JP4824562B2 - アミドメチル置換１−（カルボキシアルキル）−シクロペンチルカルボニルアミノ−ベンズアゼピン−ｎ−酢酸誘導体、これらを製造するための方法および中間生成物およびこれら化合物を含有する医薬 - Google Patents
アミドメチル置換１−（カルボキシアルキル）−シクロペンチルカルボニルアミノ−ベンズアゼピン−ｎ−酢酸誘導体、これらを製造するための方法および中間生成物およびこれら化合物を含有する医薬 Download PDFInfo
- Publication number
- JP4824562B2 JP4824562B2 JP2006527420A JP2006527420A JP4824562B2 JP 4824562 B2 JP4824562 B2 JP 4824562B2 JP 2006527420 A JP2006527420 A JP 2006527420A JP 2006527420 A JP2006527420 A JP 2006527420A JP 4824562 B2 JP4824562 B2 JP 4824562B2
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- amino
- acid
- group
- methyl
- 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.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 title claims description 153
- 238000000034 method Methods 0.000 title claims description 56
- 239000003814 drug Substances 0.000 title claims description 26
- 230000008569 process Effects 0.000 title claims description 7
- 239000013067 intermediate product Substances 0.000 title description 6
- 125000004181 carboxyalkyl group Chemical group 0.000 title description 4
- -1 phenylcarbonylmethyl Chemical group 0.000 claims description 70
- 239000002253 acid Substances 0.000 claims description 61
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 52
- 238000011282 treatment Methods 0.000 claims description 47
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 44
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 32
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 31
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 30
- 150000002148 esters Chemical class 0.000 claims description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 29
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
- 125000006239 protecting group Chemical group 0.000 claims description 28
- 206010057671 Female sexual dysfunction Diseases 0.000 claims description 25
- 125000000539 amino acid group Chemical group 0.000 claims description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 22
- 230000002265 prevention Effects 0.000 claims description 22
- 201000001880 Sexual dysfunction Diseases 0.000 claims description 19
- 231100000872 sexual dysfunction Toxicity 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 201000001881 impotence Diseases 0.000 claims description 16
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 14
- 206010019280 Heart failures Diseases 0.000 claims description 13
- 206010020772 Hypertension Diseases 0.000 claims description 13
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 10
- 150000001413 amino acids Chemical class 0.000 claims description 10
- 150000001721 carbon Chemical group 0.000 claims description 10
- 229940024606 amino acid Drugs 0.000 claims description 9
- 235000001014 amino acid Nutrition 0.000 claims description 9
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical group C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims description 8
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 8
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 8
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 229960004295 valine Drugs 0.000 claims description 8
- SNDPXSYFESPGGJ-UHFFFAOYSA-N 2-aminopentanoic acid Chemical compound CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 claims description 7
- 239000004475 Arginine Substances 0.000 claims description 7
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims description 7
- 239000004471 Glycine Substances 0.000 claims description 7
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims description 7
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 7
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 7
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 7
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 7
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 7
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 7
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 7
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 7
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 7
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 7
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 7
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 7
- 239000004472 Lysine Substances 0.000 claims description 7
- 206010057672 Male sexual dysfunction Diseases 0.000 claims description 7
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims description 7
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 7
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 7
- 229960003767 alanine Drugs 0.000 claims description 7
- 235000004279 alanine Nutrition 0.000 claims description 7
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 7
- 235000009697 arginine Nutrition 0.000 claims description 7
- 229960001230 asparagine Drugs 0.000 claims description 7
- 235000009582 asparagine Nutrition 0.000 claims description 7
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 7
- 235000004554 glutamine Nutrition 0.000 claims description 7
- 229960002743 glutamine Drugs 0.000 claims description 7
- 229960002449 glycine Drugs 0.000 claims description 7
- 229960000310 isoleucine Drugs 0.000 claims description 7
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 7
- 229960003136 leucine Drugs 0.000 claims description 7
- 229960003646 lysine Drugs 0.000 claims description 7
- 229960003104 ornithine Drugs 0.000 claims description 7
- 229960002429 proline Drugs 0.000 claims description 7
- 239000004474 valine Substances 0.000 claims description 7
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 6
- LRQKBLKVPFOOQJ-UHFFFAOYSA-N 2-aminohexanoic acid Chemical compound CCCCC(N)C(O)=O LRQKBLKVPFOOQJ-UHFFFAOYSA-N 0.000 claims description 6
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 6
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 6
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims description 6
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 6
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 6
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 6
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 6
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 6
- KKCIOUWDFWQUBT-AWEZNQCLSA-N L-thyronine Chemical compound C1=CC(C[C@H](N)C(O)=O)=CC=C1OC1=CC=C(O)C=C1 KKCIOUWDFWQUBT-AWEZNQCLSA-N 0.000 claims description 6
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 6
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 6
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 6
- 239000004473 Threonine Substances 0.000 claims description 6
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 6
- 235000003704 aspartic acid Nutrition 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 6
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 6
- 235000018417 cysteine Nutrition 0.000 claims description 6
- 235000013922 glutamic acid Nutrition 0.000 claims description 6
- 229960002989 glutamic acid Drugs 0.000 claims description 6
- 239000004220 glutamic acid Substances 0.000 claims description 6
- 229960002885 histidine Drugs 0.000 claims description 6
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 229930182817 methionine Natural products 0.000 claims description 6
- 229960004452 methionine Drugs 0.000 claims description 6
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical group N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 claims description 5
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 claims description 5
- 208000035475 disorder Diseases 0.000 claims description 5
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 4
- KYARBIJYVGJZLB-UHFFFAOYSA-N 7-amino-4-hydroxy-2-naphthalenesulfonic acid Chemical compound OC1=CC(S(O)(=O)=O)=CC2=CC(N)=CC=C21 KYARBIJYVGJZLB-UHFFFAOYSA-N 0.000 claims description 4
