゾール−5−アミン;4,4’−ビフェニルジアミン;4’−メチル−2−ビフェニルカルボニトリル;4−ビフェニロール;2−[3−(4−メチルフェニル)−1,2−オキサゾール−5−イル]エタノール;4−ビフェニルカルボキサミド;4−エチニルビフェニル;5−(4−メチルフェニル)−1H−1,2,4−トリアゾール−3−アミン;5−(4−メチルフェニル)−1H−ピラゾール−3−アミン;4−ヒドロキシカテコール;3−フェニル−1H−ピラゾール−5−カルボヒドラジド;4−メチル−1,3−ベンゼンジオール;N−(2−ヒドロキシエチル)−1,3−プロパンジアミニウム;3−メトキシ−3−メチルブタノール;4−ピリジニルメタンアミニウム;N−メチル−3−ピリジンアミン;2−メトキシピリジン;5−メチル−3−ピリジンアミン;1−(4−メチル−3−ピリジニル)メタンアミン;メシチレン;(E)−ベンズアルドキシム’(3R)−2,2,4−トリメチル−1,3−ペンタンジオール;(1R,4R)−2−アザビシクロ[2.2.1]ヘプト−2−イル酢酸;3−アセチルフェノール;3−ヒドロキシ安息香酸;1H−インドール−7−イルメタノール;3−ビニルアニリン;(3s,5s,7s)−1−イソシアナトアダマンタン;(1R,2S,5R)−2−ヒドロキシ−2,6,6−トリメチルビシクロ[3.1.1]ヘプタン−3−オン;(−)−β−ピネン;2H−イソインドール−1,3−ジアミン;(3s,5s,7s)−1−アダマンタノール;(3−アミノビシクロ[2.2.1]ヘプト−2−イル)メタノール;3−(ヒドラジノメチル)フェノール;(1S,2R)−2−カルバモイルシクロヘキサンアミニウム;(1S,4R)−1,3,3−トリメチルビシクロ[2.2.1]ヘプタン−2−オン;(1R,4S)−1,3,3−トリメチルビシクロ[2.2.1]ヘプタン−2−オン;4−メチル−4−ピペリジンカルボン酸メチル;ヘプタン酸メチル;3−メチルピリダジン;4,5−ジメチル−1,2−オキサゾール−3−アミン;2−(2−ヒドロキシエトキシ)フェノール;2−ヒドロキシ−N−(3−ピリジニルメチル)エタンアミニウム;3−フェニル−1−プロパノール;(2R)−6−メチル−2−ヘプタノール;2−フェノキシアセトヒドラジド;N−ヒドロキシオクタナミド;シクロブタンカルボヒドラジド;フェニルヒドラジン;(1S,4R)−2−アザビシクロ[2.2.1]ヘプト−5−エン−3−オン;サリチルアミド;アダマンタン;3−アザビシクロ[3.3.1]ノナン;N−ヒドロキシ−2−メチルベンゼンカルボキシミダミド;(−)−カンフェン;(1S,2S,4S)−ビシクロ[2.2.1]ヘプト−5−エン−2−イルメタノール;ジシクロペンタジエン;(8−アンチ)−3−アザビシクロ[3.2.1]オクタン−8−オール;(1R,2S,6R,7S)−トリシクロ[5.2.1.02,6]デカ−3,8−ジエン;それらの薬剤的に許容可能な形態;及びそれらの塩、の少なくとも一つを含む、方法。
- 前記異常が前記TMA、TMAO、及びそれらの誘導体の少なくとも一つに関連する心血管の異常及び腎臓の異常の少なくとも一つを含み、ここで、前記異常の前記患者への投与は、ファーミキューテス(門)及びプロテオバクテリア(門)の少なくとも一方由来の微生物のCutC酵素を阻害するための化合物の治療上有効な量を前記心血管の異常及び腎臓の異常の少なくとも一つを有する前記患者に投与すること、を含む、請求項1に記載の方法。
