JP7330202B2 - 化合物およびｐｄｅ４活性剤としてのそれらの使用 - Google Patents
化合物およびｐｄｅ４活性剤としてのそれらの使用 Download PDFInfo
- Publication number
- JP7330202B2 JP7330202B2 JP2020552732A JP2020552732A JP7330202B2 JP 7330202 B2 JP7330202 B2 JP 7330202B2 JP 2020552732 A JP2020552732 A JP 2020552732A JP 2020552732 A JP2020552732 A JP 2020552732A JP 7330202 B2 JP7330202 B2 JP 7330202B2
- Authority
- JP
- Japan
- Prior art keywords
- chloro
- triazol
- methyl
- fluorophenyl
- acetamide
- 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.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 title claims description 336
- 239000012190 activator Substances 0.000 title description 61
- 101100296720 Dictyostelium discoideum Pde4 gene Proteins 0.000 title 1
- 101100082610 Plasmodium falciparum (isolate 3D7) PDEdelta gene Proteins 0.000 title 1
- 125000003545 alkoxy group Chemical group 0.000 claims description 229
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 119
- 125000001153 fluoro group Chemical group F* 0.000 claims description 119
- 229910052736 halogen Inorganic materials 0.000 claims description 119
- 150000002367 halogens Chemical class 0.000 claims description 115
- 125000000217 alkyl group Chemical group 0.000 claims description 104
- 150000003839 salts Chemical class 0.000 claims description 70
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 66
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 65
- -1 3-chloro-5-methylphenyl Chemical group 0.000 claims description 64
- 238000011282 treatment Methods 0.000 claims description 63
- 125000001424 substituent group Chemical group 0.000 claims description 62
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 57
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 53
- 201000010099 disease Diseases 0.000 claims description 50
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
- 125000002619 bicyclic group Chemical group 0.000 claims description 42
- 125000003118 aryl group Chemical group 0.000 claims description 39
- 229910052757 nitrogen Inorganic materials 0.000 claims description 38
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 36
- 125000001072 heteroaryl group Chemical group 0.000 claims description 36
- 230000001404 mediated effect Effects 0.000 claims description 34
- 230000003834 intracellular effect Effects 0.000 claims description 30
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 30
- 229910052760 oxygen Inorganic materials 0.000 claims description 29
- 125000005842 heteroatom Chemical group 0.000 claims description 27
- 230000035772 mutation Effects 0.000 claims description 25
- 230000002265 prevention Effects 0.000 claims description 25
- 238000002560 therapeutic procedure Methods 0.000 claims description 18
- 208000010061 Autosomal Dominant Polycystic Kidney Diseases 0.000 claims description 17
- 206010060862 Prostate cancer Diseases 0.000 claims description 17
- 208000022185 autosomal dominant polycystic kidney disease Diseases 0.000 claims description 17
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 16
- 230000003213 activating effect Effects 0.000 claims description 15
- 208000002814 Autosomal Recessive Polycystic Kidney Diseases 0.000 claims description 14
- 208000017354 Autosomal recessive polycystic kidney disease Diseases 0.000 claims description 14
- 206010028980 Neoplasm Diseases 0.000 claims description 14
- 125000004122 cyclic group Chemical group 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 208000030761 polycystic kidney disease Diseases 0.000 claims description 14
- 230000011664 signaling Effects 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 206010020850 Hyperthyroidism Diseases 0.000 claims description 11
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 11
- 208000021033 autosomal dominant polycystic liver disease Diseases 0.000 claims description 11
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 11
- 201000002528 pancreatic cancer Diseases 0.000 claims description 11
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 11
- 208000028589 polycystic liver disease Diseases 0.000 claims description 11
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 claims description 10
- 208000007913 Pituitary Neoplasms Diseases 0.000 claims description 10
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 10
- 229940095074 cyclic amp Drugs 0.000 claims description 10
- 201000005947 Carney Complex Diseases 0.000 claims description 9
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 claims description 9
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 claims description 9
- 208000010067 Pituitary ACTH Hypersecretion Diseases 0.000 claims description 9
- 208000020627 Pituitary-dependent Cushing syndrome Diseases 0.000 claims description 9
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 201000001441 melanoma Diseases 0.000 claims description 9
- 241000193738 Bacillus anthracis Species 0.000 claims description 8
- 208000006029 Cardiomegaly Diseases 0.000 claims description 8
- 101001014590 Homo sapiens Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas Proteins 0.000 claims description 8
- 101001014594 Homo sapiens Guanine nucleotide-binding protein G(s) subunit alpha isoforms short Proteins 0.000 claims description 8
- 101001014610 Homo sapiens Neuroendocrine secretory protein 55 Proteins 0.000 claims description 8
- 101000797903 Homo sapiens Protein ALEX Proteins 0.000 claims description 8
- 208000024793 Jansen metaphyseal chondrodysplasia Diseases 0.000 claims description 8
- 201000005702 Pertussis Diseases 0.000 claims description 8
- 206010057644 Testis cancer Diseases 0.000 claims description 8
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 claims description 8
- 208000001061 polyostotic fibrous dysplasia Diseases 0.000 claims description 8
- 201000003120 testicular cancer Diseases 0.000 claims description 8
- 208000030507 AIDS Diseases 0.000 claims description 7
- 206010008631 Cholera Diseases 0.000 claims description 7
- 201000003874 Common Variable Immunodeficiency Diseases 0.000 claims description 7
- 201000002980 Hyperparathyroidism Diseases 0.000 claims description 7
- 206010061598 Immunodeficiency Diseases 0.000 claims description 7
- 208000029462 Immunodeficiency disease Diseases 0.000 claims description 7
- 208000006636 Jansen type metaphyseal chondrodysplasia Diseases 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 230000007813 immunodeficiency Effects 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 201000008827 tuberculosis Diseases 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 208000032839 leukemia Diseases 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- RJHBEMWQVHECRN-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-(2-hydroxyethyl)-1,2,4-triazol-3-yl]-N-[(3,5-dichlorophenyl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=CC(=C1)Cl)Cl)CCO)F RJHBEMWQVHECRN-UHFFFAOYSA-N 0.000 claims description 5
- UEUHYADFJLGDOT-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-(2-methoxyethyl)-1,2,4-triazol-3-yl]-N-[(3,5-dichlorophenyl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=CC(=C1)Cl)Cl)CCOC)F UEUHYADFJLGDOT-UHFFFAOYSA-N 0.000 claims description 5
- ATHPHOTVXKFEPY-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-(cyclopropylmethyl)-1,2,4-triazol-3-yl]-N-[(2,6-dimethylpyridin-4-yl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=NC(=C1)C)C)CC1CC1)F ATHPHOTVXKFEPY-UHFFFAOYSA-N 0.000 claims description 5
- JRAAIJOWYXUKEC-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(2,6-diethylpyridin-4-yl)methyl]acetamide Chemical compound CCc1cc(CNC(=O)Cc2nc(nn2CC)-c2ccc(Cl)c(F)c2)cc(CC)n1 JRAAIJOWYXUKEC-UHFFFAOYSA-N 0.000 claims description 5
- HEHKQOUACYTSHL-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(2,6-dimethylpyridin-4-yl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=NC(=C1)C)C)CC)F HEHKQOUACYTSHL-UHFFFAOYSA-N 0.000 claims description 5
- JTKKHNXEEZJUSM-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(4,6-dimethylpyridin-2-yl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=NC(=CC(=C1)C)C)CC)F JTKKHNXEEZJUSM-UHFFFAOYSA-N 0.000 claims description 5
- BBCHFKQRWNLSIU-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[1-(2,6-dimethylpyridin-4-yl)cyclopropyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NC1(CC1)C1=CC(=NC(=C1)C)C)CC)F BBCHFKQRWNLSIU-UHFFFAOYSA-N 0.000 claims description 5
- VOSQFNCZFILMLL-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-pyrazolo[1,5-a]pyridin-3-ylacetamide Chemical compound CCn1nc(nc1CC(=O)Nc1cnn2ccccc12)-c1ccc(Cl)c(F)c1 VOSQFNCZFILMLL-UHFFFAOYSA-N 0.000 claims description 5
- HEHKQOUACYTSHL-XERRXZQWSA-N ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=NC(=C1)C([2H])([2H])[2H])C([2H])([2H])[2H])CC)F Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=NC(=C1)C([2H])([2H])[2H])C([2H])([2H])[2H])CC)F HEHKQOUACYTSHL-XERRXZQWSA-N 0.000 claims description 5
- 108091006027 G proteins Proteins 0.000 claims description 5
- 102000030782 GTP binding Human genes 0.000 claims description 5
- 108091000058 GTP-Binding Proteins 0.000 claims description 5
- KXQHQAGEYMUCIS-UHFFFAOYSA-N N-[[2,6-bis(difluoromethyl)pyridin-4-yl]methyl]-2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]acetamide Chemical compound CCn1nc(nc1CC(=O)NCc1cc(nc(c1)C(F)F)C(F)F)-c1ccc(Cl)c(F)c1 KXQHQAGEYMUCIS-UHFFFAOYSA-N 0.000 claims description 5
- 201000005746 Pituitary adenoma Diseases 0.000 claims description 5
- 206010061538 Pituitary tumour benign Diseases 0.000 claims description 5
- 201000002454 adrenal cortex cancer Diseases 0.000 claims description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 229940088597 hormone Drugs 0.000 claims description 5
- 239000005556 hormone Substances 0.000 claims description 5
- 230000003902 lesion Effects 0.000 claims description 5
- 208000021310 pituitary gland adenoma Diseases 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 5
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 4
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 4
- MWMRHPWCMPFTSF-UHFFFAOYSA-N 2-[3-(4-chloro-3-fluorophenyl)-5-[2-[(3,5-dichlorophenyl)methylamino]-2-oxoethyl]-1,2,4-triazol-1-yl]acetic acid Chemical compound OC(=O)Cn1nc(nc1CC(=O)NCc1cc(Cl)cc(Cl)c1)-c1ccc(Cl)c(F)c1 MWMRHPWCMPFTSF-UHFFFAOYSA-N 0.000 claims description 4
- DAUKGBMWFCNTNE-UHFFFAOYSA-N 2-[5-(4-chloro-3-ethoxyphenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(3,5-dichlorophenyl)methyl]acetamide Chemical compound CCOc1cc(ccc1Cl)-c1nc(CC(=O)NCc2cc(Cl)cc(Cl)c2)n(CC)n1 DAUKGBMWFCNTNE-UHFFFAOYSA-N 0.000 claims description 4
- WFCZKRVZCSVWPR-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-(cyclopropylmethyl)-1,2,4-triazol-3-yl]-N-(1H-indazol-5-ylmethyl)acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC=1C=C2C=NNC2=CC=1)CC1CC1)F WFCZKRVZCSVWPR-UHFFFAOYSA-N 0.000 claims description 4
- WFEHAUNTZSFKSI-FQEVSTJZSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-(cyclopropylmethyl)-1,2,4-triazol-3-yl]-N-[(1S)-2,3-dihydro-1H-inden-1-yl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)N[C@H]1CCC2=CC=CC=C12)CC1CC1)F WFEHAUNTZSFKSI-FQEVSTJZSA-N 0.000 claims description 4