- 208000014644 Brain disease Diseases 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- 230000000472 traumatic effect Effects 0.000 claims description 4
- QLTHLKDCETZRKR-UHFFFAOYSA-N 2-[[1-[[1-(carboxymethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-(4-hydroxypiperidin-1-yl)-4-oxobutanoic acid Chemical compound C1CC(O)CCN1C(=O)CC(C(O)=O)CC1(C(=O)NC2C(N(CC(O)=O)C3=CC=CC=C3CC2)=O)CCCC1 QLTHLKDCETZRKR-UHFFFAOYSA-N 0.000 claims description 3
- BIENCTCRHWSPIB-UHFFFAOYSA-N 2-[[1-[[1-(carboxymethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-(diethylamino)-4-oxobutanoic acid Chemical compound C1CC2=CC=CC=C2N(CC(O)=O)C(=O)C1NC(=O)C1(CC(CC(=O)N(CC)CC)C(O)=O)CCCC1 BIENCTCRHWSPIB-UHFFFAOYSA-N 0.000 claims description 3
- QZFHWFAAUMVGHP-UHFFFAOYSA-N 2-[[1-[[1-(carboxymethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-(dimethylamino)-4-oxobutanoic acid Chemical compound C1CC2=CC=CC=C2N(CC(O)=O)C(=O)C1NC(=O)C1(CC(CC(=O)N(C)C)C(O)=O)CCCC1 QZFHWFAAUMVGHP-UHFFFAOYSA-N 0.000 claims description 3
- BCARGUJSFPCSDO-UHFFFAOYSA-N 2-[[1-[[1-(carboxymethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-[2-(dimethylamino)ethyl-methylamino]-4-oxobutanoic acid Chemical compound C1CC2=CC=CC=C2N(CC(O)=O)C(=O)C1NC(=O)C1(CC(CC(=O)N(C)CCN(C)C)C(O)=O)CCCC1 BCARGUJSFPCSDO-UHFFFAOYSA-N 0.000 claims description 3
- RHNJBVDFOOWVNF-UHFFFAOYSA-N 2-[[1-[[1-(carboxymethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-[2-hydroxyethyl(methyl)amino]-4-oxobutanoic acid Chemical compound C1CC2=CC=CC=C2N(CC(O)=O)C(=O)C1NC(=O)C1(CC(CC(=O)N(CCO)C)C(O)=O)CCCC1 RHNJBVDFOOWVNF-UHFFFAOYSA-N 0.000 claims description 3
- YWKXBEFYDKOMJL-UHFFFAOYSA-N 2-[[1-[[1-(carboxymethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-[3-hydroxypropyl(methyl)amino]-4-oxobutanoic acid Chemical compound C1CC2=CC=CC=C2N(CC(O)=O)C(=O)C1NC(=O)C1(CC(CC(=O)N(CCCO)C)C(O)=O)CCCC1 YWKXBEFYDKOMJL-UHFFFAOYSA-N 0.000 claims description 3
- KIAMLXHVHGOAGV-UHFFFAOYSA-N 2-[[1-[[1-(carboxymethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-[ethyl-[3-(ethylamino)propyl]amino]-4-oxobutanoic acid Chemical compound C1CC2=CC=CC=C2N(CC(O)=O)C(=O)C1NC(=O)C1(CC(CC(=O)N(CC)CCCNCC)C(O)=O)CCCC1 KIAMLXHVHGOAGV-UHFFFAOYSA-N 0.000 claims description 3
- WSPVCBDDMGPEDN-UHFFFAOYSA-N 2-[[1-[[1-(carboxymethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-[methyl(propan-2-yl)amino]-4-oxobutanoic acid Chemical compound C1CC2=CC=CC=C2N(CC(O)=O)C(=O)C1NC(=O)C1(CC(CC(=O)N(C)C(C)C)C(O)=O)CCCC1 WSPVCBDDMGPEDN-UHFFFAOYSA-N 0.000 claims description 3
- ZLHJFUYUXNHOON-UHFFFAOYSA-N 2-[[1-[[1-(carboxymethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-[methyl-[2-(methylamino)ethyl]amino]-4-oxobutanoic acid Chemical compound C1CC2=CC=CC=C2N(CC(O)=O)C(=O)C1NC(=O)C1(CC(CC(=O)N(C)CCNC)C(O)=O)CCCC1 ZLHJFUYUXNHOON-UHFFFAOYSA-N 0.000 claims description 3
- KIHQSHHSSSSRDK-UHFFFAOYSA-N 2-[[1-[[1-(carboxymethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-[methyl-[3-(methylamino)propyl]amino]-4-oxobutanoic acid Chemical compound C1CC2=CC=CC=C2N(CC(O)=O)C(=O)C1NC(=O)C1(CC(CC(=O)N(C)CCCNC)C(O)=O)CCCC1 KIHQSHHSSSSRDK-UHFFFAOYSA-N 0.000 claims description 3
- BQVAEKFFIBBGBW-UHFFFAOYSA-N 2-[[1-[[1-(carboxymethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-morpholin-4-yl-4-oxobutanoic acid Chemical compound O=C1N(CC(=O)O)C2=CC=CC=C2CCC1NC(=O)C1(CC(CC(=O)N2CCOCC2)C(O)=O)CCCC1 BQVAEKFFIBBGBW-UHFFFAOYSA-N 0.000 claims description 3
- ILBLANSRQKUAAE-UHFFFAOYSA-N 2-[[1-[[1-(carboxymethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-oxo-4-(4-oxopiperidin-1-yl)butanoic acid Chemical compound O=C1N(CC(=O)O)C2=CC=CC=C2CCC1NC(=O)C1(CC(CC(=O)N2CCC(=O)CC2)C(O)=O)CCCC1 ILBLANSRQKUAAE-UHFFFAOYSA-N 0.000 claims description 3
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 3
- ISJBPBPFOMLHIB-UHFFFAOYSA-N 4-[4-aminobutyl(ethyl)amino]-2-[[1-[[1-(carboxymethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-oxobutanoic acid Chemical compound C1CC2=CC=CC=C2N(CC(O)=O)C(=O)C1NC(=O)C1(CC(CC(=O)N(CCCCN)CC)C(O)=O)CCCC1 ISJBPBPFOMLHIB-UHFFFAOYSA-N 0.000 claims description 3
- UAUGBPQYORBALH-UHFFFAOYSA-N 4-[4-aminobutyl(methyl)amino]-2-[[1-[[1-(carboxymethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-oxobutanoic acid Chemical compound C1CC2=CC=CC=C2N(CC(O)=O)C(=O)C1NC(=O)C1(CC(CC(=O)N(CCCCN)C)C(O)=O)CCCC1 UAUGBPQYORBALH-UHFFFAOYSA-N 0.000 claims description 3
- BDMJNYVQOMEGPI-UHFFFAOYSA-N 4-[bis(2-hydroxyethyl)amino]-2-[[1-[[1-(carboxymethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-oxobutanoic acid Chemical compound C1CC2=CC=CC=C2N(CC(O)=O)C(=O)C1NC(=O)C1(CC(CC(=O)N(CCO)CCO)C(O)=O)CCCC1 BDMJNYVQOMEGPI-UHFFFAOYSA-N 0.000 claims description 3
- 201000006474 Brain Ischemia Diseases 0.000 claims description 3
- 206010008120 Cerebral ischaemia Diseases 0.000 claims description 3
- 239000000061 acid fraction Substances 0.000 claims description 3
- 150000001408 amides Chemical group 0.000 claims description 3
- 206010008118 cerebral infarction Diseases 0.000 claims description 3
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 claims description 3
- 125000002927 2-methoxybenzyl group Chemical group [H]C1=C([H])C([H])=C(C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims description 2
- MDIRESITLMKUFA-UHFFFAOYSA-N 4-[3-aminopropyl(ethyl)amino]-2-[[1-[[1-(carboxymethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-oxobutanoic acid Chemical compound C1CC2=CC=CC=C2N(CC(O)=O)C(=O)C1NC(=O)C1(CC(CC(=O)N(CCCN)CC)C(O)=O)CCCC1 MDIRESITLMKUFA-UHFFFAOYSA-N 0.000 claims description 2
- ILFNKIDGYZXTGL-UHFFFAOYSA-N 4-[5-aminopentyl(methyl)amino]-2-[[1-[[1-(carboxymethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-oxobutanoic acid Chemical compound C1CC2=CC=CC=C2N(CC(O)=O)C(=O)C1NC(=O)C1(CC(CC(=O)N(CCCCCN)C)C(O)=O)CCCC1 ILFNKIDGYZXTGL-UHFFFAOYSA-N 0.000 claims description 2
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 2
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 claims description 2
- 208000032382 Ischaemic stroke Diseases 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims description 2
- CAODDCZFBZNYSO-UHFFFAOYSA-N 3-oxopyrrolidine-2-carboxylic acid Chemical compound OC(=O)C1NCCC1=O CAODDCZFBZNYSO-UHFFFAOYSA-N 0.000 claims 5
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 claims 5
- 125000002252 acyl group Chemical group 0.000 claims 4
- 125000005037 alkyl phenyl group Chemical group 0.000 claims 3
- 150000003254 radicals Chemical class 0.000 claims 2
- 208000030663 Libido disease Diseases 0.000 claims 1
- 125000004185 ester group Chemical group 0.000 claims 1
- 238000012360 testing method Methods 0.000 description 64
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- 239000000243 solution Substances 0.000 description 46
- 239000000126 substance Substances 0.000 description 45
- 108090000028 Neprilysin Proteins 0.000 description 40
- 102000003729 Neprilysin Human genes 0.000 description 40
- 239000000203 mixture Substances 0.000 description 35
- 230000002829 reductive effect Effects 0.000 description 33
- 239000002904 solvent Substances 0.000 description 33
- 230000002401 inhibitory effect Effects 0.000 description 28
- 239000012074 organic phase Substances 0.000 description 28
- 230000000694 effects Effects 0.000 description 27
- 230000001568 sexual effect Effects 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 230000001965 increasing effect Effects 0.000 description 23
- 108090000765 processed proteins & peptides Proteins 0.000 description 23
- 235000002639 sodium chloride Nutrition 0.000 description 23
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- 239000012071 phase Substances 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