- 前記異常が前記TMA、TMAO、及びそれらの誘導体の少なくとも一つに関連するアテローム性動脈硬化異常を含む前記心血管の異常を含み、ここで、前記異常の前記患者への投与は、ファーミキューテス(門)及びプロテオバクテリア(門)の少なくとも一方由来の微生物のCutC酵素を阻害するための化合物の治療上有効な量を前記アテローム性動脈硬化異常を有する前記患者に投与すること、を含む、請求項2に記載の方法。
- 前記異常が前記TMA、TMAO、及びそれらの誘導体の少なくとも一つに関連する血小板凝集亢進異常及び血栓形成異常の少なくとも一つを含む前記心血管の異常を含み、ここで、前記異常の前記患者への投与は、ファーミキューテス(門)及びプロテオバクテリア(門)の少なくとも一方由来の微生物のCutC酵素を阻害するための化合物の治療上有効な量を前記血小板凝集亢進異常及び前記血栓形成異常の少なくとも一つを有する前記患者に投与すること、を含む、請求項2に記載の方法。
- 前記異常を有する前記患者に投与することは、2−エチル−1−ブタノール;(2R)−3,3−ジメチル−1,2−ブタンジオール;(2S)−3,3−ジメチル−1,2−ブタンジオール;(2S)−4−メチル−2−ペンタノール;(2S)−3−メチル−2−ブタノール;(2R)−4−メチル−2−ペンタノール;(2R)−3−メチル−2−ブタノール;(2S)−2−ペンタノール;(2S)−2−メチル−1,4−ブタンジオール;2−メチル−2,4−ブタンジオール;トリメチロールプロパン;それらの薬剤的に許容可能な形態;及びそれらの塩のうち少なくとも一つを含む3,3−ジメチル−1−ブタノール(DMB)類似体を含む前記化合物の治療上有効な量を投与すること、を含む、請求項1に記載の方法。
- 前記微生物はファーミキューテス(門)由来の微生物を含み、ここで、前記異常を有する前記患者への投与は、ファーミキューテス(門)由来の前記微生物のCutC酵素を阻害するための前記化合物の治療上有効な量を、前記異常を有する前記患者に投与することを含み、ここで、前記化合物には、3−(4−メトキシフェニル)プロパナール;1−(3−ピリジニル)−2−プロパンアミン;2−[(2R)−2−ブタニル]フェノール;4−プロピル安息香酸;(2S)−1−(ベンジルオキシ)−2−プロパノール;3−(4−ヒドロキシフェニル)プロパン酸メチル;α−メチルフェニルアラニン;2,2−ジメチル−1−フェニル−1−プロパノール;メチル(2R)−ヒドロキシ(フェニル)アセテート;(2S)−2−フェニルピロリジニウム;4−メチル−3−フェニル−1,2−オキサゾール−5−アミン;4,4’−ビフェニルジアミン;4’−メチル−2−ビフェニルカルボニトリル;4−ビフェニロール;2−[3−(4−メチルフェニル)−1,2−オキサゾール−5−イル]エタノール;4−ビフェニルカルボキサミド;4−エチニルビフェニル;5−(4−メチルフェニル)−1H−1,2,4−トリアゾール−3−アミン;5−(4−メチルフェニル)−1H−ピラゾール−3−アミン;4−ヒドロキシカテコール;3−フェニル−1H−ピラゾール−5−カルボヒドラジド;4−メチル−1,3−ベンゼンジオール;それらの薬剤的に許容可能な形態;及びそれらの塩のうち少なくとも一つを含む、請求項1に記載の方法。