- WXKOGBQRDNAHCW-IBGZPJMESA-N 2-[5-(4-chloro-3-fluorophenyl)-2-(cyclopropylmethyl)-1,2,4-triazol-3-yl]-N-[(5S)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)N[C@H]1CCC2=NC=CC=C21)CC1CC1)F WXKOGBQRDNAHCW-IBGZPJMESA-N 0.000 claims description 4
- CSWHMIVBFHTXIH-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-(cyclopropylmethyl)-1,2,4-triazol-3-yl]-N-[1-(2,6-dimethylpyridin-4-yl)cyclopropyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NC1(CC1)C1=CC(=NC(=C1)C)C)CC1CC1)F CSWHMIVBFHTXIH-UHFFFAOYSA-N 0.000 claims description 4
- QFWVFGOKMKNUIA-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-2,2-difluoro-N-[(2-methyl-3H-benzimidazol-5-yl)methyl]acetamide Chemical compound CCn1nc(nc1C(F)(F)C(=O)NCc1ccc2nc(C)[nH]c2c1)-c1ccc(Cl)c(F)c1 QFWVFGOKMKNUIA-UHFFFAOYSA-N 0.000 claims description 4
- ZNPZKFBZCPHYQD-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-(1H-indazol-7-ylmethyl)acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC=1C=CC=C2C=NNC=12)CC)F ZNPZKFBZCPHYQD-UHFFFAOYSA-N 0.000 claims description 4
- BHWSYRIYNSJHEJ-GOSISDBHSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(1R)-2,3-dihydro-1H-inden-1-yl]acetamide Chemical compound CCn1nc(nc1CC(=O)N[C@@H]1CCc2ccccc12)-c1ccc(Cl)c(F)c1 BHWSYRIYNSJHEJ-GOSISDBHSA-N 0.000 claims description 4
- DKVVHWHMNZBGIS-YLJYHZDGSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)N[C@H]1[C@@H](CC2=CC=CC=C12)O)CC)F DKVVHWHMNZBGIS-YLJYHZDGSA-N 0.000 claims description 4
- DKVVHWHMNZBGIS-FXAWDEMLSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)N[C@H]1[C@H](CC2=CC=CC=C12)O)CC)F DKVVHWHMNZBGIS-FXAWDEMLSA-N 0.000 claims description 4
- JMWWXWFUGHUVSM-QZTJIDSGSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(1R,3R)-3-hydroxy-2,3-dihydro-1H-inden-1-yl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)N[C@@H]1C[C@H](C2=CC=CC=C12)O)CC)F JMWWXWFUGHUVSM-QZTJIDSGSA-N 0.000 claims description 4
- JMWWXWFUGHUVSM-MSOLQXFVSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(1R,3S)-3-hydroxy-2,3-dihydro-1H-inden-1-yl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)N[C@@H]1C[C@@H](C2=CC=CC=C12)O)CC)F JMWWXWFUGHUVSM-MSOLQXFVSA-N 0.000 claims description 4
- BHWSYRIYNSJHEJ-SFHVURJKSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(1S)-2,3-dihydro-1H-inden-1-yl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)N[C@H]1CCC2=CC=CC=C12)CC)F BHWSYRIYNSJHEJ-SFHVURJKSA-N 0.000 claims description 4
- DKVVHWHMNZBGIS-XLIONFOSSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)N[C@@H]1[C@@H](CC2=CC=CC=C12)O)CC)F DKVVHWHMNZBGIS-XLIONFOSSA-N 0.000 claims description 4
- DKVVHWHMNZBGIS-PXNSSMCTSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)N[C@@H]1[C@H](CC2=CC=CC=C12)O)CC)F DKVVHWHMNZBGIS-PXNSSMCTSA-N 0.000 claims description 4
- JMWWXWFUGHUVSM-ZWKOTPCHSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(1S,3R)-3-hydroxy-2,3-dihydro-1H-inden-1-yl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)N[C@H]1C[C@H](C2=CC=CC=C12)O)CC)F JMWWXWFUGHUVSM-ZWKOTPCHSA-N 0.000 claims description 4
- JMWWXWFUGHUVSM-ROUUACIJSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(1S,3S)-3-hydroxy-2,3-dihydro-1H-inden-1-yl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)N[C@H]1C[C@@H](C2=CC=CC=C12)O)CC)F JMWWXWFUGHUVSM-ROUUACIJSA-N 0.000 claims description 4
- GWLILDNKMJOZPD-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(2,3-difluorophenyl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=C(C(=CC=C1)F)F)CC)F GWLILDNKMJOZPD-UHFFFAOYSA-N 0.000 claims description 4
- ALCOWUAMNRTZTI-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(2,6-dimethylpyridin-4-yl)methyl]-2,2-difluoroacetamide Chemical compound CCn1nc(nc1C(F)(F)C(=O)NCc1cc(C)nc(C)c1)-c1ccc(Cl)c(F)c1 ALCOWUAMNRTZTI-UHFFFAOYSA-N 0.000 claims description 4
- RKEMKKSHBFVRQF-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(2-oxo-3H-1,3-benzoxazol-5-yl)methyl]acetamide Chemical compound CCn1nc(nc1CC(=O)NCc1ccc2oc(=O)[nH]c2c1)-c1ccc(Cl)c(F)c1 RKEMKKSHBFVRQF-UHFFFAOYSA-N 0.000 claims description 4
- LFUIOQTZIADMHP-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(3,5-dichlorophenyl)methyl]-2,2-difluoroacetamide Chemical compound CCn1nc(nc1C(F)(F)C(=O)NCc1cc(Cl)cc(Cl)c1)-c1ccc(Cl)c(F)c1 LFUIOQTZIADMHP-UHFFFAOYSA-N 0.000 claims description 4
- NCZUYCJVXGSBKX-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(3,5-dichlorophenyl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=CC(=C1)Cl)Cl)CC)F NCZUYCJVXGSBKX-UHFFFAOYSA-N 0.000 claims description 4
- GGJCNSLCXIZENI-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(3,5-dimethoxyphenyl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=CC(=C1)OC)OC)CC)F GGJCNSLCXIZENI-UHFFFAOYSA-N 0.000 claims description 4
- XWXOBEZVHPDBNM-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(3,5-dimethylphenyl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=CC(=C1)C)C)CC)F XWXOBEZVHPDBNM-UHFFFAOYSA-N 0.000 claims description 4
- QQIUEOQFQJLJIH-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(3-fluorophenyl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=CC=C1)F)CC)F QQIUEOQFQJLJIH-UHFFFAOYSA-N 0.000 claims description 4
- DANUNXLQYBLYJY-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(3-fluorophenyl)methyl]propanamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)C(C(=O)NCC1=CC(=CC=C1)F)C)CC)F DANUNXLQYBLYJY-UHFFFAOYSA-N 0.000 claims description 4
- VMUUYRCHEOQFCV-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(3-methoxyphenyl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=CC=C1)OC)CC)F VMUUYRCHEOQFCV-UHFFFAOYSA-N 0.000 claims description 4
- GJRBPDPFNUUHAG-QGZVFWFLSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(4R)-3,4-dihydro-2H-chromen-4-yl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)N[C@@H]1CCOC2=C1C=CC=C2)CC)F GJRBPDPFNUUHAG-QGZVFWFLSA-N 0.000 claims description 4
- GJRBPDPFNUUHAG-KRWDZBQOSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)N[C@H]1CCOC2=C1C=CC=C2)CC)F GJRBPDPFNUUHAG-KRWDZBQOSA-N 0.000 claims description 4
- DDTRXRDOHPWFDU-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[[2-(difluoromethyl)pyridin-4-yl]methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=NC=C1)C(F)F)CC)F DDTRXRDOHPWFDU-UHFFFAOYSA-N 0.000 claims description 4
- RAEHKFCSFDFNLU-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[[2-(trifluoromethyl)pyridin-4-yl]methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=NC=C1)C(F)(F)F)CC)F RAEHKFCSFDFNLU-UHFFFAOYSA-N 0.000 claims description 4
- CZAQMMINPHTIPH-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-pyrazin-2-ylacetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NC1=NC=CN=C1)CC)F CZAQMMINPHTIPH-UHFFFAOYSA-N 0.000 claims description 4
- YNHGCITZABFDQC-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-methyl-1,2,4-triazol-3-yl]-N-(1H-indazol-5-ylmethyl)acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC=1C=C2C=NNC2=CC=1)C)F YNHGCITZABFDQC-UHFFFAOYSA-N 0.000 claims description 4
- GKOABZQGIZOKGE-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-methylsulfonyl-1,2,4-triazol-3-yl]-N-[(3-fluorophenyl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=CC=C1)F)S(=O)(=O)C)F GKOABZQGIZOKGE-UHFFFAOYSA-N 0.000 claims description 4
- UIEUWTISXJFSLD-UHFFFAOYSA-N 2-[5-(4-chloro-3-methoxyphenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(3,5-dichlorophenyl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=CC(=C1)Cl)Cl)CC)OC UIEUWTISXJFSLD-UHFFFAOYSA-N 0.000 claims description 4
- DYDFJXJNLCMSEY-FQEVSTJZSA-N 2-[5-(4-chloro-3-propan-2-yloxyphenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(1S)-2,3-dihydro-1H-inden-1-yl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)N[C@H]1CCC2=CC=CC=C12)CC)OC(C)C DYDFJXJNLCMSEY-FQEVSTJZSA-N 0.000 claims description 4
- ZYMIMVFAXPCBPH-UHFFFAOYSA-N 2-[5-(4-chloro-3-propan-2-yloxyphenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(3,5-dichlorophenyl)methyl]acetamide Chemical compound CCn1nc(nc1CC(=O)NCc1cc(Cl)cc(Cl)c1)-c1ccc(Cl)c(OC(C)C)c1 ZYMIMVFAXPCBPH-UHFFFAOYSA-N 0.000 claims description 4
- FIVPNCFYKZXJCL-UHFFFAOYSA-N 2-[5-(4-chloro-3-propan-2-yloxyphenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(4,6-dimethylpyridin-2-yl)methyl]acetamide Chemical compound CCn1nc(nc1CC(=O)NCc1cc(C)cc(C)n1)-c1ccc(Cl)c(OC(C)C)c1 FIVPNCFYKZXJCL-UHFFFAOYSA-N 0.000 claims description 4
- RXQZDGJPPAWSKA-IBGZPJMESA-N 2-[5-(4-chloro-3-propan-2-yloxyphenyl)-2-methyl-1,2,4-triazol-3-yl]-N-[(1S)-2,3-dihydro-1H-inden-1-yl]acetamide Chemical compound CC(C)Oc1cc(ccc1Cl)-c1nc(CC(=O)N[C@H]2CCc3ccccc23)n(C)n1 RXQZDGJPPAWSKA-IBGZPJMESA-N 0.000 claims description 4
- XBTJZUGDOOBYLP-UHFFFAOYSA-N 2-[5-(4-chloro-3-propan-2-yloxyphenyl)-2-methyl-1,2,4-triazol-3-yl]-N-[(2,6-dimethylpyridin-4-yl)methyl]acetamide Chemical compound CC(C)Oc1cc(ccc1Cl)-c1nc(CC(=O)NCc2cc(C)nc(C)c2)n(C)n1 XBTJZUGDOOBYLP-UHFFFAOYSA-N 0.000 claims description 4
- RHAYZHKTSHPFMQ-UHFFFAOYSA-N 2-[5-(4-chloro-3-propan-2-yloxyphenyl)-2-methyl-1,2,4-triazol-3-yl]-N-[(3,5-dichlorophenyl)methyl]acetamide Chemical compound CC(C)Oc1cc(ccc1Cl)-c1nc(CC(=O)NCc2cc(Cl)cc(Cl)c2)n(C)n1 RHAYZHKTSHPFMQ-UHFFFAOYSA-N 0.000 claims description 4
- LBTXFTWLYCRTJD-UHFFFAOYSA-N 2-[5-(4-chloro-3-propan-2-yloxyphenyl)-2-methyl-1,2,4-triazol-3-yl]-N-[(3-fluorophenyl)methyl]acetamide Chemical compound CC(C)Oc1cc(ccc1Cl)-c1nc(CC(=O)NCc2cccc(F)c2)n(C)n1 LBTXFTWLYCRTJD-UHFFFAOYSA-N 0.000 claims description 4
- GDVUCBIJSXHZPT-GOSISDBHSA-N 2-[5-(4-chloro-3-propan-2-yloxyphenyl)-2-methyl-1,2,4-triazol-3-yl]-N-[(4R)-3,4-dihydro-2H-chromen-4-yl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)N[C@@H]1CCOC2=C1C=CC=C2)C)OC(C)C GDVUCBIJSXHZPT-GOSISDBHSA-N 0.000 claims description 4
- GDVUCBIJSXHZPT-SFHVURJKSA-N 2-[5-(4-chloro-3-propan-2-yloxyphenyl)-2-methyl-1,2,4-triazol-3-yl]-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)N[C@H]1CCOC2=C1C=CC=C2)C)OC(C)C GDVUCBIJSXHZPT-SFHVURJKSA-N 0.000 claims description 4
- BIUXSKOICPTWIK-UHFFFAOYSA-N 2-[5-(4-cyanophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(3,5-dichlorophenyl)methyl]acetamide Chemical compound C(#N)C1=CC=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=CC(=C1)Cl)Cl)CC BIUXSKOICPTWIK-UHFFFAOYSA-N 0.000 claims description 4
- QBAKPNOXBHRHDI-UHFFFAOYSA-N 2-[5-[4-chloro-3-(2-methoxyethoxy)phenyl]-2-ethyl-1,2,4-triazol-3-yl]-N-[(3,5-dichlorophenyl)methyl]acetamide Chemical compound CCn1nc(nc1CC(=O)NCc1cc(Cl)cc(Cl)c1)-c1ccc(Cl)c(OCCOC)c1 QBAKPNOXBHRHDI-UHFFFAOYSA-N 0.000 claims description 4
- 208000003200 Adenoma Diseases 0.000 claims description 4
- 231100000699 Bacterial toxin Toxicity 0.000 claims description 4
- ALCOWUAMNRTZTI-XERRXZQWSA-N ClC1=C(C=C(C=C1)C1=NN(C(=N1)C(C(=O)NCC1=CC(=NC(=C1)C([2H])([2H])[2H])C([2H])([2H])[2H])(F)F)CC)F Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)C(C(=O)NCC1=CC(=NC(=C1)C([2H])([2H])[2H])C([2H])([2H])[2H])(F)F)CC)F ALCOWUAMNRTZTI-XERRXZQWSA-N 0.000 claims description 4
- XTBNUFHYSVRTPR-QGZVFWFLSA-N N-[(4R)-6-chloro-3,4-dihydro-2H-chromen-4-yl]-2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]acetamide Chemical compound ClC=1C=CC2=C([C@@H](CCO2)NC(CC2=NC(=NN2CC)C2=CC(=C(C=C2)Cl)F)=O)C=1 XTBNUFHYSVRTPR-QGZVFWFLSA-N 0.000 claims description 4