- 102000004190 Enzymes Human genes 0.000 description 19
- 108090000790 Enzymes Proteins 0.000 description 19
- 201000010099 disease Diseases 0.000 description 19
- 229940088598 enzyme Drugs 0.000 description 19
- 108010003205 Vasoactive Intestinal Peptide Proteins 0.000 description 18
- 102400000015 Vasoactive intestinal peptide Human genes 0.000 description 18
- 101100099158 Xenopus laevis rela gene Proteins 0.000 description 18
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 description 18
- VBUWHHLIZKOSMS-RIWXPGAOSA-N invicorp Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)C)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 VBUWHHLIZKOSMS-RIWXPGAOSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 241000700159 Rattus Species 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- 230000005764 inhibitory process Effects 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- HZZGDPLAJHVHSP-GKHTVLBPSA-N big endothelin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]2CSSC[C@@H](C(N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CSSC1)C1=CN=CN1 HZZGDPLAJHVHSP-GKHTVLBPSA-N 0.000 description 16
- 239000003921 oil Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 102100029112 Endothelin-converting enzyme 1 Human genes 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 230000009471 action Effects 0.000 description 15
- 239000003112 inhibitor Substances 0.000 description 15
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 14
- 239000011550 stock solution Substances 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 230000037007 arousal Effects 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- 239000000758 substrate Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 102400001282 Atrial natriuretic peptide Human genes 0.000 description 12
- 101800001890 Atrial natriuretic peptide Proteins 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 210000005226 corpus cavernosum Anatomy 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 210000004392 genitalia Anatomy 0.000 description 11
- 210000002216 heart Anatomy 0.000 description 11
- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- 235000011152 sodium sulphate Nutrition 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- 230000006907 apoptotic process Effects 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 230000015556 catabolic process Effects 0.000 description 10
- 238000006731 degradation reaction Methods 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 239000006260 foam Substances 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- 102000004196 processed proteins & peptides Human genes 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 208000024891 symptom Diseases 0.000 description 10
- 101800004490 Endothelin-1 Proteins 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 208000014674 injury Diseases 0.000 description 9
- 230000004044 response Effects 0.000 description 9
- 108050009340 Endothelin Proteins 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 150000007513 acids Chemical class 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 8
- 210000002569 neuron Anatomy 0.000 description 8
- 210000000056 organ Anatomy 0.000 description 8
- 102000002045 Endothelin Human genes 0.000 description 7
- 230000005526 G1 to G0 transition Effects 0.000 description 7
- 239000013543 active substance Substances 0.000 description 7
- 229940009456 adriamycin Drugs 0.000 description 7
- 239000012131 assay buffer Substances 0.000 description 7
- 230000036772 blood pressure Effects 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 230000002526 effect on cardiovascular system Effects 0.000 description 7
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 230000001404 mediated effect Effects 0.000 description 7
- 210000002460 smooth muscle Anatomy 0.000 description 7
- 230000008733 trauma Effects 0.000 description 7
- 239000012224 working solution Substances 0.000 description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
- 206010011878 Deafness Diseases 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 208000002193 Pain Diseases 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 208000006262 Psychological Sexual Dysfunctions Diseases 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 230000000875 corresponding effect Effects 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 208000016354 hearing loss disease Diseases 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000011347 resin Substances 0.000 description 6
- 229920005989 resin Polymers 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 208000019553 vascular disease Diseases 0.000 description 6
- 241000282412 Homo Species 0.000 description 5
- 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 5
- 150000001412 amines Chemical class 0.000 description 5
- 230000017531 blood circulation Effects 0.000 description 5
- 125000001589 carboacyl group Chemical group 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000002934 diuretic Substances 0.000 description 5
- 238000001802 infusion Methods 0.000 description 5
- 210000003734 kidney Anatomy 0.000 description 5
- 239000007791 liquid phase Substances 0.000 description 5
- 201000006417 multiple sclerosis Diseases 0.000 description 5
- 230000000324 neuroprotective effect Effects 0.000 description 5
- 230000018052 penile erection Effects 0.000 description 5
- 229920001184 polypeptide Polymers 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 5
- 230000002792 vascular Effects 0.000 description 5
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 208000007530 Essential hypertension Diseases 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 4
- 208000027520 Somatoform disease Diseases 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 238000000540 analysis of variance Methods 0.000 description 4
- 230000001363 autoimmune Effects 0.000 description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 4
- 208000029028 brain injury Diseases 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 206010012601 diabetes mellitus Diseases 0.000 description 4
- 230000009429 distress Effects 0.000 description 4
- 231100000673 dose–response relationship Toxicity 0.000 description 4
- 230000009977 dual effect Effects 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 230000029142 excretion Effects 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 230000010370 hearing loss Effects 0.000 description 4
- 231100000888 hearing loss Toxicity 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 208000027753 pain disease Diseases 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 4
- 208000002815 pulmonary hypertension Diseases 0.000 description 4
- 230000005855 radiation Effects 0.000 description 4
- 206010038464 renal hypertension Diseases 0.000 description 4
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 4
- 208000012201 sexual and gender identity disease Diseases 0.000 description 4
- 208000015891 sexual disease Diseases 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- 230000004873 systolic arterial blood pressure Effects 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- 208000019901 Anxiety disease Diseases 0.000 description 3
- 102100039341 Atrial natriuretic peptide receptor 2 Human genes 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 208000031229 Cardiomyopathies Diseases 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- 206010012289 Dementia Diseases 0.000 description 3
- 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 3
- 241000124008 Mammalia Species 0.000 description 3
- 102000005741 Metalloproteases Human genes 0.000 description 3
- 108010006035 Metalloproteases Proteins 0.000 description 3