- 前記微生物はプロテオバクテリア(門)由来の微生物を含み、ここで、前記異常を有する前記患者への投与は、プロテオバクテリア(門)由来の前記微生物のCutC酵素を阻害するための前記化合物の治療上有効な量を、前記異常を有する前記患者に投与することを含み、ここで、前記化合物には、N−(2−ヒドロキシエチル)−1,3−プロパンジアミニウム;3−メトキシ−3−メチルブタノール;4−ピリジニルメタンアミニウム;N−メチル−3−ピリジナミン;2−メトキシピリジン;5−メチル−3−ピリジナミン;1−(4−メチル−3−ピリジニル)メタンアミン;メシチレン;(E)−ベンズアルドキシム’(3R)−2,2,4−トリメチル−1,3−ペンタンジオール;(1R,4R)−2−アザビシクロ[2.2.1]ヘプト−2−イル酢酸;3−アセチルフェノール;3−ヒドロキシ安息香酸;1H−インドール−7−イルメタノール;3−ビニルアニリン;(3s,5s,7s)−1−イソシアナトアダマンタン;(1R,2S,5R)−2−ヒドロキシ−2,6,6−トリメチルビシクロ[3.1.1]ヘプタン−3−オン;(−)−β−ピネン;2H−イソインドール−1,3−ジアミン;(3s,5s,7s)−1−アダマンタノール;(3−アミノビシクロ[2.2.1]ヘプト−2−イル)メタノール;3−(ヒドラジノメチル)フェノ−ル;(1S,2R)−2−カルバモイルシクロヘキサンアミニウム;(1S,4R)−1,3,3−トリメチルビシクロ[2.2.1]ヘプタン−2−オン;(1R,4S)−1,3,3−トリメチルビシクロ[2.2.1]ヘプタン−2−オン;それらの薬剤的に許容可能な形態;及びそれらの塩のうち少なくとも一つを含む、請求項1に記載の方法。
- 前記微生物はファーミキューテス(門)及びプロテオバクテリア(門)由来の微生物を含み、ここで、前記異常を有する前記患者への投与は、ファーミキューテス(門)及びプロテオバクテリア(門)由来の前記微生物のCutC酵素を阻害するための前記化合物の治療上有効な量を、前記異常を有する前記患者に投与することを含み、ここで、前記化合物には、4−メチル−4−ピペリジンカルボン酸メチル;ヘプタン酸メチル;3−メチルピリダジン;4,5−ジメチル−1,2−オキサゾール−3−アミン;2−(2−ヒドロキシエトキシ)フェノ−ル;2−ヒドロキシ−N−(3−ピリジニルメチル)エタンアミニウム;3−フェニル−1−プロパノール;(2R)−6−メチル−2−ヘプタノール;2−フェノキシアセトヒドラジド;N−ヒドロキシオクタナミド;シクロブタンカルボヒドラジド;フェニルヒドラジン;(1S,4R)−2−アザビシクロ[2.2.1]ヘプト−5−エン−3−オン;サリチルアミド;アダマンタン;3−アザビシクロ[3.3.1]ノナン;N−ヒドロキシ−2−メチルベンゼンカルボキシミドアミド;(−)−カンフェン;(1S,2S,4S)−ビシクロ[2.2.1]ヘプト−5−エン−2−イルメタノール;ジシクロペンタジエン;(8−アンチ)−3−アザビシクロ[3.2.1]オクタン−8−オール;(1R,2S,6R,7S)−トリシクロ[5.2.1.02,6]デカ−3,8−ジエン;それらの薬剤的に許容可能な形態;及びそれらの塩のうち少なくとも一つを含む、請求項1に記載の方法。
- トリメチルアミン(TMA)、トリメチルアミンN−オキシド(TMAO)、及びそれらの誘導体の少なくとも一つに関連する異常を有する患者を治療する方法であって、前記方法は、ファーミキューテス(門)及びプロテオバクテリア(門)の少なくとも一方由来の微生物のRieske型オキシゲナーゼ(CntA)酵素を阻害するための化合物の治療上有効な量を、前記異常を有する前記患者に投与することを含み、ここで、前記化合物は、N−メチルグルタミン酸;4−(1−ピロリジニル)ブタン酸;4−メチル−4−ピペリジンカルボン酸;イソニペコチン酸;N−プロピルベンゼン;N−エチル−2−ピリジナミン;(4R)−4−アミノ−1−プロピル−2−ピロリジノン;2,5−ジアミノトルエン;エチルフェニルエーテル;フェニルシアネート