- DLGBBLHDLCMESB-LJQANCHMSA-N N-[(4R)-6-chloro-3,4-dihydro-2H-chromen-4-yl]-2-[5-(4-chloro-3-propan-2-yloxyphenyl)-2-ethyl-1,2,4-triazol-3-yl]acetamide Chemical compound ClC=1C=CC2=C([C@@H](CCO2)NC(CC2=NC(=NN2CC)C2=CC(=C(C=C2)Cl)OC(C)C)=O)C=1 DLGBBLHDLCMESB-LJQANCHMSA-N 0.000 claims description 4
- NKZMNFCKFXKJJX-GOSISDBHSA-N N-[(4R)-6-chloro-3,4-dihydro-2H-chromen-4-yl]-2-[5-(4-chloro-3-propan-2-yloxyphenyl)-2-methyl-1,2,4-triazol-3-yl]acetamide Chemical compound ClC=1C=CC2=C([C@@H](CCO2)NC(CC2=NC(=NN2C)C2=CC(=C(C=C2)Cl)OC(C)C)=O)C=1 NKZMNFCKFXKJJX-GOSISDBHSA-N 0.000 claims description 4
- DQFVVITXYROIAC-IBGZPJMESA-N N-[(4S)-6-chloro-3,4-dihydro-2H-chromen-4-yl]-2-[5-(4-chloro-3-fluorophenyl)-2-(cyclopropylmethyl)-1,2,4-triazol-3-yl]acetamide Chemical compound ClC=1C=CC2=C([C@H](CCO2)NC(CC2=NC(=NN2CC2CC2)C2=CC(=C(C=C2)Cl)F)=O)C=1 DQFVVITXYROIAC-IBGZPJMESA-N 0.000 claims description 4
- YYKZKSNMSWVJOM-INIZCTEOSA-N N-[(4S)-6-chloro-3,4-dihydro-2H-chromen-4-yl]-2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-2,2-difluoroacetamide Chemical compound ClC=1C=CC2=C([C@H](CCO2)NC(C(F)(F)C2=NC(=NN2CC)C2=CC(=C(C=C2)Cl)F)=O)C=1 YYKZKSNMSWVJOM-INIZCTEOSA-N 0.000 claims description 4
- XTBNUFHYSVRTPR-KRWDZBQOSA-N N-[(4S)-6-chloro-3,4-dihydro-2H-chromen-4-yl]-2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]acetamide Chemical compound ClC=1C=CC2=C([C@H](CCO2)NC(CC2=NC(=NN2CC)C2=CC(=C(C=C2)Cl)F)=O)C=1 XTBNUFHYSVRTPR-KRWDZBQOSA-N 0.000 claims description 4
- DLGBBLHDLCMESB-IBGZPJMESA-N N-[(4S)-6-chloro-3,4-dihydro-2H-chromen-4-yl]-2-[5-(4-chloro-3-propan-2-yloxyphenyl)-2-ethyl-1,2,4-triazol-3-yl]acetamide Chemical compound ClC=1C=CC2=C([C@H](CCO2)NC(CC2=NC(=NN2CC)C2=CC(=C(C=C2)Cl)OC(C)C)=O)C=1 DLGBBLHDLCMESB-IBGZPJMESA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 230000001780 adrenocortical effect Effects 0.000 claims description 4
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 4
- 239000000688 bacterial toxin Substances 0.000 claims description 4
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 claims description 4
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 claims description 4
- HEHKQOUACYTSHL-MKQHWYKPSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-2,2-dideuterio-N-[dideuterio-(2,6-dimethylpyridin-4-yl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)C(C(=O)NC([2H])([2H])C1=CC(=NC(=C1)C)C)([2H])[2H])CC)F HEHKQOUACYTSHL-MKQHWYKPSA-N 0.000 claims description 3
- XTJGSEKYHZJRCA-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-(1H-indazol-5-ylmethyl)acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC=1C=C2C=NNC2=CC=1)CC)F XTJGSEKYHZJRCA-UHFFFAOYSA-N 0.000 claims description 3
- KCXMNNCEGZXUMX-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(3-ethoxyphenyl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=CC=C1)OCC)CC)F KCXMNNCEGZXUMX-UHFFFAOYSA-N 0.000 claims description 3
- YWDSOVBEPYLKRR-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(4-methoxyphenyl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC=C(C=C1)OC)CC)F YWDSOVBEPYLKRR-UHFFFAOYSA-N 0.000 claims description 3
- MPDJJYGIVFGGNG-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-methyl-1,2,4-triazol-3-yl]-N-[(3,5-dichlorophenyl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=CC(=C1)Cl)Cl)C)F MPDJJYGIVFGGNG-UHFFFAOYSA-N 0.000 claims description 3
- VPEVFUZDDASHAI-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-methyl-1,2,4-triazol-3-yl]-N-[(3-fluorophenyl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=CC=C1)F)C)F VPEVFUZDDASHAI-UHFFFAOYSA-N 0.000 claims description 3
- QGYLSIZWIFSBRS-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-methyl-1,2,4-triazol-3-yl]-N-[(3-methoxyphenyl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=CC=C1)OC)C)F QGYLSIZWIFSBRS-UHFFFAOYSA-N 0.000 claims description 3
- NSCAJEHRKUYFEH-UHFFFAOYSA-N 2-[5-(4-chloro-3-propan-2-yloxyphenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(2,6-dimethylpyridin-4-yl)methyl]acetamide Chemical compound CCn1nc(nc1CC(=O)NCc1cc(C)nc(C)c1)-c1ccc(Cl)c(OC(C)C)c1 NSCAJEHRKUYFEH-UHFFFAOYSA-N 0.000 claims description 3
- BQPAIKZAAHMPLE-UHFFFAOYSA-N 2-[5-(4-chloro-3-propan-2-yloxyphenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(3-cyanophenyl)methyl]acetamide Chemical compound CCn1nc(nc1CC(=O)NCc1cccc(c1)C#N)-c1ccc(Cl)c(OC(C)C)c1 BQPAIKZAAHMPLE-UHFFFAOYSA-N 0.000 claims description 3
- QWVIJMDEFZTQQQ-IBGZPJMESA-N 2-[5-(4-chloro-3-propan-2-yloxyphenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)N[C@H]1CCOC2=C1C=CC=C2)CC)OC(C)C QWVIJMDEFZTQQQ-IBGZPJMESA-N 0.000 claims description 3
- WUJVHRRWOGVOQK-IBGZPJMESA-N 2-[5-(4-chloro-3-propan-2-yloxyphenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(5S)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)N[C@H]1CCC2=NC=CC=C21)CC)OC(C)C WUJVHRRWOGVOQK-IBGZPJMESA-N 0.000 claims description 3
- KRNSYSYRLQDHDK-UHFFFAOYSA-N 6,7-dihydro-5h-cyclopenta[b]pyridine Chemical compound C1=CN=C2CCCC2=C1 KRNSYSYRLQDHDK-UHFFFAOYSA-N 0.000 claims description 3
- 206010001233 Adenoma benign Diseases 0.000 claims description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 3
- OQOKYPGYFNIEBB-UHFFFAOYSA-N CCCCN1N=C(C(C=C2)=CC(F)=C2Cl)N=C1CC(NCC1=CC(Cl)=CC(Cl)=C1)=O Chemical compound CCCCN1N=C(C(C=C2)=CC(F)=C2Cl)N=C1CC(NCC1=CC(Cl)=CC(Cl)=C1)=O OQOKYPGYFNIEBB-UHFFFAOYSA-N 0.000 claims description 3
- 206010064571 Gene mutation Diseases 0.000 claims description 3
- HLWWRMNUMIMBTQ-UHFFFAOYSA-N N-[(3,5-dichlorophenyl)methyl]-2-[2-ethyl-5-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]acetamide Chemical compound ClC=1C=C(C=C(C=1)Cl)CNC(CC1=NC(=NN1CC)C1=CC=C(C=C1)OC(F)(F)F)=O HLWWRMNUMIMBTQ-UHFFFAOYSA-N 0.000 claims description 3
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 3
- 230000001960 triggered effect Effects 0.000 claims description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 258
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 165
- 238000005481 NMR spectroscopy Methods 0.000 description 123
- 238000000034 method Methods 0.000 description 123
- IVOMOUWHDPKRLL-KQYNXXCUSA-M 3',5'-cyclic AMP(1-) Chemical compound C([C@H]1O2)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-M 0.000 description 118
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 111
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 110
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 110
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 description 107
- 239000000203 mixture Substances 0.000 description 93
- 239000000243 solution Substances 0.000 description 78
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 63
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 63
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 61
- 210000004027 cell Anatomy 0.000 description 59
- 230000002829 reductive effect Effects 0.000 description 56
- 230000000694 effects Effects 0.000 description 49
- 239000007787 solid Substances 0.000 description 49
- 108010029485 Protein Isoforms Proteins 0.000 description 47
- 102000001708 Protein Isoforms Human genes 0.000 description 47
- 238000006243 chemical reaction Methods 0.000 description 47
- 239000003814 drug Substances 0.000 description 47
- 239000012044 organic layer Substances 0.000 description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 35
- 230000004913 activation Effects 0.000 description 34
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 32
- 239000012043 crude product Substances 0.000 description 32
- 229940124597 therapeutic agent Drugs 0.000 description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
- 239000000706 filtrate Substances 0.000 description 22
- 235000011054 acetic acid Nutrition 0.000 description 21
- MNWLUHFHWDJGRA-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]acetic acid Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)O)CC)F MNWLUHFHWDJGRA-UHFFFAOYSA-N 0.000 description 20
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 20
- 101150114644 Rapgef3 gene Proteins 0.000 description 20
- 238000003818 flash chromatography Methods 0.000 description 20
- UEUBEPHODYIOJJ-UHFFFAOYSA-N (2,6-dimethylpyridin-4-yl)methanamine Chemical compound CC1=CC(CN)=CC(C)=N1 UEUBEPHODYIOJJ-UHFFFAOYSA-N 0.000 description 19
- 230000001965 increasing effect Effects 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 239000012267 brine Substances 0.000 description 18
- 239000003208 petroleum Substances 0.000 description 18
- 150000003384 small molecules Chemical class 0.000 description 18
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
- 230000009467 reduction Effects 0.000 description 17
- 108010049894 Cyclic AMP-Dependent Protein Kinases Proteins 0.000 description 16
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 16
- 102000030621 adenylate cyclase Human genes 0.000 description 16
- 108060000200 adenylate cyclase Proteins 0.000 description 16
- 230000036961 partial effect Effects 0.000 description 16
- 108090000623 proteins and genes Proteins 0.000 description 16
- 230000004044 response Effects 0.000 description 16
- 239000000725 suspension Substances 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- 238000002474 experimental method Methods 0.000 description 14
- 238000004519 manufacturing process Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 102000005636 Cyclic AMP Response Element-Binding Protein Human genes 0.000 description 13
- 108010045171 Cyclic AMP Response Element-Binding Protein Proteins 0.000 description 13
- 230000011496 cAMP-mediated signaling Effects 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 13
- 229940079593 drug Drugs 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 238000009472 formulation Methods 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 208000031513 cyst Diseases 0.000 description 11
- 229940002612 prodrug Drugs 0.000 description 11
- 239000000651 prodrug Substances 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- ICIJWOWQUHHETJ-UHFFFAOYSA-N (3,5-dichlorophenyl)methanamine Chemical compound NCC1=CC(Cl)=CC(Cl)=C1 ICIJWOWQUHHETJ-UHFFFAOYSA-N 0.000 description 10
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 10
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 10
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 10
- 230000003197 catalytic effect Effects 0.000 description 10
- 230000037416 cystogenesis Effects 0.000 description 10
- 230000006806 disease prevention Effects 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 101000988419 Homo sapiens cAMP-specific 3',5'-cyclic phosphodiesterase 4D Proteins 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 230000001419 dependent effect Effects 0.000 description 9
- 125000000623 heterocyclic group Chemical group 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- 101000988423 Homo sapiens cAMP-specific 3',5'-cyclic phosphodiesterase 4C Proteins 0.000 description 8
- 102100029169 cAMP-specific 3',5'-cyclic phosphodiesterase 4C Human genes 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 8