- 208000021908 Myocardial disease Diseases 0.000 description 3
- 208000009525 Myocarditis Diseases 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 208000029901 Sexual arousal disease Diseases 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 230000036506 anxiety Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 230000030833 cell death Effects 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 208000007118 chronic progressive multiple sclerosis Diseases 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
- 210000003029 clitoris Anatomy 0.000 description 3
- 206010009887 colitis Diseases 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 239000007822 coupling agent Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 230000001882 diuretic effect Effects 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 238000006911 enzymatic reaction Methods 0.000 description 3
- 229940011871 estrogen Drugs 0.000 description 3
- 239000000262 estrogen Substances 0.000 description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 208000010125 myocardial infarction Diseases 0.000 description 3
- 210000004165 myocardium Anatomy 0.000 description 3
- 230000001452 natriuretic effect Effects 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- 230000004770 neurodegeneration Effects 0.000 description 3
- 201000001119 neuropathy Diseases 0.000 description 3
- 230000007823 neuropathy Effects 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000012188 paraffin wax Substances 0.000 description 3
- 210000003899 penis Anatomy 0.000 description 3
- 230000036513 peripheral conductance Effects 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- 208000033808 peripheral neuropathy Diseases 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 229960003604 testosterone Drugs 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000013042 tunel staining Methods 0.000 description 3
- 230000001720 vestibular Effects 0.000 description 3
- 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 2
- YSWBUAHHXOINQW-KEKNWZKVSA-N 2-[[1-[[(3s)-1-(2-ethoxy-2-oxoethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-[methyl(propan-2-yl)amino]-4-oxobutanoic acid Chemical compound N([C@H]1CCC2=CC=CC=C2N(C1=O)CC(=O)OCC)C(=O)C1(CC(CC(=O)N(C)C(C)C)C(O)=O)CCCC1 YSWBUAHHXOINQW-KEKNWZKVSA-N 0.000 description 2
- SEEYHRCMNMPHDG-UHFFFAOYSA-N 2-chloroethyl ethyl carbonate Chemical compound CCOC(=O)OCCCl SEEYHRCMNMPHDG-UHFFFAOYSA-N 0.000 description 2
- OFNISBHGPNMTMS-UHFFFAOYSA-N 3-methylideneoxolane-2,5-dione Chemical compound C=C1CC(=O)OC1=O OFNISBHGPNMTMS-UHFFFAOYSA-N 0.000 description 2
- CTSWBCBORGPXFN-UHFFFAOYSA-N 4-o-benzyl 1-o-ethyl 2-methylidenebutanedioate Chemical compound CCOC(=O)C(=C)CC(=O)OCC1=CC=CC=C1 CTSWBCBORGPXFN-UHFFFAOYSA-N 0.000 description 2
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 2
- 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 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 101710102159 Atrial natriuretic peptide receptor 2 Proteins 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- 108090000932 Calcitonin Gene-Related Peptide Proteins 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 208000034656 Contusions Diseases 0.000 description 2
- AHCYMLUZIRLXAA-SHYZEUOFSA-N Deoxyuridine 5'-triphosphate Chemical compound O1[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)C[C@@H]1N1C(=O)NC(=O)C=C1 AHCYMLUZIRLXAA-SHYZEUOFSA-N 0.000 description 2
- 206010054089 Depressive symptom Diseases 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 101100189582 Dictyostelium discoideum pdeD gene Proteins 0.000 description 2
- 201000009273 Endometriosis Diseases 0.000 description 2
- 102000005593 Endopeptidases Human genes 0.000 description 2
- 108010059378 Endopeptidases Proteins 0.000 description 2
- 108030001679 Endothelin-converting enzyme 1 Proteins 0.000 description 2
- 206010015150 Erythema Diseases 0.000 description 2
- 208000021663 Female sexual arousal disease 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
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 206010020565 Hyperaemia Diseases 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- 241001313288 Labia Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 101150098694 PDE5A gene Proteins 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- 201000011152 Pemphigus Diseases 0.000 description 2
- 102000003992 Peroxidases Human genes 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 101150037481 SMR1 gene Proteins 0.000 description 2
- 102000007637 Soluble Guanylyl Cyclase Human genes 0.000 description 2
- 108010007205 Soluble Guanylyl Cyclase Proteins 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 2
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 238000010640 amide synthesis reaction Methods 0.000 description 2
- 230000006229 amino acid addition Effects 0.000 description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
- 210000003484 anatomy Anatomy 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000002424 anti-apoptotic effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 208000034526 bruise Diseases 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- KOUZFMZJBDVSJC-AMVUTOCUSA-N butyl 2-[[1-[[(3s)-1-(2-ethoxy-2-oxoethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-[methyl(propan-2-yl)amino]-4-oxobutanoate Chemical compound N([C@@H]1C(N(CC(=O)OCC)C2=CC=CC=C2CC1)=O)C(=O)C1(CC(CC(=O)N(C)C(C)C)C(=O)OCCCC)CCCC1 KOUZFMZJBDVSJC-AMVUTOCUSA-N 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
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 2
- 102100029175 cGMP-specific 3',5'-cyclic phosphodiesterase Human genes 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 2
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 2
- 229960002327 chloral hydrate Drugs 0.000 description 2
- 208000010877 cognitive disease Diseases 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 231100000895 deafness Toxicity 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- 210000001951 dura mater Anatomy 0.000 description 2
- 230000008519 endogenous mechanism Effects 0.000 description 2
- 230000007515 enzymatic degradation Effects 0.000 description 2
- 230000001856 erectile effect Effects 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 210000001752 female genitalia Anatomy 0.000 description 2
- 210000002266 hair cells auditory Anatomy 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 231100000283 hepatitis Toxicity 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 238000007914 intraventricular administration Methods 0.000 description 2
- 210000004731 jugular vein Anatomy 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000002483 medication Methods 0.000 description 2
- 239000003475 metalloproteinase inhibitor Substances 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- XHFGWHUWQXTGAT-UHFFFAOYSA-N n-methylpropan-2-amine Chemical compound CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 231100000189 neurotoxic Toxicity 0.000 description 2
- 230000002887 neurotoxic effect Effects 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 210000004197 pelvis Anatomy 0.000 description 2
- 201000001976 pemphigus vulgaris Diseases 0.000 description 2
- 108040007629 peroxidase activity proteins Proteins 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 208000020016 psychiatric disease Diseases 0.000 description 2
- 230000004648 relaxation of smooth muscle Effects 0.000 description 2
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 2
- 230000035807 sensation Effects 0.000 description 2
- 230000036332 sexual response Effects 0.000 description 2
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 230000002889 sympathetic effect Effects 0.000 description 2