;1−(2−シクロペンテン−1−イル)アセトン;2−アミノ−3−メチルピリジニウム;E−ピリジン−3−アルドキシム;N−シクロヘキシルホルムアミド;2−メチル−2−ヘキセン酸;4−ヘプタナミニウム;3,4−アンヒドロ−3−カルボキシ−2−デオキシ−L−トレオ−ペンタン酸;2,2’−[(2−ヒドロキシエチル)イミノ]二酢酸;1H−テトラゾール−5−イル酢酸;ジアセチルアセトン;(2S)−2−アセトキシプロパン酸;4,4’−ビフタル酸無水物;ビス(1H−ベンゾトリアゾール−1−イル)メタノン;2−アントラキノンスルホン酸;3−(1,3−ジオキソ−1,3−ジヒドロ−2H−イソインドール−2−イル)ベンゾニトリル.;2−フェニルキナゾリン−4−オール;4−アミノ−2−(1,3−ベンゾチアゾール−2−イル)フェノ−ル;4−フェニル−1(2H)−フタラジノン;5−(1,3−ベンゾジオキソール−5−イル)−2−メチル−3−フロ酸;(5R)−5−(2−ナフチル)ジヒドロ−2(3H)−フラノン;3−[5−(3−メチルフェニル)−1,3,4−オキサジアゾール−2−イル]プロパン酸;9−エチニルフェナントレン;PHA−767491;3−アミノ−2−メチルフェノール;5−(4−メチルフェニル)−2−フロ酸;8−メチル−4H−チエノ[3,2−c]クロメン−2−カルボン酸;レゾルシノールモノベンゾエート;3−メトキシ−4−ビフェニルカルボアルデヒド;(7−アミノ−4−メチル−2−オキソ−2H−クロメン−3−イル)酢酸;2,3−ジヒドロ−1H−インデン−5−イル(オキソ)酢酸;3−(2−ピリジル)アニリン;4−(3−メチル−1H−1,2,4−トリアゾ−ル−5−イル)アニリン;ベンジジン;(DL)−3−O−メチルドーパ;(2E)−3−(2−アミノ−5−メチル−3−ピリジニル)アクリル酸メチル;(5−メチルフロ[2,3−b]ピリジン−2−イル)メタノール;(2R)−2,3−ジヒドロ−1,4−ベンゾジオキシン−2−イルメタンアミニウム;プロピオン酸R−フェニルエチル;安息香酸i−プロピル;4−アセトトルイド;(1S)−1−(2,5−ジメチルフェニル)エタンアミニウム;(1R)−2−メチル−2,5−シクロヘキサジエン−1−カルボン酸;(2,2−ジメトキシエチル)ベンゼン;それらの薬剤的に許容可能な形態;及びそれらの塩、の少なくとも一つを含む、方法。
- 前記異常が前記TMA、TMAO、及びそれらの誘導体の少なくとも一つに関連する心血管の異常及び腎臓の異常の少なくとも一つを含み、前記異常の前記患者への投与は、ファーミキューテス(門)及びプロテオバクテリア(門)の少なくとも一方由来の微生物のCntA酵素を阻害するための化合物の治療上有効な量を前記心血管の異常及び腎臓の異常の少なくとも一つを有する前記患者に投与すること、を含む、請求項9に記載の方法。
- 前記異常が前記TMA、TMAO、及びそれらの誘導体の少なくとも一つに関連するアテローム性動脈硬化異常を含む前記心血管の異常を含み、前記異常の前記患者への投与は、ファーミキューテス(門)及びプロテオバクテリア(門)の少なくとも一方由来の微生物のCntA酵素を阻害するための化合物の治療上有効な量を前記アテローム性動脈硬化異常を有する前記患者に投与すること、を含む、請求項10に記載の方法。
- 前記異常が前記TMA、TMAO、及びそれらの誘導体の少なくとも一つに関連する血小板凝集亢進異常及び血栓形成異常の少なくとも一つを含む前記心血管の異常を含み、前記異常の前記患者への投与は、ファーミキューテス(門)及びプロテオバクテリア(門)の少なくとも一方由来の微生物のCntA酵素を阻害するための化合物の治療上有効な量を前記血小板凝集亢進異常及び前記血栓形成異常の少なくとも一つを有する前記患者に投与すること、を含む、請求項10に記載の方法。