- 208000006155 precocious puberty Diseases 0.000 description 8
- 208000029141 primary pigmented nodular adrenocortical disease Diseases 0.000 description 8
- 230000001105 regulatory effect Effects 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- ZRAJJMQKWHUYCD-UHFFFAOYSA-N 2-[5-(4-chloro-3-propan-2-yloxyphenyl)-2-ethyl-1,2,4-triazol-3-yl]acetic acid Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)O)CC)OC(C)C ZRAJJMQKWHUYCD-UHFFFAOYSA-N 0.000 description 7
- 206010011732 Cyst Diseases 0.000 description 7
- 101001098805 Homo sapiens cAMP-specific 3',5'-cyclic phosphodiesterase 4A Proteins 0.000 description 7
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 102100037092 cAMP-specific 3',5'-cyclic phosphodiesterase 4A Human genes 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 238000011161 development Methods 0.000 description 7
- 230000018109 developmental process Effects 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 239000005457 ice water Substances 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000012453 solvate Substances 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 239000003039 volatile agent Substances 0.000 description 7
- QVSVMNXRLWSNGS-UHFFFAOYSA-N (3-fluorophenyl)methanamine Chemical compound NCC1=CC=CC(F)=C1 QVSVMNXRLWSNGS-UHFFFAOYSA-N 0.000 description 6
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 6
- 101000988424 Homo sapiens cAMP-specific 3',5'-cyclic phosphodiesterase 4B Proteins 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 239000000556 agonist Substances 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- 102100029168 cAMP-specific 3',5'-cyclic phosphodiesterase 4B Human genes 0.000 description 6
- 102100029170 cAMP-specific 3',5'-cyclic phosphodiesterase 4D Human genes 0.000 description 6
- 230000001276 controlling effect Effects 0.000 description 6
- 238000007824 enzymatic assay Methods 0.000 description 6
- 239000012091 fetal bovine serum Substances 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- 210000003734 kidney Anatomy 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 230000026731 phosphorylation Effects 0.000 description 6
- 238000006366 phosphorylation reaction Methods 0.000 description 6
- 230000035755 proliferation Effects 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 230000000638 stimulation Effects 0.000 description 6
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 6
- DLMNYSHJWHCTOD-QMMMGPOBSA-N (4s)-6-chloro-3,4-dihydro-2h-chromen-4-amine Chemical compound C1=C(Cl)C=C2[C@@H](N)CCOC2=C1 DLMNYSHJWHCTOD-QMMMGPOBSA-N 0.000 description 5
- GLPNRIIXILRHHU-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-(cyclopropylmethyl)-1,2,4-triazol-3-yl]acetic acid Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)O)CC1CC1)F GLPNRIIXILRHHU-UHFFFAOYSA-N 0.000 description 5
- GPJPWBLCSMTTTG-UHFFFAOYSA-N 2-[5-(4-chloro-3-propan-2-yloxyphenyl)-2-methyl-1,2,4-triazol-3-yl]acetic acid Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)O)C)OC(C)C GPJPWBLCSMTTTG-UHFFFAOYSA-N 0.000 description 5
- RBORURQQJIQWBS-UHFFFAOYSA-N 6-(6-amino-8-bromopurin-9-yl)-2-hydroxy-2-sulfanylidene-4a,6,7,7a-tetrahydro-4h-furo[3,2-d][1,3,2]dioxaphosphinin-7-ol Chemical compound O1C2COP(O)(=S)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1Br RBORURQQJIQWBS-UHFFFAOYSA-N 0.000 description 5
- 102100040794 Beta-1 adrenergic receptor Human genes 0.000 description 5
- SUZLHDUTVMZSEV-UHFFFAOYSA-N Deoxycoleonol Natural products C12C(=O)CC(C)(C=C)OC2(C)C(OC(=O)C)C(O)C2C1(C)C(O)CCC2(C)C SUZLHDUTVMZSEV-UHFFFAOYSA-N 0.000 description 5
- 206010019280 Heart failures Diseases 0.000 description 5
- 102000012046 Hepatocyte Nuclear Factor 1-beta Human genes 0.000 description 5
- 108010061414 Hepatocyte Nuclear Factor 1-beta Proteins 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 102100036142 Polycystin-2 Human genes 0.000 description 5
- HUOFUOCSQCYFPW-UHFFFAOYSA-N [4-(trifluoromethoxy)phenyl]boronic acid Chemical compound OB(O)C1=CC=C(OC(F)(F)F)C=C1 HUOFUOCSQCYFPW-UHFFFAOYSA-N 0.000 description 5
- 102000030484 alpha-2 Adrenergic Receptor Human genes 0.000 description 5
- 108020004101 alpha-2 Adrenergic Receptor Proteins 0.000 description 5
- 206010003119 arrhythmia Diseases 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 108010014494 beta-1 Adrenergic Receptors Proteins 0.000 description 5
- 239000013592 cell lysate Substances 0.000 description 5
- 230000004663 cell proliferation Effects 0.000 description 5
- OHCQJHSOBUTRHG-UHFFFAOYSA-N colforsin Natural products OC12C(=O)CC(C)(C=C)OC1(C)C(OC(=O)C)C(O)C1C2(C)C(O)CCC1(C)C OHCQJHSOBUTRHG-UHFFFAOYSA-N 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- MSXPLFVPODYABE-UHFFFAOYSA-N ethyl 2-[3-(4-chloro-3-fluorophenyl)-1H-1,2,4-triazol-5-yl]acetate Chemical compound ClC1=C(C=C(C=C1)C1=NNC(=N1)CC(=O)OCC)F MSXPLFVPODYABE-UHFFFAOYSA-N 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical class S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 238000011144 upstream manufacturing Methods 0.000 description 5
- XJEVHMGJSYVQBQ-VIFPVBQESA-N (1s)-2,3-dihydro-1h-inden-1-amine Chemical compound C1=CC=C2[C@@H](N)CCC2=C1 XJEVHMGJSYVQBQ-VIFPVBQESA-N 0.000 description 4
- DLMNYSHJWHCTOD-MRVPVSSYSA-N (4r)-6-chloro-3,4-dihydro-2h-chromen-4-amine Chemical compound C1=C(Cl)C=C2[C@H](N)CCOC2=C1 DLMNYSHJWHCTOD-MRVPVSSYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 4
- 102100032610 Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas Human genes 0.000 description 4
- 208000031886 HIV Infections Diseases 0.000 description 4
- 208000037357 HIV infectious disease Diseases 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 102000004310 Ion Channels Human genes 0.000 description 4
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 4
- 229930182816 L-glutamine Natural products 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 101150057959 Rapgef4 gene Proteins 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- 102000011923 Thyrotropin Human genes 0.000 description 4
- 108010061174 Thyrotropin Proteins 0.000 description 4
- UEUBEPHODYIOJJ-WFGJKAKNSA-N [2,6-bis(trideuteriomethyl)pyridin-4-yl]methanamine Chemical compound C(C1=NC(=CC(=C1)CN)C([2H])([2H])[2H])([2H])([2H])[2H] UEUBEPHODYIOJJ-WFGJKAKNSA-N 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 4
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 230000003491 cAMP production Effects 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 229960002896 clonidine Drugs 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 4
- 238000004806 packaging method and process Methods 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000028327 secretion Effects 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 229960005322 streptomycin Drugs 0.000 description 4
- LCOFMNJNNXWKOC-QMMMGPOBSA-N (4s)-3,4-dihydro-2h-chromen-4-amine Chemical compound C1=CC=C2[C@@H](N)CCOC2=C1 LCOFMNJNNXWKOC-QMMMGPOBSA-N 0.000 description 3
- BUJYYGHIOAAFOO-ZETCQYMHSA-N (5s)-6,7-dihydro-5h-cyclopenta[b]pyridin-5-amine Chemical compound C1=CC=C2[C@@H](N)CCC2=N1 BUJYYGHIOAAFOO-ZETCQYMHSA-N 0.000 description 3
- 125000001414 1,2,4-triazol-5-yl group Chemical group [H]N1N=C([H])N=C1[*] 0.000 description 3
- JIIGQRQHGWWPAM-UHFFFAOYSA-N 1-(2,6-dimethylpyridin-4-yl)cyclopropan-1-amine Chemical compound CC1=NC(C)=CC(C2(N)CC2)=C1 JIIGQRQHGWWPAM-UHFFFAOYSA-N 0.000 description 3
- AQMGFFLBKVOJLW-UHFFFAOYSA-N 1h-indazol-5-ylmethanamine Chemical compound NCC1=CC=C2NN=CC2=C1 AQMGFFLBKVOJLW-UHFFFAOYSA-N 0.000 description 3
- KMQVCYOPBMKRKH-UHFFFAOYSA-N 2,4-dimethyl-1-oxidopyridin-1-ium Chemical compound CC1=CC=[N+]([O-])C(C)=C1 KMQVCYOPBMKRKH-UHFFFAOYSA-N 0.000 description 3
- UELNIBCQRTXNJC-UHFFFAOYSA-N 2-[3-(4-chloro-3-fluorophenyl)-1H-1,2,4-triazol-5-yl]acetic acid Chemical compound ClC1=C(C=C(C=C1)C1=NNC(=N1)CC(=O)O)F UELNIBCQRTXNJC-UHFFFAOYSA-N 0.000 description 3
- SMMZVIWXDRDHCS-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-2,2-difluoroacetic acid Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)C(C(=O)O)(F)F)CC)F SMMZVIWXDRDHCS-UHFFFAOYSA-N 0.000 description 3
- HLYJUMJVSBDQBK-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-methyl-1,2,4-triazol-3-yl]acetic acid Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)O)C)F HLYJUMJVSBDQBK-UHFFFAOYSA-N 0.000 description 3
- AQFRWFUYNPZERK-UHFFFAOYSA-N 4,6-dimethylpyridine-2-carbonitrile Chemical compound CC1=CC(C)=NC(C#N)=C1 AQFRWFUYNPZERK-UHFFFAOYSA-N 0.000 description 3
- IAXRWJAGFOBLOP-UHFFFAOYSA-N 4-bromo-2,6-bis(difluoromethyl)pyridine Chemical compound FC(F)c1cc(Br)cc(n1)C(F)F IAXRWJAGFOBLOP-UHFFFAOYSA-N 0.000 description 3
- CUDCTXANKYTJTD-UHFFFAOYSA-N 4-bromopyridine-2,6-dicarbaldehyde Chemical compound BrC1=CC(C=O)=NC(C=O)=C1 CUDCTXANKYTJTD-UHFFFAOYSA-N 0.000 description 3
- MONABXVRTZNUSL-UHFFFAOYSA-N 4-chloro-3-propan-2-yloxybenzonitrile Chemical compound CC(C)Oc1cc(ccc1Cl)C#N MONABXVRTZNUSL-UHFFFAOYSA-N 0.000 description 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- AEOBEOJCBAYXBA-UHFFFAOYSA-N A2P5P Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1OP(O)(O)=O AEOBEOJCBAYXBA-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 208000035473 Communicable disease Diseases 0.000 description 3
- 102400000739 Corticotropin Human genes 0.000 description 3
- 101800000414 Corticotropin Proteins 0.000 description 3
- 208000026292 Cystic Kidney disease Diseases 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- INJOMKTZOLKMBF-UHFFFAOYSA-N Guanfacine Chemical compound NC(=N)NC(=O)CC1=C(Cl)C=CC=C1Cl INJOMKTZOLKMBF-UHFFFAOYSA-N 0.000 description 3
- 101001074444 Homo sapiens Polycystin-1 Proteins 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 206010020880 Hypertrophy Diseases 0.000 description 3
- 102000009151 Luteinizing Hormone Human genes 0.000 description 3
- 108010073521 Luteinizing Hormone Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 102000003982 Parathyroid hormone Human genes 0.000 description 3
- 108090000445 Parathyroid hormone Proteins 0.000 description 3
- 102100036143 Polycystin-1 Human genes 0.000 description 3
- 206010038423 Renal cyst Diseases 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000006793 arrhythmia Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 102000014992 beta1-adrenergic receptor activity proteins Human genes 0.000 description 3
- 108040006808 beta1-adrenergic receptor activity proteins Proteins 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 210000004413 cardiac myocyte Anatomy 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229960000258 corticotropin Drugs 0.000 description 3
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 3
- 230000001086 cytosolic effect Effects 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 238000009792 diffusion process Methods 0.000 description 3
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 3
- 229960002986 dinoprostone Drugs 0.000 description 3
- 230000003828 downregulation Effects 0.000 description 3
- 238000007876 drug discovery Methods 0.000 description 3