- 230000005062 synaptic transmission Effects 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 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
- 238000002054 transplantation Methods 0.000 description 2
- 238000000825 ultraviolet detection Methods 0.000 description 2
- 210000001215 vagina Anatomy 0.000 description 2
- 210000005166 vasculature Anatomy 0.000 description 2
- 239000005526 vasoconstrictor agent Substances 0.000 description 2
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- PTHGDVCPCZKZKR-UHFFFAOYSA-N (4-chlorophenyl)methanol Chemical compound OCC1=CC=C(Cl)C=C1 PTHGDVCPCZKZKR-UHFFFAOYSA-N 0.000 description 1
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WFSVYLFWVSFSJP-UHFFFAOYSA-N 1-(2-ethoxycarbonyl-4-oxo-4-phenylmethoxybutyl)cyclopentane-1-carboxylic acid Chemical compound C1CCCC1(C(O)=O)CC(C(=O)OCC)CC(=O)OCC1=CC=CC=C1 WFSVYLFWVSFSJP-UHFFFAOYSA-N 0.000 description 1
- BIAAQBNMRITRDV-UHFFFAOYSA-N 1-(chloromethoxy)-2-methoxyethane Chemical compound COCCOCCl BIAAQBNMRITRDV-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 description 1
- NTQSYIWTDXTRGG-UHFFFAOYSA-N 2-(1-benzazepin-1-yl)acetic acid Chemical class OC(=O)CN1C=CC=CC2=CC=CC=C12 NTQSYIWTDXTRGG-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- NIWRDYRONHJCBX-JKGBFCRXSA-N 2-[(3s)-3-[[1-[2-[(4-chlorophenyl)methoxycarbonyl]-4-oxo-4-(propan-2-ylamino)butyl]cyclopentanecarbonyl]amino]-2-oxo-4,5-dihydro-3h-1-benzazepin-1-yl]acetic acid Chemical compound C=1C=C(Cl)C=CC=1COC(=O)C(CC(=O)NC(C)C)CC1(C(=O)N[C@@H]2C(N(CC(O)=O)C3=CC=CC=C3CC2)=O)CCCC1 NIWRDYRONHJCBX-JKGBFCRXSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- CDMVAWJVBPSWBG-LBAQZLPGSA-N 2-[[1-[[(3s)-1-(2-ethoxy-2-oxoethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-(3-hydroxypropylamino)-4-oxobutanoic acid Chemical compound N([C@H]1CCC2=CC=CC=C2N(C1=O)CC(=O)OCC)C(=O)C1(CC(CC(=O)NCCCO)C(O)=O)CCCC1 CDMVAWJVBPSWBG-LBAQZLPGSA-N 0.000 description 1
- HKRVDEIJXZVSHR-GGYWPGCISA-N 2-[[1-[[(3s)-1-(carboxymethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-(3-hydroxypropylamino)-4-oxobutanoic acid Chemical compound N([C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)C(=O)C1(CC(CC(=O)NCCCO)C(O)=O)CCCC1 HKRVDEIJXZVSHR-GGYWPGCISA-N 0.000 description 1
- YSHMYCJCLGMBRG-GGYWPGCISA-N 2-[[1-[[(3s)-1-(carboxymethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-oxo-4-(propan-2-ylamino)butanoic acid Chemical compound N([C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)C(=O)C1(CC(CC(=O)NC(C)C)C(O)=O)CCCC1 YSHMYCJCLGMBRG-GGYWPGCISA-N 0.000 description 1
- UPOLJPUUZCPTLL-KEKNWZKVSA-N 2-[[1-[[(3s)-1-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-oxo-4-(propan-2-ylamino)butanoic acid Chemical compound N([C@@H]1C(N(CC(=O)OC(C)(C)C)C2=CC=CC=C2CC1)=O)C(=O)C1(CC(CC(=O)NC(C)C)C(O)=O)CCCC1 UPOLJPUUZCPTLL-KEKNWZKVSA-N 0.000 description 1
- HOSWPDPVFBCLSY-UHFFFAOYSA-N 2-azaniumyl-4-oxobutanoate Chemical compound OC(=O)C(N)CC=O HOSWPDPVFBCLSY-UHFFFAOYSA-N 0.000 description 1
- JUSXLWAFYVKNLT-UHFFFAOYSA-N 2-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1Br JUSXLWAFYVKNLT-UHFFFAOYSA-N 0.000 description 1
- HSWMKBDCSJIMKQ-YGWFNULRSA-N 2-butoxy-3-[[1-[[(3s)-1-(2-ethoxy-2-oxoethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-oxobutanoic acid Chemical compound N([C@@H]1C(N(CC(=O)OCC)C2=CC=CC=C2CC1)=O)C(=O)C1(CC(C(OCCCC)C(O)=O)C=O)CCCC1 HSWMKBDCSJIMKQ-YGWFNULRSA-N 0.000 description 1
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- DRLWLDRTKIGEGL-WWGLSMKPSA-N 4-[4-[(2s)-2-amino-3-methylbutanoyl]oxypiperidin-1-yl]-2-[[1-[[1-(carboxymethyl)-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-oxobutanoic acid Chemical compound C1CC(OC(=O)[C@@H](N)C(C)C)CCN1C(=O)CC(C(O)=O)CC1(C(=O)NC2C(N(CC(O)=O)C3=CC=CC=C3CC2)=O)CCCC1 DRLWLDRTKIGEGL-WWGLSMKPSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 206010033646 Acute and chronic pancreatitis Diseases 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 206010059245 Angiopathy Diseases 0.000 description 1
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 description 1
- 206010003439 Artificial menopause Diseases 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 208000002017 Autoimmune Hypophysitis Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- LXBYOZXQWBHQRJ-UHFFFAOYSA-N CC(C)NC(CC(CC1(CCCC1)C(CCCC(CCc1ccccc1N1CC(OC(C)(C)C)=O)C1=O)=O)C(OCOCCOC)=O)=O Chemical compound CC(C)NC(CC(CC1(CCCC1)C(CCCC(CCc1ccccc1N1CC(OC(C)(C)C)=O)C1=O)=O)C(OCOCCOC)=O)=O LXBYOZXQWBHQRJ-UHFFFAOYSA-N 0.000 description 1
- 0 CC(OCCCNC(C*CC1(CCCC1)C(CC[C@@](CCc1ccccc1N1CC(O)=O)C1=O)=O)=O)=O Chemical compound CC(OCCCNC(C*CC1(CCCC1)C(CC[C@@](CCc1ccccc1N1CC(O)=O)C1=O)=O)=O)=O 0.000 description 1
- OGRPVLLUGMFHMQ-UHFFFAOYSA-N CCOC(OC(C)OC(CN(c1ccccc1CCC1NC(C2(CC(CC(N(C)C(C)C)=O)C(OC(C)OC(OCC)=O)=O)CCCC2)=O)C1=O)=O)=O Chemical compound CCOC(OC(C)OC(CN(c1ccccc1CCC1NC(C2(CC(CC(N(C)C(C)C)=O)C(OC(C)OC(OCC)=O)=O)CCCC2)=O)C1=O)=O)=O OGRPVLLUGMFHMQ-UHFFFAOYSA-N 0.000 description 1
- FVALCSZXQBCKFT-UHFFFAOYSA-N COC(=O)CCC(=O)NC(C)C Chemical compound COC(=O)CCC(=O)NC(C)C FVALCSZXQBCKFT-UHFFFAOYSA-N 0.000 description 1
- 102100038518 Calcitonin Human genes 0.000 description 1
- 102000004414 Calcitonin Gene-Related Peptide Human genes 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010007556 Cardiac failure acute Diseases 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 1
- 208000006029 Cardiomegaly Diseases 0.000 description 1
- 206010008025 Cerebellar ataxia Diseases 0.000 description 1
- 206010008642 Cholesteatoma Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010056370 Congestive cardiomyopathy Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- 208000006343 Cutaneous Mastocytosis Diseases 0.000 description 1
- 206010011668 Cutaneous leishmaniasis Diseases 0.000 description 1
- 102000004654 Cyclic GMP-Dependent Protein Kinases Human genes 0.000 description 1
- 108010003591 Cyclic GMP-Dependent Protein Kinases Proteins 0.000 description 1
- 101710112752 Cytotoxin Proteins 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- 102100033215 DNA nucleotidylexotransferase Human genes 0.000 description 1
- 206010011903 Deafness traumatic Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 208000007163 Dermatomycoses Diseases 0.000 description 1
- 206010012504 Dermatophytosis Diseases 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
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 108010067770 Endopeptidase K Proteins 0.000 description 1
- 102000048186 Endothelin-converting enzyme 1 Human genes 0.000 description 1
- 206010059284 Epidermal necrosis Diseases 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 208000024412 Friedreich ataxia Diseases 0.000 description 1
- 201000011240 Frontotemporal dementia Diseases 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 108010078321 Guanylate Cyclase Proteins 0.000 description 1
- 102000014469 Guanylate cyclase Human genes 0.000 description 1
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 206010054272 Helicobacter gastritis Diseases 0.000 description 1
- 208000032759 Hemolytic-Uremic Syndrome Diseases 0.000 description 1
- 206010019728 Hepatitis alcoholic Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 208000002972 Hepatolenticular Degeneration Diseases 0.000 description 1
- 108010093488 His-His-His-His-His-His Proteins 0.000 description 1
- 101000961040 Homo sapiens Atrial natriuretic peptide receptor 2 Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 206010020649 Hyperkeratosis Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 208000000038 Hypoparathyroidism Diseases 0.000 description 1
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 208000005615 Interstitial Cystitis Diseases 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 208000001126 Keratosis Diseases 0.000 description 1