- 前記異常が、TMA、TMAO、及びそれらの誘導体の少なくとも一つに関連する代謝関連の異常及び栄養関連の異常の少なくとも一つを含み、前記異常の前記患者への投与は、前記代謝関連の異常及び前記栄養関連の異常の少なくとも一つを有する前記患者に、ファーミキューテス(門)及びプロテオバクテリア(門)の少なくとも一つに由来する微生物のCntA酵素を阻害するための治療上有効な量の化合物を投与すること、を含む、請求項9に記載の方法。
- 前記代謝関連の異常及び前記栄養関連の異常の少なくとも一つが、TMA、TMAO、及びそれらの誘導体の少なくとも一つに関連する体重関連異常及び高血糖関連異常の少なくとも一つを含み、前記異常の前記患者への投与は、前記体重関連異常及び前記高血糖関連異常の少なくとも一つを有する前記患者に、ファーミキューテス(門)及びプロテオバクテリア(門)の少なくとも一つに由来する微生物のCntA酵素を阻害するための治療上有効な量の化合物を投与すること、を含む、請求項13に記載の方法。
- 前記異常が、TMA、TMAO、及びそれらの誘導体の少なくとも一つに関連するトリメチルアミン尿症(TMAU)異常を含む前記代謝関連の異常を含み、前記異常の前記患者への投与は、前記TMAUを有する前記患者に、ファーミキューテス(門)及びプロテオバクテリア(門)の少なくとも一つに由来する微生物のCntA酵素を阻害するための治療上有効な量の化合物を投与すること、を含む、請求項13に記載の方法。
- 前記異常を有する前記患者に投与することは、N‐メチルグルタミン酸; 4-(1‐ピロリジニル)ブタン酸; 4-メチル-4‐ピペリジンカルボン酸; イソニペコチン酸;それらの薬剤的に許容可能な形態;及びそれらの塩のうち少なくとも一つを含むL−カルニチン類似体を含む前記化合物の治療上有効な量を投与すること、を含む、請求項9に記載の方法。
- 前記微生物はファーミキューテス(門)由来の微生物を含み、ここで、前記異常を有する前記患者への投与は、ファーミキューテス(門)由来の前記微生物のCntA酵素を阻害するための前記化合物の治療上有効な量を、前記異常を有する前記患者に投与することを含み、前記化合物には、N−プロピルベンゼン;N−エチル−2−ピリジナミン;(4R)−4−アミノ−1−プロピル−2−ピロリジノン;2,5−ジアミノトルエン;エチルフェニルエーテル;フェニルシアネート;1−(2−シクロペンテン−1−イル)アセトン;2−アミノ−3−メチルピリジニウム;E−ピリジン−3−アルドキシム;N−シクロヘキシルホルムアミド;2−メチル−2−ヘキセン酸;4−ヘプタナミニウム;それらの薬剤的に許容可能な形態;及びそれらの塩のうち少なくとも一つを含む、請求項9に記載の方法。
- 前記微生物はプロテオバクテリア(門)由来の微生物を含み、ここで、前記異常を有する前記患者への投与は、プロテオバクテリア(門)由来の前記微生物のCntA酵素を阻害するための前記化合物の治療上有効な量を、前記異常を有する前記患者に投与することを含み、ここで、前記化合物には、3,4‐アンヒドロ‐3‐カルボキシ‐2‐デオキシ‐L‐トレオ‐ペンタン酸;2,2’−[(2‐ヒドロキシエチル)イミノ]二酢酸;1H‐テトラゾール‐5‐イル酢酸;ジアセチルアセトン;(2S)−2‐アセトキシプロパン酸;それらの薬剤的に許容可能な形態;及びそれらの塩のうち少なくとも一つを含む、請求項9に記載の方法。