- 239000012636 effector Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- CASGWNHLXXQWTE-UHFFFAOYSA-N ethyl 2-[3-(4-chloro-3-propan-2-yloxyphenyl)-1H-1,2,4-triazol-5-yl]acetate Chemical compound ClC1=C(C=C(C=C1)C1=NNC(=N1)CC(=O)OCC)OC(C)C CASGWNHLXXQWTE-UHFFFAOYSA-N 0.000 description 3
- ZYUKUFCWXQGQSL-UHFFFAOYSA-N ethyl 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-2,2-difluoroacetate Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)C(C(=O)OCC)(F)F)CC)F ZYUKUFCWXQGQSL-UHFFFAOYSA-N 0.000 description 3
- 229960002048 guanfacine Drugs 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 229940040129 luteinizing hormone Drugs 0.000 description 3
- 230000002474 noradrenergic effect Effects 0.000 description 3
- 239000000199 parathyroid hormone Substances 0.000 description 3
- 229960001319 parathyroid hormone Drugs 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 230000003518 presynaptic effect Effects 0.000 description 3
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000003053 toxin Substances 0.000 description 3
- 231100000765 toxin Toxicity 0.000 description 3
- 108700012359 toxins Proteins 0.000 description 3
- 230000026683 transduction Effects 0.000 description 3
- 238000010361 transduction Methods 0.000 description 3
- DXEATJQGQHDURZ-MOSHPQCFSA-N (1z)-2-(5-tert-butyl-1,2-oxazol-3-yl)-n-(3-chloroanilino)-2-oxoethanimidoyl cyanide Chemical compound O1C(C(C)(C)C)=CC(C(=O)C(=N/NC=2C=C(Cl)C=CC=2)\C#N)=N1 DXEATJQGQHDURZ-MOSHPQCFSA-N 0.000 description 2
- WRFUQYBYHXGWPU-UHFFFAOYSA-N (2,6-diethylpyridin-4-yl)methanamine Chemical compound C(C)C1=NC(=CC(=C1)CN)CC WRFUQYBYHXGWPU-UHFFFAOYSA-N 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- GRRIMVWABNHKBX-UHFFFAOYSA-N (3-methoxyphenyl)methanamine Chemical group COC1=CC=CC(CN)=C1 GRRIMVWABNHKBX-UHFFFAOYSA-N 0.000 description 2
- UBRILBGVODOPFV-UHFFFAOYSA-N (4,6-dimethylpyridin-2-yl)methanamine Chemical compound CC1=CC(C)=NC(CN)=C1 UBRILBGVODOPFV-UHFFFAOYSA-N 0.000 description 2
- LCOFMNJNNXWKOC-MRVPVSSYSA-N (4r)-3,4-dihydro-2h-chromen-4-amine Chemical compound C1=CC=C2[C@H](N)CCOC2=C1 LCOFMNJNNXWKOC-MRVPVSSYSA-N 0.000 description 2
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 2
- ZBIWCHCUXYHWIE-GOSISDBHSA-N (R)-N-(6-chloro-2,3-dihydrochromen-4-ylidene)-2-methylpropane-2-sulfinamide Chemical compound ClC=1C=C2C(CCOC2=CC=1)=N[S@](=O)C(C)(C)C ZBIWCHCUXYHWIE-GOSISDBHSA-N 0.000 description 2
- DGXXGWIFHGQYEN-ADLMAVQZSA-N (R)-N-[(4R)-6-chloro-3,4-dihydro-2H-chromen-4-yl]-2-methylpropane-2-sulfinamide Chemical compound ClC=1C=C2[C@@H](CCOC2=CC=1)N[S@](=O)C(C)(C)C DGXXGWIFHGQYEN-ADLMAVQZSA-N 0.000 description 2
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 2
- 125000001376 1,2,4-triazolyl group Chemical class N1N=C(N=C1)* 0.000 description 2
- JYYNAJVZFGKDEQ-UHFFFAOYSA-N 2,4-Dimethylpyridine Chemical compound CC1=CC=NC(C)=C1 JYYNAJVZFGKDEQ-UHFFFAOYSA-N 0.000 description 2
- TXBLTSMCEXEFMI-WFGJKAKNSA-N 2,6-bis(trideuteriomethyl)pyridine-4-carbonitrile Chemical compound C(C=1C=C(C#N)C=C(N=1)C([2H])([2H])[2H])([2H])([2H])[2H] TXBLTSMCEXEFMI-WFGJKAKNSA-N 0.000 description 2
- NWNOPLVJKFENMY-UHFFFAOYSA-N 2,6-diethylpyridine-4-carbonitrile Chemical compound CCC1=CC(C#N)=CC(CC)=N1 NWNOPLVJKFENMY-UHFFFAOYSA-N 0.000 description 2
- ZJSCTEHSZAISNI-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-(2-methoxyethyl)-1,2,4-triazol-3-yl]acetic acid Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)O)CCOC)F ZJSCTEHSZAISNI-UHFFFAOYSA-N 0.000 description 2
- IPOVOSHRRIJKBR-UHFFFAOYSA-N 2-ethylpropanedioyl dichloride Chemical compound CCC(C(Cl)=O)C(Cl)=O IPOVOSHRRIJKBR-UHFFFAOYSA-N 0.000 description 2
- CESUXLKAADQNTB-ZETCQYMHSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](N)=O CESUXLKAADQNTB-ZETCQYMHSA-N 0.000 description 2
- GWZQVECNESCSKR-UHFFFAOYSA-N 4-chloro-3-fluorobenzonitrile Chemical compound FC1=CC(C#N)=CC=C1Cl GWZQVECNESCSKR-UHFFFAOYSA-N 0.000 description 2
- 208000006468 Adrenal Cortex Neoplasms Diseases 0.000 description 2
- 239000000275 Adrenocorticotropic Hormone Substances 0.000 description 2
- 102100022455 Adrenocorticotropic hormone receptor Human genes 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 102100032187 Androgen receptor Human genes 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- 208000023328 Basedow disease Diseases 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 108010049048 Cholera Toxin Proteins 0.000 description 2
- 102000009016 Cholera Toxin Human genes 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 102100036367 Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A Human genes 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 208000023699 Familial male-limited precocious puberty Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 208000015023 Graves' disease Diseases 0.000 description 2
- 108010051696 Growth Hormone Proteins 0.000 description 2
- 101001072029 Homo sapiens Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A Proteins 0.000 description 2
- 208000037147 Hypercalcaemia Diseases 0.000 description 2
- 208000029663 Hypophosphatemia Diseases 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 101100000866 Mus musculus Mc2r gene Proteins 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 2
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 2
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 2
- 108010016076 Octreotide Proteins 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102000006877 Pituitary Hormones Human genes 0.000 description 2
- 108010047386 Pituitary Hormones Proteins 0.000 description 2
- 101710146367 Polycystin-1 Proteins 0.000 description 2
- 101710146368 Polycystin-2 Proteins 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 101710203837 Replication-associated protein Proteins 0.000 description 2
- 102100038803 Somatotropin Human genes 0.000 description 2
- 229910000831 Steel Inorganic materials 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 102000018614 Uromodulin Human genes 0.000 description 2
- 108010027007 Uromodulin Proteins 0.000 description 2
- 230000001594 aberrant effect Effects 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 229960002122 acebutolol Drugs 0.000 description 2
- GOEMGAFJFRBGGG-UHFFFAOYSA-N acebutolol Chemical compound CCCC(=O)NC1=CC=C(OCC(O)CNC(C)C)C(C(C)=O)=C1 GOEMGAFJFRBGGG-UHFFFAOYSA-N 0.000 description 2
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229960005305 adenosine Drugs 0.000 description 2
- 210000004404 adrenal cortex Anatomy 0.000 description 2
- 201000005255 adrenal gland hyperfunction Diseases 0.000 description 2
- 239000000384 adrenergic alpha-2 receptor agonist Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- 108010080146 androgen receptors Proteins 0.000 description 2
- 230000001548 androgenic effect Effects 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 229960002274 atenolol Drugs 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 239000002876 beta blocker Substances 0.000 description 2
- 229940097320 beta blocking agent Drugs 0.000 description 2
- 229960004324 betaxolol Drugs 0.000 description 2
- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 description 2
- 230000031018 biological processes and functions Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 229960002781 bisoprolol Drugs 0.000 description 2
- VHYCDWMUTMEGQY-UHFFFAOYSA-N bisoprolol Chemical compound CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 VHYCDWMUTMEGQY-UHFFFAOYSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 125000002843 carboxylic acid group Chemical group 0.000 description 2
- 230000005961 cardioprotection Effects 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 229940000425 combination drug Drugs 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 229920006237 degradable polymer Polymers 0.000 description 2
- HRLIOXLXPOHXTA-NSHDSACASA-N dexmedetomidine Chemical compound C1([C@@H](C)C=2C(=C(C)C=CC=2)C)=CN=C[N]1 HRLIOXLXPOHXTA-NSHDSACASA-N 0.000 description 2
- 229960004253 dexmedetomidine Drugs 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 2
- PBWZKZYHONABLN-UHFFFAOYSA-N difluoroacetic acid Chemical compound OC(=O)C(F)F PBWZKZYHONABLN-UHFFFAOYSA-N 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 230000008482 dysregulation Effects 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- MXACWDINKGTJMJ-UHFFFAOYSA-N ethyl 2-[5-(4-chloro-3-fluorophenyl)-2-(2-methoxyethyl)-1,2,4-triazol-3-yl]acetate Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)OCC)CCOC)F MXACWDINKGTJMJ-UHFFFAOYSA-N 0.000 description 2
- JEWURNFYKIBHCA-UHFFFAOYSA-N ethyl 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]acetate Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)OCC)CC)F JEWURNFYKIBHCA-UHFFFAOYSA-N 0.000 description 2
- CNJOCDMTQCKZED-UHFFFAOYSA-N ethyl 2-[5-(4-chloro-3-fluorophenyl)-2-methyl-1,2,4-triazol-3-yl]acetate Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)OCC)C)F CNJOCDMTQCKZED-UHFFFAOYSA-N 0.000 description 2
- LDPVXPWXPZWTMN-UHFFFAOYSA-N ethyl 4-[3-(4-chloro-3-fluorophenyl)-5-[2-[(3,5-dichlorophenyl)methylamino]-2-oxoethyl]-1,2,4-triazol-1-yl]butanoate Chemical compound CCOC(=O)CCCn1nc(nc1CC(=O)NCc1cc(Cl)cc(Cl)c1)-c1ccc(Cl)c(F)c1 LDPVXPWXPZWTMN-UHFFFAOYSA-N 0.000 description 2
- ATHJDKZSAUWPRC-UHFFFAOYSA-N ethyl 4-chloro-3-fluorobenzenecarboximidate hydrochloride Chemical compound Cl.ClC1=C(C=C(C(OCC)=N)C=C1)F ATHJDKZSAUWPRC-UHFFFAOYSA-N 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 201000003872 goiter Diseases 0.000 description 2
- 239000000122 growth hormone Substances 0.000 description 2
- 102000048135 human PDE4D Human genes 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 208000013403 hyperactivity Diseases 0.000 description 2
- 230000000148 hypercalcaemia Effects 0.000 description 2
- 208000030915 hypercalcemia disease Diseases 0.000 description 2
- 239000000960 hypophysis hormone Substances 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000000415 inactivating effect Effects 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 210000003292 kidney cell Anatomy 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- OYQYURBKDIGJKZ-UHFFFAOYSA-N methyl 2-[3-(4-chloro-3-fluorophenyl)-5-[2-[(3,5-dichlorophenyl)methylamino]-2-oxoethyl]-1,2,4-triazol-1-yl]acetate Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(NCC1=CC(=CC(=C1)Cl)Cl)=O)CC(=O)OC)F OYQYURBKDIGJKZ-UHFFFAOYSA-N 0.000 description 2
- DWMBWWPKAYJLNG-UHFFFAOYSA-N methyl 3-[3-(4-chloro-3-fluorophenyl)-5-[2-[(3,5-dichlorophenyl)methylamino]-2-oxoethyl]-1,2,4-triazol-1-yl]propanoate Chemical compound COC(=O)CCn1nc(nc1CC(=O)NCc1cc(Cl)cc(Cl)c1)-c1ccc(Cl)c(F)c1 DWMBWWPKAYJLNG-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 229960002237 metoprolol Drugs 0.000 description 2
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 208000025113 myeloid leukemia Diseases 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 2