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 1
- 208000017119 Labyrinth disease Diseases 0.000 description 1
- 208000032514 Leukocytoclastic vasculitis Diseases 0.000 description 1
- 206010024870 Loss of libido Diseases 0.000 description 1
- 208000005777 Lupus Nephritis Diseases 0.000 description 1
- 206010063685 Lymphocytic hypophysitis Diseases 0.000 description 1
- 208000015439 Lysosomal storage disease Diseases 0.000 description 1
- 208000001940 Massive Hepatic Necrosis Diseases 0.000 description 1
- 208000003351 Melanosis Diseases 0.000 description 1
- 208000027530 Meniere disease Diseases 0.000 description 1
- 206010027202 Meningitis bacterial Diseases 0.000 description 1
- 206010027260 Meningitis viral Diseases 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 241001460074 Microsporum distortum Species 0.000 description 1
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 1
- 101100533725 Mus musculus Smr3a gene Proteins 0.000 description 1
- 208000008238 Muscle Spasticity Diseases 0.000 description 1
- 206010028570 Myelopathy Diseases 0.000 description 1
- 201000002481 Myositis 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
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 1
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 1
- 102100022397 Nitric oxide synthase, brain Human genes 0.000 description 1
- 101710111444 Nitric oxide synthase, brain Proteins 0.000 description 1
- 208000002946 Noise-Induced Hearing Loss Diseases 0.000 description 1
- XRLMLYLZTZPLHZ-UHFFFAOYSA-N O1N=CC=CC2=CC=CC=C12.S1N(CC(=O)O)CC=CC2=CC=CC=C21 Chemical class O1N=CC=CC2=CC=CC=C12.S1N(CC(=O)O)CC=CC2=CC=CC=C21 XRLMLYLZTZPLHZ-UHFFFAOYSA-N 0.000 description 1
- 206010058461 Orchitis noninfective Diseases 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 1
- 206010034277 Pemphigoid Diseases 0.000 description 1
- 102000007079 Peptide Fragments Human genes 0.000 description 1
- 108010033276 Peptide Fragments Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 208000000609 Pick Disease of the Brain Diseases 0.000 description 1
- 208000012641 Pigmentation disease Diseases 0.000 description 1
- 208000005374 Poisoning Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000097929 Porphyria Species 0.000 description 1
- 208000010642 Porphyrias Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000024777 Prion disease Diseases 0.000 description 1
- 206010067063 Progressive relapsing multiple sclerosis Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- ODHCTXKNWHHXJC-GSVOUGTGSA-N Pyroglutamic acid Natural products OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 101100149716 Rattus norvegicus Vcsa1 gene Proteins 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 208000005793 Restless legs syndrome Diseases 0.000 description 1
- 208000007014 Retinitis pigmentosa Diseases 0.000 description 1
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 description 1
- 101100286750 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) ILV2 gene Proteins 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 206010039796 Seborrhoeic keratosis Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 101800002751 Sialorphin Proteins 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 206010072170 Skin wound Diseases 0.000 description 1
- 208000010112 Spinocerebellar Degenerations Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 206010042033 Stevens-Johnson syndrome Diseases 0.000 description 1
- 231100000168 Stevens-Johnson syndrome Toxicity 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 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
- 206010043189 Telangiectasia Diseases 0.000 description 1
- 108010036928 Thiorphan Proteins 0.000 description 1
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 description 1
- 206010043561 Thrombocytopenic purpura Diseases 0.000 description 1
- 208000002474 Tinea Diseases 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 206010047642 Vitiligo Diseases 0.000 description 1
- 208000018839 Wilson disease Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000002159 abnormal effect Effects 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
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 208000002552 acute disseminated encephalomyelitis Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 208000002353 alcoholic hepatitis Diseases 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 239000002160 alpha blocker Substances 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000019552 anatomical structure morphogenesis Effects 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 206010003230 arteritis Diseases 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 210000001008 atrial appendage Anatomy 0.000 description 1
- 230000001746 atrial effect Effects 0.000 description 1
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 201000009904 bacterial meningitis Diseases 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000008901 benefit 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
- 150000008107 benzenesulfonic acids Chemical group 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 150000001576 beta-amino acids Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 230000006931 brain damage Effects 0.000 description 1
- 231100000874 brain damage Toxicity 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 208000000594 bullous pemphigoid Diseases 0.000 description 1
- QWCRAEMEVRGPNT-UHFFFAOYSA-N buspirone Chemical compound C1C(=O)N(CCCCN2CCN(CC2)C=2N=CC=CN=2)C(=O)CC21CCCC2 QWCRAEMEVRGPNT-UHFFFAOYSA-N 0.000 description 1
- 229960002495 buspirone Drugs 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 231100000457 cardiotoxic Toxicity 0.000 description 1
- 230000001451 cardiotoxic effect Effects 0.000 description 1
- 230000005792 cardiovascular activity Effects 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 208000025434 cerebellar degeneration Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000035572 chemosensitivity Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 description 1
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000009223 counseling Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 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 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 201000003929 dermatomycosis Diseases 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000004882 diastolic arterial blood pressure Effects 0.000 description 1
- 150000001990 dicarboxylic acid derivatives Chemical class 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 201000011304 dilated cardiomyopathy 1A Diseases 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 201000002664 drug-induced hearing loss Diseases 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 230000000408 embryogenic effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010014665 endocarditis Diseases 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 239000006167 equilibration buffer Substances 0.000 description 1
- 230000009986 erectile function Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- JYEXGEJKRDZJFO-RPWUZVMVSA-N ethyl (2s)-4-(3-hydroxypropylamino)-2-[[1-[[(3s)-1-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-2-oxo-4,5-dihydro-3h-1-benzazepin-3-yl]carbamoyl]cyclopentyl]methyl]-4-oxobutanoate Chemical compound N([C@@H]1C(N(CC(=O)OC(C)(C)C)C2=CC=CC=C2CC1)=O)C(=O)C1(C[C@@H](CC(=O)NCCCO)C(=O)OCC)CCCC1 JYEXGEJKRDZJFO-RPWUZVMVSA-N 0.000 description 1
- 230000000763 evoking effect Effects 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 230000001434 glomerular Effects 0.000 description 1
- 210000004565 granule cell Anatomy 0.000 description 1
- 239000003966 growth inhibitor Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 208000013643 idiopathic inflammatory myopathy Diseases 0.000 description 1
- 208000015446 immunoglobulin a vasculitis Diseases 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000030214 innervation Effects 0.000 description 1
- 239000008011 inorganic excipient Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 239000007926 intracavernous injection Substances 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- VCMGMSHEPQENPE-UHFFFAOYSA-N ketamine hydrochloride Chemical compound [Cl-].C=1C=CC=C(Cl)C=1C1([NH2+]C)CCCCC1=O VCMGMSHEPQENPE-UHFFFAOYSA-N 0.000 description 1
- 210000000231 kidney cortex Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000006651 lactation Effects 0.000 description 1
- 208000036546 leukodystrophy Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 201000001585 lymphocytic gastritis Diseases 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 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
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000009245 menopause Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- DWCZIOOZPIDHAB-UHFFFAOYSA-L methyl green Chemical compound [Cl-].[Cl-].C1=CC(N(C)C)=CC=C1C(C=1C=CC(=CC=1)[N+](C)(C)C)=C1C=CC(=[N+](C)C)C=C1 DWCZIOOZPIDHAB-UHFFFAOYSA-L 0.000 description 1
- 238000010208 microarray analysis Methods 0.000 description 1
- 208000027061 mild cognitive impairment Diseases 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- ODKLEQPZOCJQMT-UHFFFAOYSA-N n,n-diethylpyridin-4-amine Chemical compound CCN(CC)C1=CC=NC=C1 ODKLEQPZOCJQMT-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000001129 nonadrenergic effect Effects 0.000 description 1
- 230000002536 noncholinergic effect Effects 0.000 description 1
- 230000002474 noradrenergic effect Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000008012 organic excipient Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 231100000199 ototoxic Toxicity 0.000 description 1
- 230000002970 ototoxic effect Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 208000008494 pericarditis Diseases 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 229960001999 phentolamine Drugs 0.000 description 1
- MRBDMNSDAVCSSF-UHFFFAOYSA-N phentolamine Chemical compound C1=CC(C)=CC=C1N(C=1C=C(O)C=CC=1)CC1=NCCN1 MRBDMNSDAVCSSF-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- 230000008832 photodamage Effects 0.000 description 1
- 230000037081 physical activity Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000036316 preload Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 208000011610 primary hypophysitis Diseases 0.000 description 1
- 206010063401 primary progressive multiple sclerosis Diseases 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 210000001176 projection neuron Anatomy 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- 229960003908 pseudoephedrine Drugs 0.000 description 1
- 210000003689 pubic bone Anatomy 0.000 description 1
- 230000004088 pulmonary circulation Effects 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 210000002763 pyramidal cell Anatomy 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229940069575 rompun Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 230000002784 sclerotic effect Effects 0.000 description 1
- 210000004706 scrotum Anatomy 0.000 description 1
- 201000005218 sebaceous adenoma Diseases 0.000 description 1
- 201000003385 seborrheic keratosis Diseases 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 201000008628 secondary progressive multiple sclerosis Diseases 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000035946 sexual desire Effects 0.000 description 1
- 230000035936 sexual power Effects 0.000 description 1
- 230000036259 sexual stimuli Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 208000018198 spasticity Diseases 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 208000002320 spinal muscular atrophy Diseases 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000007863 steatosis Effects 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 230000002739 subcortical effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 208000009056 telangiectasis Diseases 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- LJJKNPQAGWVLDQ-SNVBAGLBSA-N thiorphan Chemical compound OC(=O)CNC(=O)[C@@H](CS)CC1=CC=CC=C1 LJJKNPQAGWVLDQ-SNVBAGLBSA-N 0.000 description 1
- 230000009772 tissue formation Effects 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000001585 trabecular meshwork Anatomy 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 230000008736 traumatic injury Effects 0.000 description 1
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 1
- 229960003991 trazodone Drugs 0.000 description 1
- 150000003628 tricarboxylic acids Chemical class 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 208000028394 ureteral disease Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 230000006492 vascular dysfunction Effects 0.000 description 1
- 230000004865 vascular response Effects 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 230000002883 vasorelaxation effect Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 201000010044 viral meningitis Diseases 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- QYEFBJRXKKSABU-UHFFFAOYSA-N xylazine hydrochloride Chemical compound Cl.CC1=CC=CC(C)=C1NC1=NCCCS1 QYEFBJRXKKSABU-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- 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
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
- C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Immunology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Endocrinology (AREA)
- Genetics & Genomics (AREA)
- Reproductive Health (AREA)
- Molecular Biology (AREA)
- Heart & Thoracic Surgery (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Dermatology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Gastroenterology & Hepatology (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Hospice & Palliative Care (AREA)
- Psychology (AREA)
- Urology & Nephrology (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10344848A DE10344848A1 (de) | 2003-09-26 | 2003-09-26 | Amidomethyl-substituierte l-(Carboxyalkyl)-cyclopentylcarbonylamino-benzazepin-N-essigsäurederivate, Verfahren und Zwischenprodukte zu ihrer Herstellung und diese Verbindungen enhaltende Arzneimittel |
| DE10344848.9 | 2003-09-26 | ||
| EP04100065 | 2004-01-12 | ||
| EP04100065.4 | 2004-01-12 | ||
| PCT/EP2004/052289 WO2005030795A1 (fr) | 2003-09-26 | 2004-09-23 | Derives d'acide 1-(carboxyalkyl)-cyclopentylcarbonylamino-benzazepine-n-acetique a substitution amidomethyle, procede pour les preparer et medicaments contenant ces composes |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2007535482A JP2007535482A (ja) | 2007-12-06 |
| JP2007535482A5 JP2007535482A5 (fr) | 2011-08-04 |
| JP4824562B2 true JP4824562B2 (ja) | 2011-11-30 |
Family
ID=34395054
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2006527420A Expired - Fee Related JP4824562B2 (ja) | 2003-09-26 | 2004-09-23 | アミドメチル置換１−（カルボキシアルキル）−シクロペンチルカルボニルアミノ−ベンズアゼピン−ｎ−酢酸誘導体、これらを製造するための方法および中間生成物およびこれら化合物を含有する医薬 |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP1670814A1 (fr) |
| JP (1) | JP4824562B2 (fr) |
| KR (1) | KR101264934B1 (fr) |
| AR (1) | AR045798A1 (fr) |
| AU (1) | AU2004276002B2 (fr) |
| BR (1) | BRPI0414744A (fr) |
| CA (1) | CA2539895A1 (fr) |
| HK (1) | HK1096105A1 (fr) |
| IL (1) | IL174373A (fr) |
| MX (1) | MXPA06003226A (fr) |
| NO (1) | NO20061821L (fr) |
| RU (1) | RU2368601C2 (fr) |
| SA (1) | SA04250283B1 (fr) |
| TW (1) | TWI332947B (fr) |
| WO (1) | WO2005030795A1 (fr) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005112939A1 (fr) * | 2004-05-14 | 2005-12-01 | Solvay Pharmaceuticals Gmbh | Medicaments renfermant des inhibiteurs a action double de l'endopeptidase neutre et de l'endopeptidase humaine soluble et destines au traitement de la dysfonction sexuelle |
| EP1776095A1 (fr) * | 2004-06-23 | 2007-04-25 | Solvay Pharmaceuticals GmbH | Compositions pharmaceutiques comprenant des inhibiteurs de l'epn, inhibiteurs du systeme de production de l'endotheline endogene et antagonistes du recepteur at1 |
| EP1827448A1 (fr) | 2004-12-15 | 2007-09-05 | Solvay Pharmaceuticals GmbH | Compositions pharmaceutiques comprenant des inhibiteurs nep, inhibiteurs du systeme de production de l'endotheline endogene et inhibiteurs de la reductase hmg coa |
| DE602006013792D1 (de) * | 2005-02-18 | 2010-06-02 | Solvay Pharm Gmbh | Pharmazeutische zusammensetzungen mit nep-inhibitoren, inhibitoren des endogenes endothelin produzierenden systems und diuretika |
| CA2681267C (fr) * | 2007-04-13 | 2013-11-19 | Southern Research Institute | Agents anti-angiogeniques et procedes d'utilisation |
| AR071375A1 (es) * | 2008-04-22 | 2010-06-16 | Solvay Pharm Gmbh | Formulaciones para ingredientes farmaceuticos activos de permeabilidad deficiente, proceso de preparacion y producto |
| PL424452A1 (pl) * | 2018-01-31 | 2019-08-12 | Forty-Four Pharmaceuticals Spółka Z Ograniczoną Odpowiedzialnością | Inhibitory obojętnej endopeptydazy (NEP) i ludzkiej rozpuszczalnej endopeptydazy (hSEP) do profilaktyki i leczenia chorób oczu |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08269001A (ja) * | 1995-01-28 | 1996-10-15 | Merck Patent Gmbh | ４−アミノベンゾイルグアニジン誘導体 |
| JPH11292886A (ja) * | 1997-11-12 | 1999-10-26 | Solvay Pharmaceut Gmbh | ホスホン酸で置換されたベンズアゼピノン−ｎ−酢酸誘導体、並びにその製法及びこの化合物を含有する薬剤 |
| JP2002537258A (ja) * | 1999-02-16 | 2002-11-05 | ゾルファイ ファーマスーティカルズ ゲゼルシャフト ミット ベシュレンクテル ハフツング | 高血圧の治療のための医薬 |
| WO2003059939A1 (fr) * | 2002-01-16 | 2003-07-24 | Solvay Pharmaceuticals B.V. | Composes de benzazepine de sels solides et leur utilisation dans la preparation de composes pharmaceutiques |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19510566A1 (de) * | 1995-03-23 | 1996-09-26 | Kali Chemie Pharma Gmbh | Benzazepin-, Benzoxazepin- und Benzothiazepin-N-essigsäurederivate sowie Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel |
-
2004
- 2004-09-12 SA SA04250283A patent/SA04250283B1/ar unknown
- 2004-09-22 TW TW093128652A patent/TWI332947B/zh active
- 2004-09-22 AR ARP040103409A patent/AR045798A1/es not_active Application Discontinuation
- 2004-09-23 MX MXPA06003226A patent/MXPA06003226A/es active IP Right Grant
- 2004-09-23 EP EP04766846A patent/EP1670814A1/fr not_active Withdrawn
- 2004-09-23 BR BRPI0414744-8A patent/BRPI0414744A/pt not_active IP Right Cessation
- 2004-09-23 CA CA002539895A patent/CA2539895A1/fr not_active Abandoned
- 2004-09-23 JP JP2006527420A patent/JP4824562B2/ja not_active Expired - Fee Related
- 2004-09-23 AU AU2004276002A patent/AU2004276002B2/en not_active Ceased
- 2004-09-23 WO PCT/EP2004/052289 patent/WO2005030795A1/fr active Application Filing
- 2004-09-23 RU RU2006113946/04A patent/RU2368601C2/ru not_active IP Right Cessation
-
2006
- 2006-03-16 IL IL174373A patent/IL174373A/en not_active IP Right Cessation
- 2006-03-24 KR KR1020067005869A patent/KR101264934B1/ko not_active IP Right Cessation
- 2006-04-25 NO NO20061821A patent/NO20061821L/no not_active Application Discontinuation
-
2007
- 2007-03-30 HK HK07103455.5A patent/HK1096105A1/xx not_active IP Right Cessation
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08269001A (ja) * | 1995-01-28 | 1996-10-15 | Merck Patent Gmbh | ４−アミノベンゾイルグアニジン誘導体 |
| JPH11292886A (ja) * | 1997-11-12 | 1999-10-26 | Solvay Pharmaceut Gmbh | ホスホン酸で置換されたベンズアゼピノン−ｎ−酢酸誘導体、並びにその製法及びこの化合物を含有する薬剤 |
| JP2002537258A (ja) * | 1999-02-16 | 2002-11-05 | ゾルファイ ファーマスーティカルズ ゲゼルシャフト ミット ベシュレンクテル ハフツング | 高血圧の治療のための医薬 |
| WO2003059939A1 (fr) * | 2002-01-16 | 2003-07-24 | Solvay Pharmaceuticals B.V. | Composes de benzazepine de sels solides et leur utilisation dans la preparation de composes pharmaceutiques |
Also Published As
| Publication number | Publication date |
|---|---|
| AR045798A1 (es) | 2005-11-16 |
| JP2007535482A (ja) | 2007-12-06 |
| RU2368601C2 (ru) | 2009-09-27 |
| WO2005030795A1 (fr) | 2005-04-07 |
| CA2539895A1 (fr) | 2005-04-07 |
| AU2004276002A1 (en) | 2005-04-07 |
| IL174373A0 (en) | 2006-08-01 |
| KR101264934B1 (ko) | 2013-05-20 |
| HK1096105A1 (en) | 2007-05-25 |
| MXPA06003226A (es) | 2006-05-22 |
| BRPI0414744A (pt) | 2006-11-21 |
| NO20061821L (no) | 2006-06-22 |
| SA04250283B1 (ar) | 2008-05-26 |
| RU2006113946A (ru) | 2007-11-10 |
| TWI332947B (en) | 2010-11-11 |
| TW200524874A (en) | 2005-08-01 |
| EP1670814A1 (fr) | 2006-06-21 |
| IL174373A (en) | 2011-12-29 |
| KR20060101460A (ko) | 2006-09-25 |
| AU2004276002B2 (en) | 2010-07-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101264934B1 (ko) | 아미도메틸-치환1-(카르복시알킬)-시클로펜틸카보닐아미노-벤자제핀-ｎ-아세트산 유도체, 그것의 제조를 위한 공정 및 중간체 생성물및 이들 화합물을 포함하는 의약품 | |
| US9969772B2 (en) | Covalent granzyme B inhibitors | |
| US9458193B1 (en) | Proline compounds as Granzyme B inhibitors | |
| US9849112B2 (en) | Pyrrole compounds as Granzyme B inhibitors | |
| EP3186270B1 (fr) | Composés d'urée cyclique en tant qu'inhibiteurs du granzyme b | |
| US20200062803A1 (en) | Azaindoline compounds as granzyme b inhibitors | |
| CN101817769B (zh) | 脲基类肽氨肽酶n抑制剂及其应用 | |
| JP4359859B2 (ja) | 成長ホルモン放出特性を有する化合物 | |
| JP2001515919A (ja) | 骨代謝障害を治療するためのアルギニン擬態物質を含有するペプチド、それらの製造及びこれらの化合物を含有する薬物 | |
| US7410962B2 (en) | Amidomethyl-substituted 1-(carboxyalkyl) cyclopentyl-carbonylamino-benzazepine-N-acetic acid compounds, process and intermediate products for their preparation and pharmaceutical compositions containing them | |
| US7427611B2 (en) | Amidomethyl-substituted 1-(carboxyalkyl)-cyclopentyl-carbonylamino-benzazepine-N-acetic acid compounds, process and intermediate products for their preparation and pharmaceutical compositions containing them | |
| FR2733995A1 (fr) | Inhibiteurs de l'inactivation de neuropeptides endogenes notamment la cholecystokinine, leurs procedes de preparation leur utilisation comme medicaments et procede de criblage de medicaments | |
| JP2008019188A (ja) | 新規カルノシン誘導体及び組成物 | |
| JPH05148277A (ja) | アミノホスホン酸誘導体 | |
| US7452875B2 (en) | Amidomethyl-substituted 1-(carboxyalkyl) cyclopentyl-carbonylamino-benzazepine-N-acetic acid compounds, process and intermediate products for their preparation and pharmaceutical compositions containing them | |
| CN100497372C (zh) | 酰胺甲基取代的1-(羧烷基)-环戊基羰基氨基-苯并氮杂-n-乙酸衍生物、它们的制备方法和中间产物以及含这些化合物的药物 | |
| US6593300B1 (en) | (3R)-3-amino-4-carboxybutyraldehyde derivatives inhibiting the release of interleukin-1/beta | |
| CN115160204A (zh) | 一种成纤维细胞活化蛋白抑制剂及其制备方法和应用 | |
| WO2006009325A1 (fr) | Inhibiteur de métalloprotéase | |
| JPH11292894A (ja) | Ｎ−アシルテトラヒドロキノリン誘導体 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20101217 |
|
| RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20101228 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20110127 |
|
| A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20110203 |
|
| A524 | Written submission of copy of amendment under article 19 pct |
Free format text: JAPANESE INTERMEDIATE CODE: A524 Effective date: 20110617 |
|
| 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: 20110817 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20110908 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20140916 Year of fee payment: 3 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| LAPS | Cancellation because of no payment of annual fees |