- 前記微生物は、ファーミキューテス(門)及びプロテオバクテリア(門)由来の微生物を含み、ここで、前記異常を有する前記患者への投与は、ファーミキューテス(門)及びプロテオバクテリア(門)由来の前記微生物のCntA酵素を阻害するための前記化合物の治療上有効な量を、前記異常を有する前記患者に投与することを含み、ここで、前記化合物には、4,4’−ビフタル酸無水物;ビス(1H−ベンゾトリアゾール−1−イル)メタノン;2−アントラキノンスルホン酸;3−(1,3−ジオキソ−1,3−ジヒドロ−2H−イソインドール−2−イル)ベンゾニトリル.;2−フェニルキナゾリン−4−オール;4−アミノ−2−(1,3−ベンゾチアゾール−2−イル)フェノ−ル;4−フェニル−1(2H)−フタラジノン;5−(1,3−ベンゾジオキソール−5−イル)−2−メチル−3−フロ酸;(5R)−5−(2−ナフチル)ジヒドロ−2(3H)−フラノン;3−[5−(3−メチルフェニル)−1,3,4−オキサジアゾール−2−イル]プロパン酸;9−エチニルフェナントレン;PHA−767491;3−アミノ−2−メチルフェノール;5−(4−メチルフェニル)−2−フロ酸;8−メチル−4H−チエノ[3,2−c]クロメン−2−カルボン酸;レゾルシノールモノベンゾエート;3−メトキシ−4−ビフェニルカルボアルデヒド;(7−アミノ−4−メチル−2−オキソ−2H−クロメン−3−イル)酢酸;2,3−ジヒドロ−1H−インデン−5−イル(オキソ)酢酸;3−(2−ピリジル)アニリン;4−(3−メチル−1H−1,2,4−トリアゾ−ル−5−イル)アニリン;ベンジジン;(DL)−3−O−メチルドーパ;(2E)−3−(2−アミノ−5−メチル−3−ピリジニル)アクリル酸メチル;(5−メチルフロ[2,3−b]ピリジン−2−イル)メタノール;(2R)−2,3−ジヒドロ−1,4−ベンゾジオキシン−2−イルメタンアミニウム;プロピオン酸R−フェニルエチル;安息香酸i−プロピル;4−アセトトルイド;(1S)−1−(2,5−ジメチルフェニル)エタンアミニウム;(1R)−2−メチル−2,5−シクロヘキサジエン−1−カルボン酸;(2,2−ジメトキシエチル)ベンゼン;それらの薬剤的に許容可能な形態;及びそれらの塩のうち少なくとも一つを含む、請求項9に記載の方法。
- トリメチルアミン(TMA)、トリメチルアミンN−オキシド(TMAO)、及びそれらの誘導体の少なくとも一つに関連する異常を有する患者を治療するための少なくとも一つの化合物を同定する方法であって、前記方法は:
TMA、TMAO、及びそれらの誘導体の少なくとも一つに関連する酵素の代表的な配列を決定すること、ここで前記代表的な配列は、微生物分類群のセットからの少なくとも一つの分類群の酵素の配列セットの代表を表し;
前記酵素の前記代表的な配列に基づいて前記酵素のタンパク質構造モデルを生成すること;
前記タンパク質構造モデルと対照分子を用いた対照ドッキングシミュレーションに基づいて、前記酵素への対照結合パラメータを決定すること;
前記タンパク質構造モデル及び化合物のライブラリを使用した化合物ドッキングシミュレーションのセットに基づいて前記酵素への化合物結合パラメータのセットを決定すること;並びに、
前記対照結合パラメータと前記化合物結合パラメータのセットとの比較に基づいて、前記TMA、TMAO、及びそれらの誘導体の少なくとも一つに関連する前記異常を有する前記患者を治療するための前記少なくとも1つの化合物を前記化合物のライブラリから同定すること、
を含む方法。 - 前記酵素は、コリントリメチルアミンリアーゼ(CutC)酵素及びRieske型オキシゲナーゼ(CntA)酵素の少なくとも一つを含み、前記少なくとも一つの分類群は、ファーミキューテス(門)及びプロテオバクテリア(門)の少なくとも一つを含む、請求項20に記載の方法。
- 前記少なくとも一つの化合物は、2−エチル−1−ブタノール;(2R)−3,3−ジメチル−1,2−ブタンジオール;(2S)−3,3−ジメチル−1,2−ブタンジオール;(2S)−4−メチル−2−ペンタノール;(2S)−3−メチル−2−ブタノール;(2R)−4−メチル−2−ペンタノール;(2R)−3−メチル−2−ブタノール;(2S)−2−ペンタノール;(2S)−2−メチル−1,4−ブタンジオール;2−メチル−2,4−ブタンジオール;トリメチロールプロパン;3−(4−メトキシフェニル)プロパナール;1−(3−ピリジニル)−2−プロパンアミン;2−[(2R)−2−ブタニル]フェノール;4−プロピル安息香酸;(2S)−1−(ベンジルオキシ)−2−プロパノール;3−(4−ヒドロキシフェニル)プロパン酸メチル;α−メチルフェニルアラニン;2,2−ジメチル−1−フェニル−1−プロパノール;メチル(2R)−ヒドロキシ(フェニル)アセテート;(2S)−2−フェニルピロリジニウム;4−メチル−3−フェニル−1,2−オキサゾール−5−アミン;4,4’−ビフェニルジアミン;4’−メチル−2−ビフェニルカルボニトリル;4−ビフェニロール;2−[3−(4−メチルフェニル)−1,2−オキサゾール−5−イル]エタノール;4−ビフェニルカルボキサミド;4−エチニルビフェニル;5−(4−メチルフェニル)−1H−1,2,4−トリアゾール−3−アミン;5−(4−メチルフェニル)−1H−ピラゾール−3−アミン;4−ヒドロキシカテコール;3−フェニル−1H−ピラゾール−5−カルボヒドラジド;4−メチル−1,3−ベンゼンジオール;N−(2−ヒドロキシエチル)−1,3−プロパンジアミニウム;3−メトキシ−3−メチルブタノール;4−ピリジニルメタンアミニウム;N−メチル−3−ピリジンアミン;2−メトキシピリジン;5−メチル−3−ピリジンアミン;1−(4−メチル−3−ピリジニル)メタンアミン;メシチレン;(E)−ベンズアルドキシム’(3R)−2,2,4−トリメチル−1,3−ペンタンジオール;(1R,4R)−2−アザビシクロ[2.2.1]ヘプト−2−イル酢酸;3−アセチルフェノール;3−ヒドロキシ安息香酸;1H−インドール−7−イルメタノール;3−ビニルアニリン;(3s,5s,7s)−1−イソシアナトアダマンタン;(1R,2S,5R)−2−ヒドロキシ−2,6,6−トリメチルビシクロ[3.1.1]ヘプタン−3−オン;(−)−β−ピネン;2H−イソインドール−1,3−ジアミン;(3s,5s,7s)−1−アダマンタノール;(3−アミノビシクロ[2.2.1]ヘプト−2−イル)メタノール;3−(ヒドラジノメチル)フェノール;(1S,2R)−2−カルバモイルシクロヘキサンアミニウム;(1S,4R)−1,3,3−トリメチルビシクロ[2.2.1]ヘプタン−2−オン;(1R,4S)−1,3,3−トリメチルビシクロ[2.2.1]ヘプタン−2−オン;4−メチル−4−ピペリジンカルボン酸メチル;ヘプタン酸メチル;3−メチルピリダジン;4,5−ジメチル−1,2−オキサゾール−3−アミン;2−(2−ヒドロキシエトキシ)フェノール;2−ヒドロキシ−N−(3−ピリジニルメチル)エタンアミニウム;3−フェニル−1−プロパノール;(2R)−6−メチル−2−ヘプタノール;2−フェノキシアセトヒドラジド;N−ヒドロキシオクタナミド;シクロブタンカルボヒドラジド;フェニルヒドラジン;(1S,4R)−2−アザビシクロ[2.2.1]ヘプト−5−エン−3−オン;サリチルアミド;アダマンタン;3−アザビシクロ[3.3.1]ノナン;N−ヒドロキシ−2−メチルベンゼンカルボキシミダミド;(−)−カンフェン;(1S,2S,4S)−ビシクロ[2.2.1]ヘプト−5−エン−2−イルメタノール;ジシクロペンタジエン;(8−アンチ)−3−アザビシクロ[3.2.1]オクタン−8−オール;(1R,2S,6R,7S)−トリシクロ[5.2.1.02,6]デカ−3,8−ジエン;N−メチルグルタミン酸;4−(1−ピロリジニル)ブタン酸;4−メチル−4−ピペリジンカルボン酸;イソニペコチン酸;N−プロピルベンゼン;N−エチル−2−ピリジナミン;(4R)−4−アミノ−1−プロピル−2−ピロリジノン;2,5−ジアミノトルエン;エチルフェニルエーテル;フェニルシアネート;1−(2−シクロペンテン−1−イル)アセトン;2−アミノ−3−メチルピリジニウム;E−ピリジン−3−アルドキシム;N−シクロヘキシルホルムアミド;2−メチル−2−ヘキセン酸;4−ヘプタナミニウム;3,4−アンヒドロ−3−カルボキシ−2−デオキシ−L−トレオ−ペンタン酸;2,2’−[(2−ヒドロキシエチル)イミノ]二酢酸;1H−テトラゾール−5−イル酢酸;ジアセチルアセトン;(2S)−2−アセトキシプロパン酸;4,4’−ビフタル酸無水物;ビス(1H−ベンゾトリアゾール−1−イル)メタノン;2−アントラキノンスルホン酸;3−(1,3−ジオキソ−1,3−ジヒドロ−2H−イソインドール−2−イル)ベンゾニトリル.;2−フェニルキナゾリン−4−オール;4−アミノ−2−(1,3−ベンゾチアゾール−2−イル)フェノ−ル;4−フェニル−1(2H)−フタラジノン;5−(1,3−ベンゾジオキソール−5−イル)−2−メチル−3−フロ酸;(5R)−5−(2−ナフチル)ジヒドロ−2(3H)−フラノン;3−[5−(3−メチルフェニル)−1,3,4−オキサジアゾール−2−イル]プロパン酸;9−エチニルフェナントレン;PHA−767491;3−アミノ−2−メチルフェノール;5−(4−メチルフェニル)−2−フロ酸;8−メチル−4H−チエノ[3,2−c]クロメン−2−カルボン酸;レゾルシノールモノベンゾエート;3−メトキシ−4−ビフェニルカルボアルデヒド;(7−アミノ−4−メチル−2−オキソ−2H−クロメン−3−イル)酢酸;2,3−ジヒドロ−1H−インデン−5−イル(オキソ)酢酸;3−(2−ピリジル)アニリン;4−(3−メチル−1H−1,2,4−トリアゾ−ル−5−イル)アニリン;ベンジジン;(DL)−3−O−メチルドーパ;(2E)−3−(2−アミノ−5−メチル−3−ピリジニル)アクリル酸メチル;(5−メチルフロ[2,3−b]ピリジン−2−イル)メタノール;(2R)−2,3−ジヒドロ−1,4−ベンゾジオキシン−2−イルメタンアミニウム;プロピオン酸R−フェニルエチル;安息香酸i−プロピル;4−アセトトルイド;(1S)−1−(2,5−ジメチルフェニル)エタンアミニウム;(1R)−2−メチル−2,5−シクロヘキサジエン−1−カルボン酸;(2,2−ジメトキシエチル)ベンゼン;それらの薬剤的に許容可能な形態;及びそれらの塩、の少なくとも一つを含む、請求項21に記載の方法。
- 前記異常が、心血管の異常、腎臓の異常、代謝関連の異常及び栄養関連の異常の少なくとも一つを含む、請求項22に記載の方法。
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