- 229960002700 octreotide Drugs 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 239000005022 packaging material Substances 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 206010033675 panniculitis Diseases 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 238000012877 positron emission topography Methods 0.000 description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- DWDHDSPZVVNBSC-UHFFFAOYSA-N pyrazolo[1,5-a]pyridin-3-amine;hydrochloride Chemical compound Cl.C1=CC=CC2=C(N)C=NN21 DWDHDSPZVVNBSC-UHFFFAOYSA-N 0.000 description 2
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 2
- 239000010959 steel Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 210000004304 subcutaneous tissue Anatomy 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 125000001010 sulfinic acid amide group Chemical group 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- IRYLDOUKPWMKMP-UHFFFAOYSA-N tert-butyl N-pyrazolo[1,5-a]pyridin-3-ylcarbamate Chemical compound CC(C)(C)OC(=O)Nc1cnn2ccccc12 IRYLDOUKPWMKMP-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 2
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 2
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 150000003852 triazoles Chemical class 0.000 description 2
- 229910052727 yttrium Inorganic materials 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 1
- XJEVHMGJSYVQBQ-SECBINFHSA-N (1r)-2,3-dihydro-1h-inden-1-amine Chemical compound C1=CC=C2[C@H](N)CCC2=C1 XJEVHMGJSYVQBQ-SECBINFHSA-N 0.000 description 1
- PRVIGUZMXLBANS-RKDXNWHRSA-N (1r,3r)-3-amino-2,3-dihydro-1h-inden-1-ol Chemical compound C1=CC=C2[C@H](N)C[C@@H](O)C2=C1 PRVIGUZMXLBANS-RKDXNWHRSA-N 0.000 description 1
- PRVIGUZMXLBANS-DTWKUNHWSA-N (1r,3s)-3-amino-2,3-dihydro-1h-inden-1-ol Chemical compound C1=CC=C2[C@@H](N)C[C@@H](O)C2=C1 PRVIGUZMXLBANS-DTWKUNHWSA-N 0.000 description 1
- PRVIGUZMXLBANS-BDAKNGLRSA-N (1s,3r)-3-amino-2,3-dihydro-1h-inden-1-ol Chemical compound C1=CC=C2[C@H](N)C[C@H](O)C2=C1 PRVIGUZMXLBANS-BDAKNGLRSA-N 0.000 description 1
- PRVIGUZMXLBANS-IUCAKERBSA-N (1s,3s)-3-amino-2,3-dihydro-1h-inden-1-ol Chemical compound C1=CC=C2[C@@H](N)C[C@H](O)C2=C1 PRVIGUZMXLBANS-IUCAKERBSA-N 0.000 description 1
- OHZUCDHZOHSBPZ-UHFFFAOYSA-N (2,3-difluorophenyl)methanamine Chemical compound NCC1=CC=CC(F)=C1F OHZUCDHZOHSBPZ-UHFFFAOYSA-N 0.000 description 1
- XFMATJBLGFMLBT-UHFFFAOYSA-N (2-methyl-3h-benzimidazol-5-yl)methanamine Chemical compound C1=C(CN)C=C2NC(C)=NC2=C1 XFMATJBLGFMLBT-UHFFFAOYSA-N 0.000 description 1
- YGZJTYCCONJJGZ-UHFFFAOYSA-N (3,5-dimethoxyphenyl)methanamine Chemical compound COC1=CC(CN)=CC(OC)=C1 YGZJTYCCONJJGZ-UHFFFAOYSA-N 0.000 description 1
- DZBHNPJZCQWUCG-UHFFFAOYSA-N (3,5-dimethylphenyl)methanamine Chemical compound CC1=CC(C)=CC(CN)=C1 DZBHNPJZCQWUCG-UHFFFAOYSA-N 0.000 description 1
- YIUQWUGXTNVAOV-UHFFFAOYSA-N (3-chloro-5-methylphenyl)methanamine Chemical compound CC1=CC(Cl)=CC(CN)=C1 YIUQWUGXTNVAOV-UHFFFAOYSA-N 0.000 description 1
- ORFDOJUUDDVASP-UHFFFAOYSA-N (3-ethoxyphenyl)methanamine Chemical compound CCOC1=CC=CC(CN)=C1 ORFDOJUUDDVASP-UHFFFAOYSA-N 0.000 description 1
- CMISIIAYQCJJSW-UHFFFAOYSA-N (3-fluoro-5-methylphenyl)methanamine Chemical compound CC1=CC(F)=CC(CN)=C1 CMISIIAYQCJJSW-UHFFFAOYSA-N 0.000 description 1
- WYEAKFIRTXVYNS-UHFFFAOYSA-N (4-chloro-3-ethoxyphenyl)boronic acid Chemical group CCOC1=CC(B(O)O)=CC=C1Cl WYEAKFIRTXVYNS-UHFFFAOYSA-N 0.000 description 1
- DZNNRXURZJLARZ-UHFFFAOYSA-N (4-chloro-3-methoxyphenyl)boronic acid Chemical group COC1=CC(B(O)O)=CC=C1Cl DZNNRXURZJLARZ-UHFFFAOYSA-N 0.000 description 1
- CEBAHYWORUOILU-UHFFFAOYSA-N (4-cyanophenyl)boronic acid Chemical group OB(O)C1=CC=C(C#N)C=C1 CEBAHYWORUOILU-UHFFFAOYSA-N 0.000 description 1
- AUOIYQDHPOAYQZ-UHFFFAOYSA-N (6-methoxypyridin-3-yl)methanamine Chemical compound COC1=CC=C(CN)C=N1 AUOIYQDHPOAYQZ-UHFFFAOYSA-N 0.000 description 1
- RIMMPHHCGOSJAV-INIZCTEOSA-N (S)-N-(6,7-dihydrocyclopenta[b]pyridin-5-ylidene)-2-methylpropane-2-sulfinamide Chemical compound N1=C2C(=CC=C1)C(CC2)=N[S@@](=O)C(C)(C)C RIMMPHHCGOSJAV-INIZCTEOSA-N 0.000 description 1
- ZBIWCHCUXYHWIE-SFHVURJKSA-N (S)-N-(6-chloro-2,3-dihydrochromen-4-ylidene)-2-methylpropane-2-sulfinamide Chemical compound ClC=1C=C2C(CCOC2=CC=1)=N[S@@](=O)C(C)(C)C ZBIWCHCUXYHWIE-SFHVURJKSA-N 0.000 description 1
- DGXXGWIFHGQYEN-VOJFVSQTSA-N (S)-N-[(4S)-6-chloro-3,4-dihydro-2H-chromen-4-yl]-2-methylpropane-2-sulfinamide Chemical compound ClC=1C=C2[C@H](CCOC2=CC=1)N[S@@](=O)C(C)(C)C DGXXGWIFHGQYEN-VOJFVSQTSA-N 0.000 description 1
- CIKIBXYWDNVJSN-ZBEGNZNMSA-N (S)-N-[(5S)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl]-2-methylpropane-2-sulfinamide Chemical compound N1=C2C(=CC=C1)[C@H](CC2)N[S@@](=O)C(C)(C)C CIKIBXYWDNVJSN-ZBEGNZNMSA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 description 1
- OGFAWKRXZLGJSK-UHFFFAOYSA-N 1-(2,4-dihydroxyphenyl)-2-(4-nitrophenyl)ethanone Chemical compound OC1=CC(O)=CC=C1C(=O)CC1=CC=C([N+]([O-])=O)C=C1 OGFAWKRXZLGJSK-UHFFFAOYSA-N 0.000 description 1
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 1
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 1
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- XJEVHMGJSYVQBQ-UHFFFAOYSA-N 2,3-dihydro-1h-inden-1-amine Chemical compound C1=CC=C2C(N)CCC2=C1 XJEVHMGJSYVQBQ-UHFFFAOYSA-N 0.000 description 1
- KLSYPEZICDEQPQ-UHFFFAOYSA-N 2,6-bis(difluoromethyl)pyridine-4-carbonitrile Chemical compound FC(F)c1cc(cc(n1)C(F)F)C#N KLSYPEZICDEQPQ-UHFFFAOYSA-N 0.000 description 1
- LDGOZMLBIGWHFP-UHFFFAOYSA-N 2-(5-bromo-2-ethyl-1,2,4-triazol-3-yl)-N-[(3,5-dichlorophenyl)methyl]acetamide Chemical compound BrC1=NN(C(=N1)CC(=O)NCC1=CC(=CC(=C1)Cl)Cl)CC LDGOZMLBIGWHFP-UHFFFAOYSA-N 0.000 description 1
- LUOQURANCYSBEE-UHFFFAOYSA-N 2-(5-bromo-2-ethyl-1,2,4-triazol-3-yl)acetic acid Chemical compound BrC1=NN(C(=N1)CC(=O)O)CC LUOQURANCYSBEE-UHFFFAOYSA-N 0.000 description 1
- ATRQECRSCHYSNP-UHFFFAOYSA-N 2-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=CC=N1 ATRQECRSCHYSNP-UHFFFAOYSA-N 0.000 description 1
- MLFFNKLBERSEPF-UHFFFAOYSA-N 2-(trifluoromethyl)pyridine-4-carbonitrile Chemical compound FC(F)(F)C1=CC(C#N)=CC=N1 MLFFNKLBERSEPF-UHFFFAOYSA-N 0.000 description 1
- WELOJSIXCNVHOT-UHFFFAOYSA-N 2-[3-(4-chloro-3-fluorophenyl)-1H-1,2,4-triazol-5-yl]-N-[(3,5-dichlorophenyl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NNC(=N1)CC(=O)NCC1=CC(=CC(=C1)Cl)Cl)F WELOJSIXCNVHOT-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- UFAPTDQNGHWUQZ-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-(2,3-dihydro-1H-inden-2-yl)acetamide Chemical compound CCn1nc(nc1CC(=O)NC1Cc2ccccc2C1)-c1ccc(Cl)c(F)c1 UFAPTDQNGHWUQZ-UHFFFAOYSA-N 0.000 description 1
- OZGROVIODCJSSU-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-(5-methyl-1,2-oxazol-3-yl)acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NC1=NOC(=C1)C)CC)F OZGROVIODCJSSU-UHFFFAOYSA-N 0.000 description 1
- BRCYALHEKUPEJG-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(2,6-dimethyl-1-oxidopyridin-1-ium-4-yl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=[N+](C(=C1)C)[O-])C)CC)F BRCYALHEKUPEJG-UHFFFAOYSA-N 0.000 description 1
- IIUUPRLALOOOIL-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(3-chloro-5-methylphenyl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=CC(=C1)C)Cl)CC)F IIUUPRLALOOOIL-UHFFFAOYSA-N 0.000 description 1
- MXUSXLOWTUWBSO-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(3-fluoro-5-methylphenyl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC1=CC(=CC(=C1)C)F)CC)F MXUSXLOWTUWBSO-UHFFFAOYSA-N 0.000 description 1
- CXJHNRGJJGGKHG-UHFFFAOYSA-N 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-[(6-methoxypyridin-3-yl)methyl]acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC=1C=NC(=CC=1)OC)CC)F CXJHNRGJJGGKHG-UHFFFAOYSA-N 0.000 description 1
- PYPBHXJCDTZVMR-UHFFFAOYSA-N 2-[5-(4-chloro-3-propan-2-yloxyphenyl)-2-ethyl-1,2,4-triazol-3-yl]-N-(1H-indazol-5-ylmethyl)acetamide Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)NCC=1C=C2C=NNC2=CC=1)CC)OC(C)C PYPBHXJCDTZVMR-UHFFFAOYSA-N 0.000 description 1
- LMHHFZAXSANGGM-UHFFFAOYSA-N 2-aminoindane Chemical compound C1=CC=C2CC(N)CC2=C1 LMHHFZAXSANGGM-UHFFFAOYSA-N 0.000 description 1
- CESUXLKAADQNTB-SSDOTTSWSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@](N)=O CESUXLKAADQNTB-SSDOTTSWSA-N 0.000 description 1
- ALLXEACAFYSEDP-UHFFFAOYSA-N 2-propan-2-yloxybenzamide;hydrochloride Chemical compound Cl.CC(C)OC1=CC=CC=C1C(N)=O ALLXEACAFYSEDP-UHFFFAOYSA-N 0.000 description 1
- DQSQBZXDMHDHEO-UHFFFAOYSA-N 2-pyridin-2-ylpropan-2-amine Chemical compound CC(C)(N)C1=CC=CC=N1 DQSQBZXDMHDHEO-UHFFFAOYSA-N 0.000 description 1
- LCOFMNJNNXWKOC-UHFFFAOYSA-N 3,4-dihydro-2h-chromen-4-amine Chemical compound C1=CC=C2C(N)CCOC2=C1 LCOFMNJNNXWKOC-UHFFFAOYSA-N 0.000 description 1
- XFKPORAVEUOIRF-UHFFFAOYSA-N 3-(aminomethyl)benzonitrile Chemical compound NCC1=CC=CC(C#N)=C1 XFKPORAVEUOIRF-UHFFFAOYSA-N 0.000 description 1
- ONGZXOQSAQNWNI-UHFFFAOYSA-N 3-[3-(4-chloro-3-fluorophenyl)-5-[2-[(3,5-dichlorophenyl)methylamino]-2-oxoethyl]-1,2,4-triazol-1-yl]propanoic acid Chemical compound OC(=O)CCn1nc(nc1CC(=O)NCc1cc(Cl)cc(Cl)c1)-c1ccc(Cl)c(F)c1 ONGZXOQSAQNWNI-UHFFFAOYSA-N 0.000 description 1
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 1
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- ZBOBPRFTJXSTQH-UHFFFAOYSA-N 4-[3-(4-chloro-3-fluorophenyl)-5-[2-[(3,5-dichlorophenyl)methylamino]-2-oxoethyl]-1,2,4-triazol-1-yl]butanoic acid Chemical compound OC(=O)CCCn1nc(nc1CC(=O)NCc1cc(Cl)cc(Cl)c1)-c1ccc(Cl)c(F)c1 ZBOBPRFTJXSTQH-UHFFFAOYSA-N 0.000 description 1
- QAIRPCMWTLMPCW-UHFFFAOYSA-N 4-bromo-2,6-diethylpyridine Chemical compound CCC1=CC(Br)=CC(CC)=N1 QAIRPCMWTLMPCW-UHFFFAOYSA-N 0.000 description 1
- UPJKSWLLCONYMW-UHFFFAOYSA-N 5'-Adenosine monophosphate Natural products COc1cc(O)c(C(=O)C)c(OC2OC(COC3OC(C)C(O)C(O)C3O)C(O)C(O)C2O)c1 UPJKSWLLCONYMW-UHFFFAOYSA-N 0.000 description 1
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 1
- QUXZATWAGGRNSE-UHFFFAOYSA-N 5-(aminomethyl)-3h-1,3-benzoxazol-2-one Chemical compound NCC1=CC=C2OC(=O)NC2=C1 QUXZATWAGGRNSE-UHFFFAOYSA-N 0.000 description 1
- BUJYYGHIOAAFOO-UHFFFAOYSA-N 6,7-dihydro-5h-cyclopenta[b]pyridin-5-amine Chemical compound C1=CC=C2C(N)CCC2=N1 BUJYYGHIOAAFOO-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000017275 ACTH-dependent Cushing syndrome Diseases 0.000 description 1
- 206010000599 Acromegaly Diseases 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 1
- 208000031295 Animal disease Diseases 0.000 description 1
- 102000000827 Anterior Pituitary Hormones Human genes 0.000 description 1
- 108010001897 Anterior Pituitary Hormones Proteins 0.000 description 1
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 1
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- 238000000035 BCA protein assay Methods 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000588832 Bordetella pertussis Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 102000000584 Calmodulin Human genes 0.000 description 1
- 108010041952 Calmodulin Proteins 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 description 1
- 102000012422 Collagen Type I Human genes 0.000 description 1
- 108010022452 Collagen Type I Proteins 0.000 description 1
- 208000026372 Congenital cystic kidney disease Diseases 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 1
- 241000271532 Crotalus Species 0.000 description 1
- 101710105094 Cyclic AMP-responsive element-binding protein Proteins 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 description 1
- 241000252212 Danio rerio Species 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical class [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 101001072031 Drosophila melanogaster Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11 Proteins 0.000 description 1
- 101100407340 Drosophila melanogaster Pde8 gene Proteins 0.000 description 1
- 206010058314 Dysplasia Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 1
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 1
- 102000034354 Gi proteins Human genes 0.000 description 1
- 108091006101 Gi proteins Proteins 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010018498 Goitre Diseases 0.000 description 1
- 102000006771 Gonadotropins Human genes 0.000 description 1
- 108010086677 Gonadotropins Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 206010019646 Hepatic cyst Diseases 0.000 description 1
- 208000028782 Hereditary disease Diseases 0.000 description 1
- 108010025076 Holoenzymes Proteins 0.000 description 1
- 101100407338 Homo sapiens PDE8B gene Proteins 0.000 description 1
- 101001026573 Homo sapiens cAMP-dependent protein kinase type I-alpha regulatory subunit Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 208000008454 Hyperhidrosis Diseases 0.000 description 1
- 206010020707 Hyperparathyroidism primary Diseases 0.000 description 1
- 206010020843 Hyperthermia Diseases 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000024556 Mendelian disease Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 101100407337 Mus musculus Pde8a gene Proteins 0.000 description 1
- 108010021466 Mutant Proteins Proteins 0.000 description 1
- 102000008300 Mutant Proteins Human genes 0.000 description 1
- 101000909851 Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) cAMP/cGMP dual specificity phosphodiesterase Rv0805 Proteins 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 206010031240 Osteodystrophy Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 101150081699 PDE8B gene Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010033603 Pancreatic atrophy Diseases 0.000 description 1
- 108010081690 Pertussis Toxin Proteins 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920000331 Polyhydroxybutyrate Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 201000000981 Primary Hyperparathyroidism Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 108010009736 Protein Hydrolysates Proteins 0.000 description 1
- 206010037407 Pulmonary hypoplasia Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 102100029143 RNA 3'-terminal phosphate cyclase Human genes 0.000 description 1
- 208000035977 Rare disease Diseases 0.000 description 1
- 208000037340 Rare genetic disease Diseases 0.000 description 1
- 208000020221 Short stature Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 101710176630 Snake venom 5'-nucleotidase Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 102000005157 Somatostatin Human genes 0.000 description 1
- 108010056088 Somatostatin Proteins 0.000 description 1
- 229940123051 Somatostatin receptor agonist Drugs 0.000 description 1
- 229920002472 Starch Chemical class 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000002847 Surgical Wound Diseases 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 206010063654 Testotoxicosis Diseases 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical compound IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 1
- 208000000323 Tourette Syndrome Diseases 0.000 description 1
- 208000016620 Tourette disease Diseases 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102000004136 Vasopressin Receptors Human genes 0.000 description 1
- 108090000643 Vasopressin Receptors Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- HHJPTKITRHFYMV-UHFFFAOYSA-N [2,6-bis(difluoromethyl)pyridin-4-yl]methanamine Chemical compound NCc1cc(nc(c1)C(F)F)C(F)F HHJPTKITRHFYMV-UHFFFAOYSA-N 0.000 description 1
- BPRLXHWZWXRXMB-UHFFFAOYSA-N [2-(difluoromethyl)pyridin-4-yl]methanamine;hydrochloride Chemical compound Cl.NCC1=CC=NC(C(F)F)=C1 BPRLXHWZWXRXMB-UHFFFAOYSA-N 0.000 description 1
- LETQLOMLPJORPB-UHFFFAOYSA-N [2-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound NCC1=CC=NC(C(F)(F)F)=C1 LETQLOMLPJORPB-UHFFFAOYSA-N 0.000 description 1
- BDDKPNSDKMBCNT-UHFFFAOYSA-N [2-(trifluoromethyl)pyridin-4-yl]methanamine;hydrochloride Chemical compound Cl.NCC1=CC=NC(C(F)(F)F)=C1 BDDKPNSDKMBCNT-UHFFFAOYSA-N 0.000 description 1
- YKHIIERVIUJUBD-UHFFFAOYSA-N [4-bromo-6-(hydroxymethyl)pyridin-2-yl]methanol Chemical compound OCC1=CC(Br)=CC(CO)=N1 YKHIIERVIUJUBD-UHFFFAOYSA-N 0.000 description 1
- DQKODDSMRUVJSP-UHFFFAOYSA-N [4-chloro-3-(2-methoxyethoxy)phenyl]boronic acid Chemical compound COCCOC1=CC(B(O)O)=CC=C1Cl DQKODDSMRUVJSP-UHFFFAOYSA-N 0.000 description 1
- CSUIVNWDPGSJIX-UHFFFAOYSA-N [C-]#N.[Zn+2].C(C)C=1C=C(C#N)C=C(N=1)CC.[C-]#N Chemical compound [C-]#N.[Zn+2].C(C)C=1C=C(C#N)C=C(N=1)CC.[C-]#N CSUIVNWDPGSJIX-UHFFFAOYSA-N 0.000 description 1
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 1
- 238000002679 ablation Methods 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003329 adenohypophysis hormone Substances 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 239000000674 adrenergic antagonist Substances 0.000 description 1
- 229940126157 adrenergic receptor agonist Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000036626 alertness Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 208000022338 anthrax infection Diseases 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 208000025261 autosomal dominant disease Diseases 0.000 description 1
- 229940065181 bacillus anthracis Drugs 0.000 description 1
- 238000007630 basic procedure Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003181 biological factor Substances 0.000 description 1
- 230000001851 biosynthetic effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 description 1
- 230000001593 cAMP accumulation Effects 0.000 description 1
- 238000013262 cAMP assay Methods 0.000 description 1
- 102100037490 cAMP-dependent protein kinase type I-alpha regulatory subunit Human genes 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000007248 cellular mechanism Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 229920002678 cellulose Chemical class 0.000 description 1
- 239000001913 cellulose Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 210000004081 cilia Anatomy 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000006552 constitutive activation Effects 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 239000011903 deuterated solvents Substances 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- WYROXHCDUWIUMW-UHFFFAOYSA-N dimethyl 4-bromopyridine-2,6-dicarboxylate Chemical compound COC(=O)C1=CC(Br)=CC(C(=O)OC)=N1 WYROXHCDUWIUMW-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 229940112141 dry powder inhaler Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000005014 ectopic expression Effects 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 208000028208 end stage renal disease Diseases 0.000 description 1
- 201000000523 end stage renal failure Diseases 0.000 description 1
- 210000003890 endocrine cell Anatomy 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 238000009585 enzyme analysis Methods 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 201000006517 essential tremor Diseases 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- QUDOWYWXQLJPBP-UHFFFAOYSA-N ethyl 2-[5-(4-chloro-3-fluorophenyl)-2-(cyclopropylmethyl)-1,2,4-triazol-3-yl]acetate Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)OCC)CC1CC1)F QUDOWYWXQLJPBP-UHFFFAOYSA-N 0.000 description 1
- OCSAOSUMWHTJTA-UHFFFAOYSA-N ethyl 2-[5-(4-chloro-3-fluorophenyl)-2-ethyl-1,2,4-triazol-3-yl]propanoate Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)C(C(=O)OCC)C)CC)F OCSAOSUMWHTJTA-UHFFFAOYSA-N 0.000 description 1
- RFKYSIYZIPYKAD-UHFFFAOYSA-N ethyl 2-[5-(4-chloro-3-fluorophenyl)-2-methylsulfonyl-1,2,4-triazol-3-yl]acetate Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)OCC)S(=O)(=O)C)F RFKYSIYZIPYKAD-UHFFFAOYSA-N 0.000 description 1
- YIIUYMMDXUBAMS-UHFFFAOYSA-N ethyl 2-[5-(4-chloro-3-propan-2-yloxyphenyl)-2-ethyl-1,2,4-triazol-3-yl]acetate Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)OCC)CC)OC(C)C YIIUYMMDXUBAMS-UHFFFAOYSA-N 0.000 description 1
- IZHVHLWBLIMWFA-UHFFFAOYSA-N ethyl 2-[5-(4-chloro-3-propan-2-yloxyphenyl)-2-methyl-1,2,4-triazol-3-yl]acetate Chemical compound ClC1=C(C=C(C=C1)C1=NN(C(=N1)CC(=O)OCC)C)OC(C)C IZHVHLWBLIMWFA-UHFFFAOYSA-N 0.000 description 1
- CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 description 1
- XBPOBCXHALHJFP-UHFFFAOYSA-N ethyl 4-bromobutanoate Chemical compound CCOC(=O)CCCBr XBPOBCXHALHJFP-UHFFFAOYSA-N 0.000 description 1
- JDFSXHRSBURVCU-UHFFFAOYSA-N ethyl 4-chloro-3-propan-2-yloxybenzenecarboximidate hydrochloride Chemical compound Cl.CCOC(=N)c1ccc(Cl)c(OC(C)C)c1 JDFSXHRSBURVCU-UHFFFAOYSA-N 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 208000001936 exophthalmos Diseases 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 229940028334 follicle stimulating hormone Drugs 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000002622 gonadotropin Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 210000005003 heart tissue Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003284 homeostatic effect Effects 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000037417 hyperactivation Effects 0.000 description 1
- 230000037315 hyperhidrosis Effects 0.000 description 1
- 201000005991 hyperphosphatemia Diseases 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000036031 hyperthermia Effects 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 230000007124 immune defense Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000004537 indazol-5-yl group Chemical group N1N=CC2=CC(=CC=C12)* 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000008316 intracellular mechanism Effects 0.000 description 1
- 102000027411 intracellular receptors Human genes 0.000 description 1
- 108091008582 intracellular receptors Proteins 0.000 description 1
- 238000000185 intracerebroventricular administration Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007916 intrasternal administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007915 intraurethral administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 230000019948 ion homeostasis Effects 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 150000003854 isothiazoles Chemical class 0.000 description 1
- 150000002545 isoxazoles Chemical class 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000002332 leydig cell Anatomy 0.000 description 1
- 230000002197 limbic effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 230000004777 loss-of-function mutation Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- KQEVIFKPZOGBMZ-UHFFFAOYSA-N methyl 3-bromopropanoate Chemical compound COC(=O)CCBr KQEVIFKPZOGBMZ-UHFFFAOYSA-N 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 108091006026 monomeric small GTPases Proteins 0.000 description 1
- 210000000066 myeloid cell Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 description 1
- UVEDQUMYFTWIPC-UHFFFAOYSA-N n-methyl-1,2-oxazol-3-amine Chemical compound CNC=1C=CON=1 UVEDQUMYFTWIPC-UHFFFAOYSA-N 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 230000008035 nerve activity Effects 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- KHPXUQMNIQBQEV-UHFFFAOYSA-N oxaloacetic acid Chemical compound OC(=O)CC(=O)C(O)=O KHPXUQMNIQBQEV-UHFFFAOYSA-N 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 210000002990 parathyroid gland Anatomy 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 210000004694 pigment cell Anatomy 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 210000003635 pituitary gland Anatomy 0.000 description 1
- 208000013207 pituitary-dependent Cushing disease Diseases 0.000 description 1
- 239000005015 poly(hydroxybutyrate) Substances 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 229940043437 protein kinase A inhibitor Drugs 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- XFTQRUTUGRCSGO-UHFFFAOYSA-N pyrazin-2-amine Chemical compound NC1=CN=CC=N1 XFTQRUTUGRCSGO-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- GPHQHTOMRSGBNZ-UHFFFAOYSA-N pyridine-4-carbonitrile Chemical compound N#CC1=CC=NC=C1 GPHQHTOMRSGBNZ-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 210000005000 reproductive tract Anatomy 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000011808 rodent model Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000007727 signaling mechanism Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 102000030938 small GTPase Human genes 0.000 description 1
- 239000003998 snake venom Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 229940075620 somatostatin analogue Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008107 starch Chemical class 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000010009 steroidogenesis Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 210000002820 sympathetic nervous system Anatomy 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- PCAWZDWCVXBUDQ-UHFFFAOYSA-N tert-butyl N-[(E)-[amino-(4-chloro-3-fluorophenyl)methylidene]amino]carbamate Chemical compound ClC1=C(C=C(C=C1)C(NNC(=O)OC(C)(C)C)=N)F PCAWZDWCVXBUDQ-UHFFFAOYSA-N 0.000 description 1
- WYJNPSONHWLXPN-UHFFFAOYSA-N tert-butyl N-[(E)-[amino-(4-chloro-3-propan-2-yloxyphenyl)methylidene]amino]carbamate Chemical compound ClC1=C(C=C(C=C1)C(NNC(=O)OC(C)(C)C)=N)OC(C)C WYJNPSONHWLXPN-UHFFFAOYSA-N 0.000 description 1
- GHHJONKWTNLARH-UHFFFAOYSA-N tert-butyl n-[[2-(difluoromethyl)pyridin-4-yl]methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1=CC=NC(C(F)F)=C1 GHHJONKWTNLARH-UHFFFAOYSA-N 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940034208 thyroxine Drugs 0.000 description 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 229940035722 triiodothyronine Drugs 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000004926 tubular epithelial cell Anatomy 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- 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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Pulmonology (AREA)
- Urology & Nephrology (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1805527.7 | 2018-04-04 | ||
| GBGB1805527.7A GB201805527D0 (en) | 2018-04-04 | 2018-04-04 | Compounds and their use as pde4 activators |
| PCT/GB2019/050976 WO2019193342A1 (en) | 2018-04-04 | 2019-04-04 | Compounds and their use as pde4 activators |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2021520340A JP2021520340A (ja) | 2021-08-19 |
| JP2021520340A5 JP2021520340A5 (enExample) | 2022-03-15 |
| JP7330202B2 true JP7330202B2 (ja) | 2023-08-21 |
Family
ID=62142313
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2020552732A Active JP7330202B2 (ja) | 2018-04-04 | 2019-04-04 | 化合物およびｐｄｅ４活性剤としてのそれらの使用 |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US11560373B2 (enExample) |
| EP (1) | EP3774780B1 (enExample) |
| JP (1) | JP7330202B2 (enExample) |
| GB (1) | GB201805527D0 (enExample) |
| WO (1) | WO2019193342A1 (enExample) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112194620B (zh) * | 2020-12-04 | 2021-02-26 | 苏州开元民生科技股份有限公司 | 一种2-乙基-4-氰基吡啶的制备方法 |
| GB202102088D0 (en) | 2021-02-15 | 2021-03-31 | Mironid Ltd | Compounds and their use as pde4 activators |
| TW202304865A (zh) | 2021-03-23 | 2023-02-01 | 美商百愛及生物醫藥公司 | Nlrp3發炎體之抑制劑 |
| CN119053602A (zh) | 2022-01-28 | 2024-11-29 | 柏奥艾奇实验室公司 | Nlrp3炎性体的n-氧化物抑制剂 |
| GB202212000D0 (en) | 2022-08-17 | 2022-09-28 | Mironid Ltd | Compounds and their use as PDE4 activators |
| GB202211999D0 (en) | 2022-08-17 | 2022-09-28 | Mironid Ltd | Compounds and their use as PDE4 activators |
| IT202200024948A1 (it) * | 2022-12-05 | 2024-06-05 | Angelini Pharma S P A | Composti attivatori dei canali potassio KV7.2/KV7.3 |
| US12509459B2 (en) | 2024-03-26 | 2025-12-30 | BioAge Labs, Inc. | Inhibitors of NLRP3 inflammasome |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016151300A1 (en) | 2015-03-20 | 2016-09-29 | Mironid Limited | Triazole derivatives and their use as pde4 activators |
Family Cites Families (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ178996A (en) | 1974-11-15 | 1978-06-02 | Kornis G | Pyrfazole amides and thioamides;herbicidal compositions |
| JP3890453B2 (ja) | 1996-09-18 | 2007-03-07 | リードケミカル株式会社 | 新規２，４−ジオキソピロリジンおよび２，４−ジオキソテトラヒドロフラン誘導体及び該化合物を有効成分とする医薬 |
| CA2514363A1 (en) | 2003-02-12 | 2004-08-26 | Transtech Pharma, Inc. | Substituted azole derivatives as therapeutic agents |
| EP1631568A1 (en) | 2003-04-18 | 2006-03-08 | Memory Pharmaceuticals Corporation | Pyrazole derivatives as phosphodiesterase 4 inhibitors |
| US7056932B2 (en) | 2003-12-19 | 2006-06-06 | Hoffman-La Roche Inc. | Heterocyclyl substituted 1-alkoxy acetic acid amides |
| US7726930B2 (en) | 2005-05-16 | 2010-06-01 | Swaploader U.S.A., Ltd. | Adjustable height jib for a hook-lift hoist |
| US20070191711A1 (en) | 2006-02-15 | 2007-08-16 | Misonix, Incorporated | Liquid processing and handling apparatus and associated method for use in medical procedures |
| EP2013176A2 (en) | 2006-02-27 | 2009-01-14 | Sterix Limited | Diaryl compounds as non-steroidal inhibitors of 17-beta hydroxysteroid dehydrogenase and/or steroid sulphatase for the treatment of oestrogen-related diseases such as hormone dependent breast cancer |
| EP2057152A1 (de) | 2006-08-07 | 2009-05-13 | Boehringer Ingelheim International GmbH | Enantiomerenreine betaagonisten, verfahren zu deren herstellung und deren verwendung als arzneimittel |
| WO2009131956A1 (en) | 2008-04-21 | 2009-10-29 | Institute For Oneworld Health | Compounds, compositions and methods comprising triazole derivatives |
| US20100144733A1 (en) | 2008-04-28 | 2010-06-10 | Institute For Oneworld Health | Compounds, compositions and methods comprising heteroaromatic derivatives |
| WO2010059838A2 (en) | 2008-11-20 | 2010-05-27 | Decode Genetics Ehf | Pde4 inhibitors selective for the long form of pde4 for treating inflammation and avoiding side effects |
| DE102009013642A1 (de) | 2009-03-18 | 2010-09-23 | Bayer Schering Pharma Aktiengesellschaft | Substituierte Phenylalaninderivate und deren Verwendung |
| US8343976B2 (en) | 2009-04-20 | 2013-01-01 | Institute For Oneworld Health | Compounds, compositions and methods comprising pyrazole derivatives |
| ES2700877T3 (es) | 2009-05-12 | 2019-02-19 | Koninklijke Philips Nv | Fosfodiesterasa 4D7 como marcador de cáncer de próstata |
| KR102110469B1 (ko) | 2009-05-12 | 2020-05-14 | 코닌클리케 필립스 엔.브이. | 악성의 호르몬 민감성 전립선 암에 대한 마커로서의 포스포디에스테라제 4ｄ7 |
| MX341050B (es) | 2010-04-07 | 2016-08-05 | Celgene Corp * | Metodos para tratar infeccion viral respiratoria. |
| EP2742030B1 (de) | 2011-08-11 | 2016-07-27 | Bayer Intellectual Property GmbH | 1,2,4-triazolyl-substituierte ketoenole zum einsatz im pflanzenschutz |
| US8642774B2 (en) | 2011-12-08 | 2014-02-04 | Boehringer Ingelheim International Gmbh | Compounds |
| US8889677B2 (en) | 2012-01-17 | 2014-11-18 | Boehringer Ingellheim International GmbH | Substituted triazoles useful as mGlu5 receptor modulators |
| EP2968266B1 (en) | 2013-03-15 | 2019-05-01 | Shifa Biomedical Corporation | Anti-proprotein convertase subtilisin kexin type 9 (anti-pcsk9) compounds in the treatment and/or prevention of cardiovascular diseases |
| WO2015175956A1 (en) | 2014-05-16 | 2015-11-19 | Celgene Corporation | Compositions and methods for the treatment of atherosclerotic cardiovascular diseases with pde4 modulators |
| CN108472284A (zh) | 2015-09-11 | 2018-08-31 | 维纳拓尔斯制药公司 | β-内酰胺酶抑制剂 |
| GB201616439D0 (en) | 2016-09-28 | 2016-11-09 | Mironid Limited | Compounds and uses |
-
2018
- 2018-04-04 GB GBGB1805527.7A patent/GB201805527D0/en not_active Ceased
-
2019
- 2019-04-04 WO PCT/GB2019/050976 patent/WO2019193342A1/en not_active Ceased
- 2019-04-04 EP EP19717570.6A patent/EP3774780B1/en active Active
- 2019-04-04 US US17/044,007 patent/US11560373B2/en active Active
- 2019-04-04 JP JP2020552732A patent/JP7330202B2/ja active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016151300A1 (en) | 2015-03-20 | 2016-09-29 | Mironid Limited | Triazole derivatives and their use as pde4 activators |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3774780A1 (en) | 2021-02-17 |
| GB201805527D0 (en) | 2018-05-16 |
| EP3774780B1 (en) | 2022-11-23 |
| US11560373B2 (en) | 2023-01-24 |
| WO2019193342A1 (en) | 2019-10-10 |
| JP2021520340A (ja) | 2021-08-19 |
| US20210032231A1 (en) | 2021-02-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7330202B2 (ja) | 化合物およびｐｄｅ４活性剤としてのそれらの使用 | |
| JP7062643B2 (ja) | 化合物およびｐｄｅ４活性剤としてのそれらの使用 | |
| JP6236067B2 (ja) | ＲＯＲγ活性を阻害し疾患を治療するための二環式スルホン化合物 | |
| US10793531B2 (en) | Triazole derivatives and their use as PDE4 activators | |
| AU2020277293B2 (en) | Anti-cancer compounds targeting ral gtpases and methods of using the same | |
| TW202333563A (zh) | 用於治療疾病或障礙之二胺基環戊基吡啶衍生物 | |
| KR20140022063A (ko) | 신경 변성 질환을 치료하기 위한 방법 및 조성물 | |
| JP6587637B2 (ja) | カルボキサミド誘導体 | |
| JP2015536921A (ja) | アミノアルキルピペラジンの尿素及びアミド誘導体並びにその使用 | |
| US20240150339A1 (en) | Compounds and Their Use as PDE4 Activators | |
| KR20250068738A (ko) | 치환된 옥소이소인돌리닐 피페리딘-2,6-디온 화합물 | |
| US20260007680A1 (en) | Compounds and Their Use as PDE4 Activators | |
| US20260001876A1 (en) | Compounds and Their Use as PDE4 Activators | |
| KR20230016190A (ko) | Ddr 억제제로서 벤질아민 유도체 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220307 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20220307 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20230222 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230308 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230509 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20230802 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20230808 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 7330202 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |