CA2433025A1 - Substituted piperidines/piperazines as melanocortin receptor agonists - Google Patents
Substituted piperidines/piperazines as melanocortin receptor agonists Download PDFInfo
- Publication number
- CA2433025A1 CA2433025A1 CA002433025A CA2433025A CA2433025A1 CA 2433025 A1 CA2433025 A1 CA 2433025A1 CA 002433025 A CA002433025 A CA 002433025A CA 2433025 A CA2433025 A CA 2433025A CA 2433025 A1 CA2433025 A1 CA 2433025A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- compound
- formula
- hydrogen
- independently
- 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.)
- Abandoned
Links
- 239000000336 melanocortin receptor agonist Substances 0.000 title abstract description 10
- 150000003053 piperidines Chemical class 0.000 title description 5
- 150000004885 piperazines Chemical class 0.000 title description 2
- 206010057671 Female sexual dysfunction Diseases 0.000 claims abstract description 14
- 208000008589 Obesity Diseases 0.000 claims abstract description 11
- 235000020824 obesity Nutrition 0.000 claims abstract description 11
- 206010057672 Male sexual dysfunction Diseases 0.000 claims abstract description 10
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 465
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 248
- 125000000217 alkyl group Chemical group 0.000 claims description 153
- 229910052739 hydrogen Inorganic materials 0.000 claims description 136
- 239000001257 hydrogen Substances 0.000 claims description 134
- 238000000034 method Methods 0.000 claims description 105
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 92
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 81
- 125000003118 aryl group Chemical group 0.000 claims description 75
- -1 flouro Chemical group 0.000 claims description 74
- 150000002431 hydrogen Chemical class 0.000 claims description 72
- 229920006395 saturated elastomer Polymers 0.000 claims description 70
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 62
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 54
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 53
- 150000003839 salts Chemical class 0.000 claims description 53
- 125000000623 heterocyclic group Chemical group 0.000 claims description 52
- 238000005859 coupling reaction Methods 0.000 claims description 48
- 230000008878 coupling Effects 0.000 claims description 43
- 238000010168 coupling process Methods 0.000 claims description 43
- 125000005843 halogen group Chemical group 0.000 claims description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- 125000001424 substituent group Chemical group 0.000 claims description 40
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 32
- 229910052757 nitrogen Inorganic materials 0.000 claims description 31
- 125000003545 alkoxy group Chemical group 0.000 claims description 30
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 30
- 125000001188 haloalkyl group Chemical group 0.000 claims description 29
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 28
- 229910052799 carbon Inorganic materials 0.000 claims description 27
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 25
- 150000001412 amines Chemical class 0.000 claims description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 24
- 125000001544 thienyl group Chemical group 0.000 claims description 24
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 22
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 22
- 230000008569 process Effects 0.000 claims description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 102000004877 Insulin Human genes 0.000 claims description 16
- 108090001061 Insulin Proteins 0.000 claims description 16
- 229940125396 insulin Drugs 0.000 claims description 16
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 15
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 15
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 13
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 12
- 241000124008 Mammalia Species 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 125000001624 naphthyl group Chemical group 0.000 claims description 12
- 125000006239 protecting group Chemical group 0.000 claims description 12
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 11
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 10
- 150000002466 imines Chemical class 0.000 claims description 10
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 9
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical group C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 claims description 9
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 201000001881 impotence Diseases 0.000 claims description 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 8
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 8
- 238000006845 Michael addition reaction Methods 0.000 claims description 8
- 230000002378 acidificating effect Effects 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 238000005984 hydrogenation reaction Methods 0.000 claims description 7
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 7
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 claims description 6
- 230000003213 activating effect Effects 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 5
- 229940125898 compound 5 Drugs 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 239000003112 inhibitor Substances 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 claims description 5
- 238000010626 work up procedure Methods 0.000 claims description 5
- BWKMGYQJPOAASG-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1=CC=C2CNC(C(=O)O)CC2=C1 BWKMGYQJPOAASG-UHFFFAOYSA-N 0.000 claims description 4
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 claims description 3
- 229940122355 Insulin sensitizer Drugs 0.000 claims description 3
- 229940100389 Sulfonylurea Drugs 0.000 claims description 3
- 239000003529 anticholesteremic agent Substances 0.000 claims description 3
- 229940127226 anticholesterol agent Drugs 0.000 claims description 3
- 150000001768 cations Chemical class 0.000 claims description 3
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 3
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 150000004713 phosphodiesters Chemical class 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- 125000001422 pyrrolinyl group Chemical group 0.000 claims description 3
- 239000003352 sequestering agent Substances 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 3
- 125000001425 triazolyl group Chemical group 0.000 claims description 3
- 239000000670 adrenergic alpha-2 receptor antagonist Substances 0.000 claims description 2
- 239000003888 alpha glucosidase inhibitor Substances 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 230000003635 deoxygenating effect Effects 0.000 claims description 2
- 239000002660 neuropeptide Y receptor antagonist Substances 0.000 claims description 2
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 229940126158 β3 adrenergic receptor agonist Drugs 0.000 claims description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 65
- 101100533877 Hypocrea jecorina (strain QM6a) sor8 gene Proteins 0.000 claims 5
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims 2
- FFCCKWBZIGDVJP-UHFFFAOYSA-N n-[3-(4-chlorophenyl)-1-[4-[7-(diethylamino)-5,6,7,8-tetrahydronaphthalen-1-yl]piperazin-1-yl]-1-oxopropan-2-yl]-2-(1,2,3,4-tetrahydroisoquinolin-1-yl)acetamide Chemical compound C=12CC(N(CC)CC)CCC2=CC=CC=1N(CC1)CCN1C(=O)C(NC(=O)CC1C2=CC=CC=C2CCN1)CC1=CC=C(Cl)C=C1 FFCCKWBZIGDVJP-UHFFFAOYSA-N 0.000 claims 1
- FTACVMNNXLBFQB-UHFFFAOYSA-N n-[3-(4-chlorophenyl)-1-oxo-1-[4-[7-(2h-pyridin-1-yl)-5,6,7,8-tetrahydronaphthalen-1-yl]piperazin-1-yl]propan-2-yl]-2-(2,3-dihydro-1h-isoindol-1-yl)acetamide Chemical compound C1=CC(Cl)=CC=C1CC(C(=O)N1CCN(CC1)C=1C=2CC(CCC=2C=CC=1)N1C=CC=CC1)NC(=O)CC1C2=CC=CC=C2CN1 FTACVMNNXLBFQB-UHFFFAOYSA-N 0.000 claims 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 323
- 239000000203 mixture Substances 0.000 description 289
- 238000002360 preparation method Methods 0.000 description 214
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 155
- 235000019439 ethyl acetate Nutrition 0.000 description 151
- 239000000243 solution Substances 0.000 description 125
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 117
- 229910001868 water Inorganic materials 0.000 description 105
- 239000000047 product Substances 0.000 description 94
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 87
- 238000006243 chemical reaction Methods 0.000 description 83
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 78
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 75
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 75
- ZHGNHOOVYPHPNJ-UHFFFAOYSA-N Amigdalin Chemical compound FC(F)(F)C(=O)OCC1OC(OCC2OC(OC(C#N)C3=CC=CC=C3)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C2OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C1OC(=O)C(F)(F)F ZHGNHOOVYPHPNJ-UHFFFAOYSA-N 0.000 description 73
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 72
- 239000007787 solid Substances 0.000 description 63
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 60
- 239000012267 brine Substances 0.000 description 59
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 59
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 43
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 40
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 39
- 238000003818 flash chromatography Methods 0.000 description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 38
- 239000003921 oil Substances 0.000 description 37
- 239000000741 silica gel Substances 0.000 description 37
- 229910002027 silica gel Inorganic materials 0.000 description 37
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- 239000000463 material Substances 0.000 description 35
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- 239000002253 acid Substances 0.000 description 30
- 239000010410 layer Substances 0.000 description 30
- 238000004587 chromatography analysis Methods 0.000 description 29
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 29
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 29
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 28
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 27
- 238000012799 strong cation exchange Methods 0.000 description 27
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 25
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 24
- 239000012467 final product Substances 0.000 description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 23
- 239000012044 organic layer Substances 0.000 description 22
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 21
- 238000010898 silica gel chromatography Methods 0.000 description 21
- 229940093499 ethyl acetate Drugs 0.000 description 20
- 238000001914 filtration Methods 0.000 description 20
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 20
- 238000010992 reflux Methods 0.000 description 20
- 239000007858 starting material Substances 0.000 description 20
- 238000007792 addition Methods 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
- 238000010511 deprotection reaction Methods 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 18
- 241001465754 Metazoa Species 0.000 description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 17
- 150000002148 esters Chemical class 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 17
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 17
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 16
- 239000002002 slurry Substances 0.000 description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 15
- 229940086542 triethylamine Drugs 0.000 description 15
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 14
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- 239000000556 agonist Substances 0.000 description 14
- 239000000284 extract Substances 0.000 description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 238000004255 ion exchange chromatography Methods 0.000 description 13
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 description 13
- 230000002829 reductive effect Effects 0.000 description 13
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 12
- 239000007821 HATU Substances 0.000 description 12
- 238000003556 assay Methods 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- 108090000950 Melanocortin Receptors Proteins 0.000 description 11
- 102000004378 Melanocortin Receptors Human genes 0.000 description 11
- 230000037406 food intake Effects 0.000 description 11
- 235000012631 food intake Nutrition 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- 238000006268 reductive amination reaction Methods 0.000 description 11
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 11
- 229910004373 HOAc Inorganic materials 0.000 description 10
- 229960000583 acetic acid Drugs 0.000 description 10
- 239000005557 antagonist Substances 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 229960004132 diethyl ether Drugs 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 239000006260 foam Substances 0.000 description 10
- 230000004044 response Effects 0.000 description 10
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 10
- 241000700159 Rattus Species 0.000 description 9
- UAHFGYDRQSXQEB-LEBBXHLNSA-N afamelanotide Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(N)=O)NC(=O)[C@H](CO)NC(C)=O)C1=CC=C(O)C=C1 UAHFGYDRQSXQEB-LEBBXHLNSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 238000011156 evaluation Methods 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 9
- 150000001299 aldehydes Chemical group 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 8
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 8
- 239000012528 membrane Substances 0.000 description 8
- 239000011347 resin Substances 0.000 description 8
- 229920005989 resin Polymers 0.000 description 8
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 8
- NDOPHXWIAZIXPR-UHFFFAOYSA-N 2-bromobenzaldehyde Chemical compound BrC1=CC=CC=C1C=O NDOPHXWIAZIXPR-UHFFFAOYSA-N 0.000 description 7
- 108700034262 4-Nle-7-Phe-alpha- MSH Proteins 0.000 description 7
- YNXLDZYAFGPNHL-UHFFFAOYSA-N 8-bromo-1,2,3,4-tetrahydronaphthalen-2-amine Chemical compound C1=CC(Br)=C2CC(N)CCC2=C1 YNXLDZYAFGPNHL-UHFFFAOYSA-N 0.000 description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 125000001072 heteroaryl group Chemical group 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 150000004702 methyl esters Chemical class 0.000 description 7
- WFDJZTQNOUIKPB-UHFFFAOYSA-N tert-butyl 4-(1,2,3,4-tetrahydroisoquinolin-8-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=CC2=C1CNCC2 WFDJZTQNOUIKPB-UHFFFAOYSA-N 0.000 description 7
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 7
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 150000001717 carbocyclic compounds Chemical class 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- 229910052744 lithium Inorganic materials 0.000 description 6
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 6
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical group CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 6
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 6
- 230000004224 protection Effects 0.000 description 6
- 230000011514 reflex Effects 0.000 description 6
- 229910052814 silicon oxide Inorganic materials 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
- DPRIHFQFWWCIGY-UHFFFAOYSA-N 8-bromoisoquinoline Chemical compound C1=NC=C2C(Br)=CC=CC2=C1 DPRIHFQFWWCIGY-UHFFFAOYSA-N 0.000 description 5
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 5
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 5
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000010779 crude oil Substances 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 150000002081 enamines Chemical class 0.000 description 5
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- JZKXXXDKRQWDET-UHFFFAOYSA-N meta-tyrosine Natural products OC(=O)C(N)CC1=CC=CC(O)=C1 JZKXXXDKRQWDET-UHFFFAOYSA-N 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 241000039077 Copula Species 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 4
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical class C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000011324 bead Substances 0.000 description 4
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 238000006392 deoxygenation reaction Methods 0.000 description 4
- 208000037765 diseases and disorders Diseases 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 4
- 239000008188 pellet Substances 0.000 description 4
- 210000003899 penis Anatomy 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 239000012258 stirred mixture Substances 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- NIGWMJHCCYYCSF-MRVPVSSYSA-N (2r)-2-amino-3-(4-chlorophenyl)propanoic acid Chemical compound OC(=O)[C@H](N)CC1=CC=C(Cl)C=C1 NIGWMJHCCYYCSF-MRVPVSSYSA-N 0.000 description 3
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 3
- PXLFPAMVHOMIIC-UHFFFAOYSA-N 8-bromo-1,2,3,4-tetrahydronaphthalen-2-ol Chemical compound C1=CC(Br)=C2CC(O)CCC2=C1 PXLFPAMVHOMIIC-UHFFFAOYSA-N 0.000 description 3
- RWEVGLMABSFMKW-UHFFFAOYSA-N 8-bromo-3,4-dihydro-1h-naphthalen-2-one Chemical compound C1CC(=O)CC2=C1C=CC=C2Br RWEVGLMABSFMKW-UHFFFAOYSA-N 0.000 description 3
- SLTPPQIDSQSJIC-UHFFFAOYSA-N 8-piperazin-1-ylisoquinoline Chemical compound C1CNCCN1C1=CC=CC2=CC=NC=C12 SLTPPQIDSQSJIC-UHFFFAOYSA-N 0.000 description 3
- 102000006822 Agouti Signaling Protein Human genes 0.000 description 3
- 108010072151 Agouti Signaling Protein Proteins 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- 241000484025 Cuniculus Species 0.000 description 3
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 3
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 3
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- JZKXXXDKRQWDET-QMMMGPOBSA-N L-m-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC(O)=C1 JZKXXXDKRQWDET-QMMMGPOBSA-N 0.000 description 3
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 238000006929 Pictet-Spengler synthesis reaction Methods 0.000 description 3
- 108010069820 Pro-Opiomelanocortin Proteins 0.000 description 3
- 239000000683 Pro-Opiomelanocortin Substances 0.000 description 3
- 102100027467 Pro-opiomelanocortin Human genes 0.000 description 3
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- JVVXZOOGOGPDRZ-SLFFLAALSA-N [(1R,4aS,10aR)-1,4a-dimethyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthren-1-yl]methanamine Chemical compound NC[C@]1(C)CCC[C@]2(C)C3=CC=C(C(C)C)C=C3CC[C@H]21 JVVXZOOGOGPDRZ-SLFFLAALSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000012148 binding buffer Substances 0.000 description 3
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 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
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 239000013058 crude material Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 description 3
- USVZFSNDGFNNJT-UHFFFAOYSA-N cyclopenta-1,4-dien-1-yl(diphenyl)phosphane (2,3-dichlorocyclopenta-1,4-dien-1-yl)-diphenylphosphane iron(2+) Chemical compound [Fe++].c1cc[c-](c1)P(c1ccccc1)c1ccccc1.Clc1c(cc[c-]1Cl)P(c1ccccc1)c1ccccc1 USVZFSNDGFNNJT-UHFFFAOYSA-N 0.000 description 3
- 239000002027 dichloromethane extract Substances 0.000 description 3
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 238000005580 one pot reaction Methods 0.000 description 3
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 229940117803 phenethylamine Drugs 0.000 description 3
- 229960005190 phenylalanine Drugs 0.000 description 3
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000000159 protein binding assay Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000011369 resultant mixture Substances 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 230000006103 sulfonylation Effects 0.000 description 3
- 238000005694 sulfonylation reaction Methods 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 2
- HFPVZPNLMJDJFB-GFCCVEGCSA-N (3r)-2-[(2-methylpropan-2-yl)oxycarbonyl]-3,4-dihydro-1h-isoquinoline-3-carboxylic acid Chemical compound C1=CC=C2C[C@H](C(O)=O)N(C(=O)OC(C)(C)C)CC2=C1 HFPVZPNLMJDJFB-GFCCVEGCSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- OFKFBEJYOHXPIA-UHFFFAOYSA-N 2,3-dihydro-1h-isoindol-2-ium-1-carboxylate Chemical class C1=CC=C2C(C(=O)O)NCC2=C1 OFKFBEJYOHXPIA-UHFFFAOYSA-N 0.000 description 2
- CMNLNCAHSRIGNB-UHFFFAOYSA-N 2-(2-methyl-1,3-dihydroisoindol-1-yl)acetic acid Chemical compound C1=CC=C2C(CC(O)=O)N(C)CC2=C1 CMNLNCAHSRIGNB-UHFFFAOYSA-N 0.000 description 2
- BBMCBMREDOQCDU-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonyl]-1,3-dihydroisoindole-1-carboxylic acid Chemical compound C1=CC=C2C(C(O)=O)N(C(=O)OC(C)(C)C)CC2=C1 BBMCBMREDOQCDU-UHFFFAOYSA-N 0.000 description 2
- XSSWFYSBSGAYOD-UHFFFAOYSA-N 2-[2-[(2-methylpropan-2-yl)oxycarbonyl]-1,3-dihydroisoindol-1-yl]acetic acid Chemical compound C1=CC=C2C(CC(O)=O)N(C(=O)OC(C)(C)C)CC2=C1 XSSWFYSBSGAYOD-UHFFFAOYSA-N 0.000 description 2
- 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
- XNHKTMIWQCNZST-UHFFFAOYSA-N 2-bromo-5-methoxybenzaldehyde Chemical compound COC1=CC=C(Br)C(C=O)=C1 XNHKTMIWQCNZST-UHFFFAOYSA-N 0.000 description 2
- CHODTZCXWXCALP-UHFFFAOYSA-N 5-bromoquinoline Chemical compound C1=CC=C2C(Br)=CC=CC2=N1 CHODTZCXWXCALP-UHFFFAOYSA-N 0.000 description 2
- MUBNVVQOLQPCFS-UHFFFAOYSA-N 5-piperazin-1-ylisoquinoline Chemical compound C1CNCCN1C1=CC=CC2=CN=CC=C12 MUBNVVQOLQPCFS-UHFFFAOYSA-N 0.000 description 2
- OMUGTYURPIFBDU-UHFFFAOYSA-N 5-piperazin-1-ylquinoline Chemical compound C1CNCCN1C1=CC=CC2=NC=CC=C12 OMUGTYURPIFBDU-UHFFFAOYSA-N 0.000 description 2
- LMIKROMBLAHKDQ-UHFFFAOYSA-N 8-bromo-n,n-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine Chemical compound C1=CC(Br)=C2CC(N(C)C)CCC2=C1 LMIKROMBLAHKDQ-UHFFFAOYSA-N 0.000 description 2
- PIWNKSHCLTZKSZ-UHFFFAOYSA-N 8-bromoquinoline Chemical compound C1=CN=C2C(Br)=CC=CC2=C1 PIWNKSHCLTZKSZ-UHFFFAOYSA-N 0.000 description 2
- DCUZDOXGNVJQQL-UHFFFAOYSA-N 8-piperazin-1-ylquinoline Chemical compound C1CNCCN1C1=CC=CC2=CC=CN=C12 DCUZDOXGNVJQQL-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 101100294115 Caenorhabditis elegans nhr-4 gene Proteins 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical class COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 2
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 101000978431 Homo sapiens Melanocortin receptor 3 Proteins 0.000 description 2
- 101000978418 Homo sapiens Melanocortin receptor 4 Proteins 0.000 description 2
- 206010020710 Hyperphagia Diseases 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 238000012369 In process control Methods 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 102000016267 Leptin Human genes 0.000 description 2
- 108010092277 Leptin Proteins 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- 229940124757 MC-4 agonist Drugs 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 102100023726 Melanocortin receptor 3 Human genes 0.000 description 2
- 102100023724 Melanocortin receptor 4 Human genes 0.000 description 2
- 101710151321 Melanostatin Proteins 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical compound CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 102400000064 Neuropeptide Y Human genes 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 2
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 2
- 108010016731 PPAR gamma Proteins 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 102100038825 Peroxisome proliferator-activated receptor gamma Human genes 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 206010052005 Psychogenic erectile dysfunction Diseases 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 239000002262 Schiff base Substances 0.000 description 2
- 150000004753 Schiff bases Chemical class 0.000 description 2
- 201000001880 Sexual dysfunction Diseases 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 229920004890 Triton X-100 Polymers 0.000 description 2
- 210000000577 adipose tissue Anatomy 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 150000003862 amino acid derivatives Chemical class 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000037007 arousal Effects 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 235000011148 calcium chloride Nutrition 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000013066 combination product Substances 0.000 description 2
- 229940127555 combination product Drugs 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000003750 conditioning effect Effects 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 230000006806 disease prevention Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000003821 enantio-separation Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 238000010965 in-process control Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 150000002537 isoquinolines Chemical class 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 238000011813 knockout mouse model Methods 0.000 description 2
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 2
- 229940039781 leptin Drugs 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
- 159000000002 lithium salts Chemical class 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
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- GRWIABMEEKERFV-UHFFFAOYSA-N methanol;oxolane Chemical compound OC.C1CCOC1 GRWIABMEEKERFV-UHFFFAOYSA-N 0.000 description 2
- RHVNHKWMQOUSLJ-UHFFFAOYSA-N methoxymethanamine;hydrochloride Chemical compound Cl.COCN RHVNHKWMQOUSLJ-UHFFFAOYSA-N 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- URPYMXQQVHTUDU-OFGSCBOVSA-N nucleopeptide y Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 URPYMXQQVHTUDU-OFGSCBOVSA-N 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000018052 penile erection Effects 0.000 description 2
- 238000005897 peptide coupling reaction Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- 210000002826 placenta Anatomy 0.000 description 2
- 229910003446 platinum oxide Inorganic materials 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 2
- 230000036515 potency Effects 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 239000002516 radical scavenger Substances 0.000 description 2
- 238000003653 radioligand binding assay Methods 0.000 description 2
- 239000000837 restrainer Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 231100000872 sexual dysfunction Toxicity 0.000 description 2
- 230000001568 sexual effect 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
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000002356 single layer Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000012453 sprague-dawley rat model Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000012607 strong cation exchange resin Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 238000004114 suspension culture Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 150000003892 tartrate salts Chemical class 0.000 description 2
- VCOVIOYPTIKGCS-CQSZACIVSA-N tert-butyl (3r)-3-[methoxy(methyl)carbamoyl]-3,4-dihydro-1h-isoquinoline-2-carboxylate Chemical compound C1=CC=C2CN(C(=O)OC(C)(C)C)[C@@H](C(=O)N(C)OC)CC2=C1 VCOVIOYPTIKGCS-CQSZACIVSA-N 0.000 description 2
- ZAGGFTSZPNYRBK-UHFFFAOYSA-N tert-butyl 4-(1,2,3,4-tetrahydroquinolin-8-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=CC2=C1NCCC2 ZAGGFTSZPNYRBK-UHFFFAOYSA-N 0.000 description 2
- OCZNKFFKIOUFBW-UHFFFAOYSA-N tert-butyl 4-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=CC2=C1CC(O)CC2 OCZNKFFKIOUFBW-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
- 150000008648 triflates Chemical class 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- DBGIVFWFUFKIQN-VIFPVBQESA-N (+)-Fenfluramine Chemical compound CCN[C@@H](C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-VIFPVBQESA-N 0.000 description 1
- DBGIVFWFUFKIQN-UHFFFAOYSA-N (+-)-Fenfluramine Chemical compound CCNC(C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-UHFFFAOYSA-N 0.000 description 1
- RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 description 1
- XFQNWPYGEGCIMF-HCUGAJCMSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].[Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 XFQNWPYGEGCIMF-HCUGAJCMSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- MDEJOHXOXKDGOU-UHFFFAOYSA-N (2-bromophenyl)methanamine;hydrochloride Chemical compound Cl.NCC1=CC=CC=C1Br MDEJOHXOXKDGOU-UHFFFAOYSA-N 0.000 description 1
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 1
- RCXSXRAUMLKRRL-LLVKDONJSA-N (2r)-3-(4-fluorophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](C(O)=O)CC1=CC=C(F)C=C1 RCXSXRAUMLKRRL-LLVKDONJSA-N 0.000 description 1
- RDEIXVOBVLKYNT-VQBXQJRRSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(1-aminoethyl)oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol;(2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(aminomethyl)oxan-2-yl]o Chemical compound OS(O)(=O)=O.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@@H](CN)O2)N)[C@@H](N)C[C@H]1N.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@H](O2)C(C)N)N)[C@@H](N)C[C@H]1N.O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N RDEIXVOBVLKYNT-VQBXQJRRSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 1
- HFPVZPNLMJDJFB-LBPRGKRZSA-N (3s)-2-[(2-methylpropan-2-yl)oxycarbonyl]-3,4-dihydro-1h-isoquinoline-3-carboxylic acid Chemical compound C1=CC=C2C[C@@H](C(O)=O)N(C(=O)OC(C)(C)C)CC2=C1 HFPVZPNLMJDJFB-LBPRGKRZSA-N 0.000 description 1
- GGYWLZFXFKFWKL-GLWNXGLNSA-N (3s,6s,9r,12s,15r,23s)-15-[[(2r)-2-acetamidohexanoyl]amino]-6-[3-(diaminomethylideneamino)propyl]-12-(1h-imidazol-5-ylmethyl)-3-(1h-indol-3-ylmethyl)-9-(naphthalen-2-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-23-carboxamide Chemical compound C([C@H]1C(=O)N[C@H](CC=2C=C3C=CC=CC3=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCNC(=O)C[C@H](C(N1)=O)NC(=O)[C@H](NC(C)=O)CCCC)C(N)=O)C1=CNC=N1 GGYWLZFXFKFWKL-GLWNXGLNSA-N 0.000 description 1
- XKRRJFYQNKYWPJ-UHFFFAOYSA-N (4-chlorophenyl) propanoate Chemical compound CCC(=O)OC1=CC=C(Cl)C=C1 XKRRJFYQNKYWPJ-UHFFFAOYSA-N 0.000 description 1
- RWIUTHWKQHRQNP-ZDVGBALWSA-N (9e,12e)-n-(1-phenylethyl)octadeca-9,12-dienamide Chemical compound CCCCC\C=C\C\C=C\CCCCCCCC(=O)NC(C)C1=CC=CC=C1 RWIUTHWKQHRQNP-ZDVGBALWSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 1
- OXFGRWIKQDSSLY-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinolin-2-ium-1-carboxylate Chemical compound C1=CC=C2C(C(=O)O)NCCC2=C1 OXFGRWIKQDSSLY-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- QACMXJJLQXUOPQ-UHFFFAOYSA-N 1,2-dichloroethane;3-(ethyliminomethylideneamino)-n,n-dimethylpropan-1-amine Chemical compound ClCCCl.CCN=C=NCCCN(C)C QACMXJJLQXUOPQ-UHFFFAOYSA-N 0.000 description 1
- JUXAVSAMVBLDKO-UHFFFAOYSA-N 1-(1-azabicyclo[2.2.2]octan-3-yl)-3-[3-(1h-indol-3-yl)-1-oxo-1-spiro[1,2-dihydroindene-3,4'-piperidine]-1'-ylpropan-2-yl]urea Chemical compound C1N(CC2)CCC2C1NC(=O)NC(C(=O)N1CCC2(C3=CC=CC=C3CC2)CC1)CC1=CNC2=CC=CC=C12 JUXAVSAMVBLDKO-UHFFFAOYSA-N 0.000 description 1
- NDMFETHQFUOIQX-UHFFFAOYSA-N 1-(3-chloropropyl)imidazolidin-2-one Chemical compound ClCCCN1CCNC1=O NDMFETHQFUOIQX-UHFFFAOYSA-N 0.000 description 1
- KYSHIDFDITVXDG-UHFFFAOYSA-N 1-(carboxymethyl)-1,3-dihydroisoindole-2-carboxylic acid Chemical compound C1=CC=C2C(CC(=O)O)N(C(O)=O)CC2=C1 KYSHIDFDITVXDG-UHFFFAOYSA-N 0.000 description 1
- HVHBWJPAJIYKPD-UHFFFAOYSA-N 1-(carboxymethyl)-3,4-dihydro-1h-isoquinoline-2-carboxylic acid Chemical compound C1=CC=C2C(CC(=O)O)N(C(O)=O)CCC2=C1 HVHBWJPAJIYKPD-UHFFFAOYSA-N 0.000 description 1
- BJNDCXAOGGSLIW-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]-3,4-dihydro-2h-isoquinoline-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)OC(C)(C)C)(C(O)=O)NCCC2=C1 BJNDCXAOGGSLIW-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- YTNVPKYXIQOHLT-UHFFFAOYSA-N 1-[2-[[1-carboxy-2-(4-chlorophenyl)ethyl]amino]-2-oxoethyl]-1,3-dihydroisoindole-2-carboxylic acid Chemical compound C(=O)(O)C(CC1=CC=C(C=C1)Cl)NC(=O)CC1N(CC2=CC=CC=C12)C(=O)O YTNVPKYXIQOHLT-UHFFFAOYSA-N 0.000 description 1
- JZUMPNUYDJBTNO-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1.C1=CC=C2N(O)N=NC2=C1 JZUMPNUYDJBTNO-UHFFFAOYSA-N 0.000 description 1
- YKYWUHHZZRBGMG-JWTNVVGKSA-N 1-methyl-2-[[(1r,5s)-6-[[5-(trifluoromethyl)pyridin-2-yl]methoxymethyl]-3-azabicyclo[3.1.0]hexan-3-yl]methyl]benzimidazole Chemical compound C1([C@@H]2CN(C[C@@H]21)CC=1N(C2=CC=CC=C2N=1)C)COCC1=CC=C(C(F)(F)F)C=N1 YKYWUHHZZRBGMG-JWTNVVGKSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- QBAYNEIYLJCYCZ-UHFFFAOYSA-N 2,2,2-trifluoro-1-(4-isoquinolin-8-ylpiperazin-1-yl)ethanone Chemical compound C1CN(C(=O)C(F)(F)F)CCN1C1=CC=CC2=CC=NC=C12 QBAYNEIYLJCYCZ-UHFFFAOYSA-N 0.000 description 1
- JHAFLRIMTSPLCY-UHFFFAOYSA-N 2,2,2-trifluoro-1-[4-(1,2,3,4-tetrahydroisoquinolin-8-yl)piperazin-1-yl]ethanone Chemical compound C1CN(C(=O)C(F)(F)F)CCN1C1=CC=CC2=C1CNCC2 JHAFLRIMTSPLCY-UHFFFAOYSA-N 0.000 description 1
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- BUAVPRGEIAVFBF-UHFFFAOYSA-N 2-(1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid Chemical compound C1=CC=C2C(CC(=O)O)NCCC2=C1 BUAVPRGEIAVFBF-UHFFFAOYSA-N 0.000 description 1
- XITJWUMAALXOKV-UHFFFAOYSA-N 2-(2,3-dihydro-1h-isoindol-1-yl)acetic acid Chemical compound C1=CC=C2C(CC(=O)O)NCC2=C1 XITJWUMAALXOKV-UHFFFAOYSA-N 0.000 description 1
- VOKNFSKZJCPWRP-UHFFFAOYSA-N 2-(2-butyl-1,3-dihydroisoindol-1-yl)acetic acid Chemical compound C1=CC=C2C(CC(O)=O)N(CCCC)CC2=C1 VOKNFSKZJCPWRP-UHFFFAOYSA-N 0.000 description 1
- XKXREZRZDGQXOA-UHFFFAOYSA-N 2-(2-methyl-3,4-dihydro-1h-isoquinolin-1-yl)acetic acid Chemical compound C1=CC=C2C(CC(O)=O)N(C)CCC2=C1 XKXREZRZDGQXOA-UHFFFAOYSA-N 0.000 description 1
- DVWGICSQDVNBJR-UHFFFAOYSA-N 2-(2-propan-2-yl-1,3-dihydroisoindol-1-yl)acetic acid Chemical compound C1=CC=C2C(CC(O)=O)N(C(C)C)CC2=C1 DVWGICSQDVNBJR-UHFFFAOYSA-N 0.000 description 1
- HFPVZPNLMJDJFB-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonyl]-3,4-dihydro-1h-isoquinoline-3-carboxylic acid Chemical compound C1=CC=C2CC(C(O)=O)N(C(=O)OC(C)(C)C)CC2=C1 HFPVZPNLMJDJFB-UHFFFAOYSA-N 0.000 description 1
- IPGWZQZZAVXIIS-UHFFFAOYSA-N 2-[1-[(2-methylpropan-2-yl)oxycarbonyl]-3,4-dihydro-2h-isoquinolin-1-yl]acetic acid Chemical compound C1=CC=C2C(C(=O)OC(C)(C)C)(CC(O)=O)NCCC2=C1 IPGWZQZZAVXIIS-UHFFFAOYSA-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
- DQVHIQQUGLBAOE-UHFFFAOYSA-N 2-[2-[(2-methylpropan-2-yl)oxycarbonyl]-3,4-dihydro-1h-isoquinolin-1-yl]acetic acid Chemical compound C1=CC=C2C(CC(O)=O)N(C(=O)OC(C)(C)C)CCC2=C1 DQVHIQQUGLBAOE-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- AUVALWUPUHHNQV-UHFFFAOYSA-N 2-hydroxy-3-propylbenzoic acid Chemical class CCCC1=CC=CC(C(O)=O)=C1O AUVALWUPUHHNQV-UHFFFAOYSA-N 0.000 description 1
- YSEFYOVWKJXNCH-UHFFFAOYSA-N 2-methoxyacetaldehyde Chemical compound COCC=O YSEFYOVWKJXNCH-UHFFFAOYSA-N 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- PPWLAQVKIFDULF-UHFFFAOYSA-N 2-phenyl-1h-pyrrolo[2,3-b]pyridine Chemical compound N1C2=NC=CC=C2C=C1C1=CC=CC=C1 PPWLAQVKIFDULF-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UHFFFAOYSA-N 2-{[3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy}-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound OCC1OC(CO)(OC2OC(CO)C(O)C(O)C2O)C(O)C1O CZMRCDWAGMRECN-UHFFFAOYSA-N 0.000 description 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 1
- DLPDBBPTTGBGRX-UHFFFAOYSA-N 3,4-dihydro-1h-isoquinoline-2-carboxylic acid Chemical compound C1=CC=C2CN(C(=O)O)CCC2=C1 DLPDBBPTTGBGRX-UHFFFAOYSA-N 0.000 description 1
- COZXRXUXWCWDFI-UHFFFAOYSA-N 3-(4-chlorophenyl)-2-[(1,1-dimethyl-3,4-dihydro-2h-isoquinoline-3-carbonyl)amino]propanoic acid Chemical compound C1C2=CC=CC=C2C(C)(C)NC1C(=O)NC(C(O)=O)CC1=CC=C(Cl)C=C1 COZXRXUXWCWDFI-UHFFFAOYSA-N 0.000 description 1
- KADRCUOKMHSJJV-UHFFFAOYSA-N 3-(4-chlorophenyl)-2-[[2-[(2-methylpropan-2-yl)oxycarbonyl]-1,3-dihydroisoindole-1-carbonyl]amino]propanoic acid Chemical compound CC(C)(C)OC(=O)N1CC2=CC=CC=C2C1C(=O)NC(C(O)=O)CC1=CC=C(Cl)C=C1 KADRCUOKMHSJJV-UHFFFAOYSA-N 0.000 description 1
- LJCXJZNVTCRXIE-UHFFFAOYSA-N 3-(4-chlorophenyl)-2-[[2-[(2-methylpropan-2-yl)oxycarbonyl]-3,4-dihydro-1H-isoquinolin-3-yl]methylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N1CC2=CC=CC=C2CC1CNC(C(O)=O)CC1=CC=C(Cl)C=C1 LJCXJZNVTCRXIE-UHFFFAOYSA-N 0.000 description 1
- TYJQLISLQAGJTF-UHFFFAOYSA-N 3-(4-methoxyphenyl)-2-[[2-[2-[(2-methylpropan-2-yl)oxycarbonyl]-1,3-dihydroisoindol-1-yl]acetyl]amino]propanoic acid Chemical compound C1=CC(OC)=CC=C1CC(C(O)=O)NC(=O)CC1C2=CC=CC=C2CN1C(=O)OC(C)(C)C TYJQLISLQAGJTF-UHFFFAOYSA-N 0.000 description 1
- NBALJQROYLBLRV-UHFFFAOYSA-N 3-[[[3-(4-chlorophenyl)-1-methoxy-1-oxopropan-2-yl]amino]methyl]-3,4-dihydro-1h-isoquinoline-2-carboxylic acid Chemical compound C1C2=CC=CC=C2CN(C(O)=O)C1CNC(C(=O)OC)CC1=CC=C(Cl)C=C1 NBALJQROYLBLRV-UHFFFAOYSA-N 0.000 description 1
- HBNFCHQJTMDNMW-UHFFFAOYSA-N 3-formyl-3,4-dihydro-1h-isoquinoline-2-carboxylic acid Chemical compound C1=CC=C2CC(C=O)N(C(=O)O)CC2=C1 HBNFCHQJTMDNMW-UHFFFAOYSA-N 0.000 description 1
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 1
- MVQVNTPHUGQQHK-UHFFFAOYSA-N 3-pyridinemethanol Chemical compound OCC1=CC=CN=C1 MVQVNTPHUGQQHK-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- MVDXXGIBARMXSA-PYUWXLGESA-N 5-[[(2r)-2-benzyl-3,4-dihydro-2h-chromen-6-yl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound S1C(=O)NC(=O)C1CC1=CC=C(O[C@@H](CC=2C=CC=CC=2)CC2)C2=C1 MVDXXGIBARMXSA-PYUWXLGESA-N 0.000 description 1
- CYJZJGYYTFQQBY-UHFFFAOYSA-N 5-bromoisoquinoline Chemical compound N1=CC=C2C(Br)=CC=CC2=C1 CYJZJGYYTFQQBY-UHFFFAOYSA-N 0.000 description 1
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 1
- RDSVSEFWZUWZHW-UHFFFAOYSA-N 7-bromo-1h-indole Chemical compound BrC1=CC=CC2=C1NC=C2 RDSVSEFWZUWZHW-UHFFFAOYSA-N 0.000 description 1
- XKDAUEWDPSMDGG-UHFFFAOYSA-N 7-piperazin-1-yl-1h-indole Chemical compound C1CNCCN1C1=CC=CC2=C1NC=C2 XKDAUEWDPSMDGG-UHFFFAOYSA-N 0.000 description 1
- DZYOXXKFNXECMC-UHFFFAOYSA-N 8-[1-[(2-methylpropan-2-yl)oxy]piperidin-4-yl]-1,2,3,4-tetrahydroisoquinoline Chemical compound C1CN(OC(C)(C)C)CCC1C1=CC=CC2=C1CNCC2 DZYOXXKFNXECMC-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- 102100034159 Beta-3 adrenergic receptor Human genes 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- ODKQUWBDBJOSQT-UHFFFAOYSA-N C1=CC=C2C([N])=NC=CC2=C1 Chemical compound C1=CC=C2C([N])=NC=CC2=C1 ODKQUWBDBJOSQT-UHFFFAOYSA-N 0.000 description 1
- JSUNPSPUCYGGCC-UHFFFAOYSA-N C1C=CC=C2C(C(O)=O)N(C(=O)OC(C)(C)C)CCC21 Chemical compound C1C=CC=C2C(C(O)=O)N(C(=O)OC(C)(C)C)CCC21 JSUNPSPUCYGGCC-UHFFFAOYSA-N 0.000 description 1
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 1
- HDJMKBAKCRUFSI-UHFFFAOYSA-N CNCC1=CC=CC=C1.C1=CC=C2CNCC2=C1 Chemical compound CNCC1=CC=CC=C1.C1=CC=C2CNCC2=C1 HDJMKBAKCRUFSI-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241001432959 Chernes Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229920001268 Cholestyramine Polymers 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- RGJOEKWQDUBAIZ-IBOSZNHHSA-N CoASH Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS)O[C@H]1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-IBOSZNHHSA-N 0.000 description 1
- 229920002911 Colestipol Polymers 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 102000008064 Corticotropin Receptors Human genes 0.000 description 1
- 108010074311 Corticotropin Receptors Proteins 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 102000007260 Deoxyribonuclease I Human genes 0.000 description 1
- 108010008532 Deoxyribonuclease I Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 1
- 101100456896 Drosophila melanogaster metl gene Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 206010014486 Elevated triglycerides Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical group FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 102100037907 High mobility group protein B1 Human genes 0.000 description 1
- 101710168537 High mobility group protein B1 Proteins 0.000 description 1
- 101100456320 Homo sapiens NR3C2 gene Proteins 0.000 description 1
- 238000006043 Intramolecular Michael addition reaction Methods 0.000 description 1
- WQZGKKKJIJFFOK-ZZWDRFIYSA-N L-glucose Chemical compound OC[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@H]1O WQZGKKKJIJFFOK-ZZWDRFIYSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000007623 Lordosis Diseases 0.000 description 1
- 229940126661 MC4 antagonist Drugs 0.000 description 1
- 241001347978 Major minor Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 1
- 101800002739 Melanin-concentrating hormone Proteins 0.000 description 1
- 102000001796 Melanocortin 4 receptors Human genes 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 102000003979 Mineralocorticoid Receptors Human genes 0.000 description 1
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- 230000006181 N-acylation Effects 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- FXEVVFDHVHRUTN-UHFFFAOYSA-N N.BOC Chemical compound N.BOC FXEVVFDHVHRUTN-UHFFFAOYSA-N 0.000 description 1
- 108020000002 NR3 subfamily Proteins 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- 102000003797 Neuropeptides Human genes 0.000 description 1
- 101100285000 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) his-3 gene Proteins 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 101150024701 PPH3 gene Proteins 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 102100038831 Peroxisome proliferator-activated receptor alpha Human genes 0.000 description 1
- 102100038824 Peroxisome proliferator-activated receptor delta Human genes 0.000 description 1
- 241000700145 Petromus typicus Species 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 1
- 108010021820 SHU 9119 Proteins 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 102000001494 Sterol O-Acyltransferase Human genes 0.000 description 1
- 108010054082 Sterol O-acyltransferase Proteins 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 108010021436 Type 4 Melanocortin Receptor Proteins 0.000 description 1
- 102000003425 Tyrosinase Human genes 0.000 description 1
- 108060008724 Tyrosinase Proteins 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 229960002632 acarbose Drugs 0.000 description 1
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Chemical group COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- NUOSMPRKGYYHRO-UHFFFAOYSA-N acetic acid;1,2,3,4-tetrahydroisoquinoline Chemical class CC(O)=O.C1=CC=C2CNCCC2=C1 NUOSMPRKGYYHRO-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000002404 acyltransferase inhibitor Substances 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 210000000593 adipose tissue white Anatomy 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 239000000674 adrenergic antagonist Substances 0.000 description 1
- 229940126157 adrenergic receptor agonist Drugs 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 102000030484 alpha-2 Adrenergic Receptor Human genes 0.000 description 1
- 108020004101 alpha-2 Adrenergic Receptor Proteins 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 230000003579 anti-obesity Effects 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 1
- 229960004046 apomorphine Drugs 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 229940076810 beta sitosterol Drugs 0.000 description 1
- 108010014502 beta-3 Adrenergic Receptors Proteins 0.000 description 1
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 description 1
- NJKOMDUNNDKEAI-UHFFFAOYSA-N beta-sitosterol Natural products CCC(CCC(C)C1CCC2(C)C3CC=C4CC(O)CCC4C3CCC12C)C(C)C NJKOMDUNNDKEAI-UHFFFAOYSA-N 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 1
- YTIVTFGABIZHHX-UHFFFAOYSA-N butynedioic acid Chemical compound OC(=O)C#CC(O)=O YTIVTFGABIZHHX-UHFFFAOYSA-N 0.000 description 1
- 230000001593 cAMP accumulation Effects 0.000 description 1
- 230000003491 cAMP production Effects 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 229960003340 calcium silicate Drugs 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000001906 cholesterol absorption Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 1
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 description 1
- 239000005516 coenzyme A Substances 0.000 description 1
- 229940093530 coenzyme a Drugs 0.000 description 1
- GMRWGQCZJGVHKL-UHFFFAOYSA-N colestipol Chemical compound ClCC1CO1.NCCNCCNCCNCCN GMRWGQCZJGVHKL-UHFFFAOYSA-N 0.000 description 1
- 229960002604 colestipol Drugs 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 230000000056 copulatory effect Effects 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- OQSZZLUNAYKSGI-UHFFFAOYSA-N cyanomethyl butanoate Chemical compound CCCC(=O)OCC#N OQSZZLUNAYKSGI-UHFFFAOYSA-N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 description 1
- 229960004597 dexfenfluramine Drugs 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- BSHICDXRSZQYBP-UHFFFAOYSA-N dichloromethane;palladium(2+) Chemical compound [Pd+2].ClCCl BSHICDXRSZQYBP-UHFFFAOYSA-N 0.000 description 1
- 238000013229 diet-induced obese mouse Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 239000013024 dilution buffer Substances 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 108700003601 dimethylglycine Proteins 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229950002375 englitazone Drugs 0.000 description 1
- 230000001856 erectile effect Effects 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229940093495 ethanethiol Drugs 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- LHNNBAUXZXOHDD-UHFFFAOYSA-N ethyl 1,1-dimethyl-3,4-dihydro-2h-isoquinoline-3-carboxylate Chemical compound C1=CC=C2C(C)(C)NC(C(=O)OCC)CC2=C1 LHNNBAUXZXOHDD-UHFFFAOYSA-N 0.000 description 1
- OOIVWSXZWFQHQS-UHFFFAOYSA-N ethyl 1,2,3,4-tetrahydroisoquinoline-1-carboxylate Chemical compound C1=CC=C2C(C(=O)OCC)NCCC2=C1 OOIVWSXZWFQHQS-UHFFFAOYSA-N 0.000 description 1
- WCSOQNUPONWLSG-UHFFFAOYSA-N ethyl 6-methoxy-1,1-dimethyl-3,4-dihydro-2h-isoquinoline-3-carboxylate Chemical compound COC1=CC=C2C(C)(C)NC(C(=O)OCC)CC2=C1 WCSOQNUPONWLSG-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 210000003499 exocrine gland Anatomy 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000004634 feeding behavior Effects 0.000 description 1
- 229960001582 fenfluramine Drugs 0.000 description 1
- 229960002297 fenofibrate Drugs 0.000 description 1
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 1
- MQOBSOSZFYZQOK-UHFFFAOYSA-N fenofibric acid Chemical class C1=CC(OC(C)(C)C(O)=O)=CC=C1C(=O)C1=CC=C(Cl)C=C1 MQOBSOSZFYZQOK-UHFFFAOYSA-N 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 229960003765 fluvastatin Drugs 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960003627 gemfibrozil Drugs 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 229960001381 glipizide Drugs 0.000 description 1
- 230000009229 glucose formation Effects 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 230000021061 grooming behavior Effects 0.000 description 1
- 230000003370 grooming effect Effects 0.000 description 1
- 239000003324 growth hormone secretagogue Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 229940060367 inert ingredients Drugs 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 150000002518 isoindoles Chemical class 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000003041 ligament Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000004130 lipolysis Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- FKBSHNBSEUWDAC-UHFFFAOYSA-L lithium sodium dihydroxide Chemical compound [Li+].[OH-].[OH-].[Na+] FKBSHNBSEUWDAC-UHFFFAOYSA-L 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 210000002752 melanocyte Anatomy 0.000 description 1
- 230000001802 melanotrophic effect Effects 0.000 description 1
- 229950008446 melinamide Drugs 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- FBHPVOLRIXZZMD-SECBINFHSA-N methyl (2r)-2-amino-3-(4-chlorophenyl)propanoate Chemical compound COC(=O)[C@H](N)CC1=CC=C(Cl)C=C1 FBHPVOLRIXZZMD-SECBINFHSA-N 0.000 description 1
- WJUICTUIEHPGCS-UHFFFAOYSA-N methyl 2-(2-butyl-1,3-dihydroisoindol-1-yl)acetate Chemical compound C1=CC=C2C(CC(=O)OC)N(CCCC)CC2=C1 WJUICTUIEHPGCS-UHFFFAOYSA-N 0.000 description 1
- NTNUDYROPUKXNA-UHFFFAOYSA-N methyl 2-(triphenyl-$l^{5}-phosphanylidene)acetate Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OC)C1=CC=CC=C1 NTNUDYROPUKXNA-UHFFFAOYSA-N 0.000 description 1
- WEVQBYZWFCWAJV-UHFFFAOYSA-N methyl 3-(4-chlorophenyl)-2-[(1,1-dimethyl-3,4-dihydro-2h-isoquinoline-3-carbonyl)amino]propanoate Chemical compound C1C2=CC=CC=C2C(C)(C)NC1C(=O)NC(C(=O)OC)CC1=CC=C(Cl)C=C1 WEVQBYZWFCWAJV-UHFFFAOYSA-N 0.000 description 1
- IZYBEMGNIUSSAX-UHFFFAOYSA-N methyl benzenecarboperoxoate Chemical compound COOC(=O)C1=CC=CC=C1 IZYBEMGNIUSSAX-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000006452 multicomponent reaction Methods 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 229940078490 n,n-dimethylglycine Drugs 0.000 description 1
- PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
- JFCHSQDLLFJHOA-UHFFFAOYSA-N n,n-dimethylsulfamoyl chloride Chemical compound CN(C)S(Cl)(=O)=O JFCHSQDLLFJHOA-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- PKWDZWYVIHVNKS-UHFFFAOYSA-N netoglitazone Chemical compound FC1=CC=CC=C1COC1=CC=C(C=C(CC2C(NC(=O)S2)=O)C=C2)C2=C1 PKWDZWYVIHVNKS-UHFFFAOYSA-N 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960004738 nicotinyl alcohol Drugs 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 1
- 229960001243 orlistat Drugs 0.000 description 1
- 238000013021 overheating Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 description 1
- 108091008765 peroxisome proliferator-activated receptors β/δ Proteins 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 description 1
- 229960003243 phenformin Drugs 0.000 description 1
- 229960003562 phentermine Drugs 0.000 description 1
- 229960003056 phentolamine mesylate Drugs 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-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
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 208000024335 physical disease Diseases 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical compound OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-N 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 206010036596 premature ejaculation Diseases 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
- 229960003912 probucol Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- DRINJBFRTLBHNF-UHFFFAOYSA-N propane-2-sulfonyl chloride Chemical compound CC(C)S(Cl)(=O)=O DRINJBFRTLBHNF-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- XMIAFAKRAAMSGX-UHFFFAOYSA-N quinolin-5-amine Chemical compound C1=CC=C2C(N)=CC=CC2=N1 XMIAFAKRAAMSGX-UHFFFAOYSA-N 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 229910052705 radium Inorganic materials 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 239000013643 reference control Substances 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 210000001732 sebaceous gland Anatomy 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 239000003772 serotonin uptake inhibitor Substances 0.000 description 1
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- 230000035946 sexual desire Effects 0.000 description 1
- 229960004425 sibutramine Drugs 0.000 description 1
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 description 1
- 229950005143 sitosterol Drugs 0.000 description 1
- ZVCDLGYNFYZZOK-UHFFFAOYSA-M sodium cyanate Chemical compound [Na]OC#N ZVCDLGYNFYZZOK-UHFFFAOYSA-M 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000012058 sterile packaged powder Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- BIBSWYPUCMKWBY-GFCCVEGCSA-N tert-butyl (1R)-1,2,3,4-tetrahydroisoquinoline-1-carboxylate Chemical compound C(=O)(OC(C)(C)C)[C@@H]1NCCC2=CC=CC=C12 BIBSWYPUCMKWBY-GFCCVEGCSA-N 0.000 description 1
- MZBJCRNZEDCXLB-UHFFFAOYSA-N tert-butyl 1-(2-methoxy-2-oxoethyl)-1,3-dihydroisoindole-2-carboxylate Chemical compound C1=CC=C2C(CC(=O)OC)N(C(=O)OC(C)(C)C)CC2=C1 MZBJCRNZEDCXLB-UHFFFAOYSA-N 0.000 description 1
- GRBKVGAUFUQJKQ-UHFFFAOYSA-N tert-butyl 3-[[3-(4-chlorophenyl)-1-methoxy-1-oxopropan-2-yl]carbamoyl]-3,4-dihydro-1h-isoquinoline-2-carboxylate Chemical compound C1C2=CC=CC=C2CN(C(=O)OC(C)(C)C)C1C(=O)NC(C(=O)OC)CC1=CC=C(Cl)C=C1 GRBKVGAUFUQJKQ-UHFFFAOYSA-N 0.000 description 1
- ZNPOYWZXWYOVLH-UHFFFAOYSA-N tert-butyl 3-[[[3-(4-chlorophenyl)-1-methoxy-1-oxopropan-2-yl]amino]methyl]-3,4-dihydro-1h-isoquinoline-2-carboxylate Chemical compound C1C2=CC=CC=C2CN(C(=O)OC(C)(C)C)C1CNC(C(=O)OC)CC1=CC=C(Cl)C=C1 ZNPOYWZXWYOVLH-UHFFFAOYSA-N 0.000 description 1
- VZTIJDATARWPGU-UHFFFAOYSA-N tert-butyl 4-(1,2,3,4-tetrahydroisoquinolin-5-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=CC2=C1CCNC2 VZTIJDATARWPGU-UHFFFAOYSA-N 0.000 description 1
- YTXGTLBHRQYTPM-UHFFFAOYSA-N tert-butyl 4-(1h-indol-7-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=CC2=C1NC=C2 YTXGTLBHRQYTPM-UHFFFAOYSA-N 0.000 description 1
- PDGHFZRBOPGNGL-UHFFFAOYSA-N tert-butyl 4-(2,3-dihydro-1h-indol-7-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=CC2=C1NCC2 PDGHFZRBOPGNGL-UHFFFAOYSA-N 0.000 description 1
- WAOLPHNHDQKIEP-UHFFFAOYSA-N tert-butyl 4-(2-ethyl-3,4-dihydro-1h-isoquinolin-5-yl)piperazine-1-carboxylate Chemical compound C1N(CC)CCC2=C1C=CC=C2N1CCN(C(=O)OC(C)(C)C)CC1 WAOLPHNHDQKIEP-UHFFFAOYSA-N 0.000 description 1
- HOVNGZCRYBSLOH-UHFFFAOYSA-N tert-butyl 4-(7-amino-1,2,3,4,4a,5,6,7,8,8a-decahydronaphthalen-1-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1C2CC(N)CCC2CCC1 HOVNGZCRYBSLOH-UHFFFAOYSA-N 0.000 description 1
- NHFVAONVLCETEV-UHFFFAOYSA-N tert-butyl 4-isoquinolin-5-ylpiperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=CC2=CN=CC=C12 NHFVAONVLCETEV-UHFFFAOYSA-N 0.000 description 1
- NOJSXNUVMOOLOA-UHFFFAOYSA-N tert-butyl 4-isoquinolin-8-yl-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC(C=2C3=CN=CC=C3C=CC=2)=C1 NOJSXNUVMOOLOA-UHFFFAOYSA-N 0.000 description 1
- ZTXJCCMGHPXAGQ-UHFFFAOYSA-N tert-butyl 4-isoquinolin-8-ylpiperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=CC2=CC=NC=C12 ZTXJCCMGHPXAGQ-UHFFFAOYSA-N 0.000 description 1
- UYKBAQJGGFRIOK-UHFFFAOYSA-N tert-butyl 4-quinolin-8-ylpiperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=CC2=CC=CN=C12 UYKBAQJGGFRIOK-UHFFFAOYSA-N 0.000 description 1
- UIYOVVYZPVVUMJ-UHFFFAOYSA-N tert-butyl carbamoyl carbonate Chemical compound CC(C)(C)OC(=O)OC(N)=O UIYOVVYZPVVUMJ-UHFFFAOYSA-N 0.000 description 1
- DFNZFCPEUDSNEO-UHFFFAOYSA-N tert-butyl n-[(2-bromophenyl)methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1=CC=CC=C1Br DFNZFCPEUDSNEO-UHFFFAOYSA-N 0.000 description 1
- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Substances C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000035924 thermogenesis Effects 0.000 description 1
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- 230000000929 thyromimetic effect Effects 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
- 229960001641 troglitazone Drugs 0.000 description 1
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 206010046947 vaginismus Diseases 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- WHNFPRLDDSXQCL-UAZQEYIDSA-N α-msh Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(N)=O)NC(=O)[C@H](CO)NC(C)=O)C1=CC=C(O)C=C1 WHNFPRLDDSXQCL-UAZQEYIDSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P15/10—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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Reproductive Health (AREA)
- Emergency Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Gynecology & Obstetrics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US26359501P | 2001-01-23 | 2001-01-23 | |
| US60/263,595 | 2001-01-23 | ||
| PCT/US2002/000516 WO2002059107A1 (en) | 2001-01-23 | 2002-01-23 | Substituted piperidines/piperazines as melanocortin receptor agonists |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2433025A1 true CA2433025A1 (en) | 2002-08-01 |
Family
ID=23002443
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002433025A Abandoned CA2433025A1 (en) | 2001-01-23 | 2002-01-23 | Substituted piperidines/piperazines as melanocortin receptor agonists |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US7157463B2 (enExample) |
| EP (1) | EP1368339A1 (enExample) |
| JP (1) | JP2004521117A (enExample) |
| CA (1) | CA2433025A1 (enExample) |
| WO (1) | WO2002059107A1 (enExample) |
Families Citing this family (97)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1358163A1 (en) | 2001-01-23 | 2003-11-05 | Eli Lilly And Company | Melanocortin receptor agonists |
| JP2004523530A (ja) | 2001-01-23 | 2004-08-05 | イーライ・リリー・アンド・カンパニー | メラノコルチン受容体アゴニストとしてのピペラジンおよびピペリジン誘導体 |
| EP1363898A4 (en) | 2001-03-02 | 2004-12-08 | Bristol Myers Squibb Co | COMPOUNDS SUITABLE AS MODULATORS OF MELANOCORTIN RECEPTORS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| US6911447B2 (en) | 2001-04-25 | 2005-06-28 | The Procter & Gamble Company | Melanocortin receptor ligands |
| US6977264B2 (en) | 2001-07-25 | 2005-12-20 | Amgen Inc. | Substituted piperidines and methods of use |
| US7115607B2 (en) | 2001-07-25 | 2006-10-03 | Amgen Inc. | Substituted piperazinyl amides and methods of use |
| US7354923B2 (en) | 2001-08-10 | 2008-04-08 | Palatin Technologies, Inc. | Piperazine melanocortin-specific compounds |
| US7456184B2 (en) | 2003-05-01 | 2008-11-25 | Palatin Technologies Inc. | Melanocortin receptor-specific compounds |
| EP1469851B1 (en) | 2002-01-23 | 2006-10-11 | Eli Lilly And Company | Melanocortin receptor agonists |
| US7026335B2 (en) | 2002-04-30 | 2006-04-11 | The Procter & Gamble Co. | Melanocortin receptor ligands |
| US7105526B2 (en) | 2002-06-28 | 2006-09-12 | Banyu Pharmaceuticals Co., Ltd. | Benzimidazole derivatives |
| US7414057B2 (en) | 2002-09-11 | 2008-08-19 | Merck & Co., Inc. | Piperazine urea derivatives as melanocortin-4 receptor agonists |
| US7132539B2 (en) * | 2002-10-23 | 2006-11-07 | The Procter & Gamble Company | Melanocortin receptor ligands |
| AU2003281978A1 (en) * | 2002-11-22 | 2004-06-18 | Boehringer Ingelheim International Gmbh | 2,5-diketopiperazines for the treatment of obesity |
| US7772188B2 (en) | 2003-01-28 | 2010-08-10 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
| US7160886B2 (en) | 2003-03-03 | 2007-01-09 | Merck & Co., Inc. | Acylated piperazine derivatives as melanocortin-4 receptor agonists |
| JP2006515341A (ja) | 2003-03-03 | 2006-05-25 | エフ．ホフマン−ラ ロシュ アーゲー | ５−ｈｔ６調節物質として使用するための２，５−および２，６−置換テトラヒドロイソキノリン |
| EP1468999A1 (en) * | 2003-03-20 | 2004-10-20 | MyoContract Ltd. | Substituted piperidine and piperazine derivatives as melanocortin-4 receptor modulators |
| ATE474577T1 (de) | 2003-03-26 | 2010-08-15 | Merck Sharp & Dohme | Bicyclische piperidin-derivate als melanocortin-4 rezeptor-agonisten |
| WO2005028438A1 (ja) | 2003-09-22 | 2005-03-31 | Banyu Pharmaceutical Co., Ltd. | 新規ピペリジン誘導体 |
| US20050192286A1 (en) * | 2003-10-22 | 2005-09-01 | Neurocrine Biosciences, Inc. | Ligands of melanocortin receptors and compositions and methods related thereto |
| US20050119252A1 (en) * | 2003-10-22 | 2005-06-02 | Neurocrine Biosciences, Inc. | Ligands of melanocortin receptors and compositions and methods related thereto |
| TWI341835B (en) | 2003-11-12 | 2011-05-11 | Lg Life Sciences Ltd | Melanocortin receptor agonists |
| US20080125403A1 (en) | 2004-04-02 | 2008-05-29 | Merck & Co., Inc. | Method of Treating Men with Metabolic and Anthropometric Disorders |
| US7449481B2 (en) * | 2004-04-13 | 2008-11-11 | Cephalon, Inc. | Thio-substituted biaryl-methanesulfinyl derivatives |
| EP1892241B1 (en) | 2005-05-30 | 2016-03-30 | Msd K.K. | Novel piperidine derivative |
| EP1916239A4 (en) | 2005-08-10 | 2009-10-21 | Banyu Pharma Co Ltd | PYRIDOLVERBINDUNG |
| US7875633B2 (en) | 2005-08-24 | 2011-01-25 | Banyu Pharmaceutical Co., Ltd. | Phenylpyridone derivative |
| WO2007029847A1 (ja) | 2005-09-07 | 2007-03-15 | Banyu Pharmaceutical Co., Ltd. | 二環性芳香族置換ピリドン誘導体 |
| KR20080048502A (ko) | 2005-09-29 | 2008-06-02 | 머크 앤드 캄파니 인코포레이티드 | 멜라노코르틴-4 수용체 조절제로서의 아실화스피로피페리딘 유도체 |
| CA2625877A1 (en) | 2005-10-18 | 2007-04-26 | Merck & Co., Inc. | Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators |
| RU2008119687A (ru) | 2005-10-21 | 2009-11-27 | Новартис АГ (CH) | Комбинации органических соединений |
| AU2006307046A1 (en) | 2005-10-27 | 2007-05-03 | Msd K.K. | Novel benzoxathiin derivative |
| RU2428423C2 (ru) | 2005-11-10 | 2011-09-10 | Баниу Фармасьютикал Ко., Лтд. | Азазамещенные спиропроизводные |
| TWI332501B (en) * | 2006-07-14 | 2010-11-01 | Lg Life Sciences Ltd | Melanocortin receptor agonists |
| AU2007300627B2 (en) | 2006-09-22 | 2012-02-16 | Merck Sharp & Dohme Corp. | Method of treatment using fatty acid synthesis inhibitors |
| EP2072519A4 (en) | 2006-09-28 | 2009-10-21 | Banyu Pharma Co Ltd | DIARYLKETIMINDERIVAT |
| AU2008233662B2 (en) | 2007-04-02 | 2012-08-23 | Msd K.K. | Indoledione derivative |
| US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
| WO2008151257A2 (en) | 2007-06-04 | 2008-12-11 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| AU2009220605A1 (en) | 2008-03-06 | 2009-09-11 | Msd K.K. | Alkylaminopyridine derivative |
| CA2717384A1 (en) | 2008-03-28 | 2009-10-01 | Banyu Pharmaceutical Co., Ltd. | Diarylmethylamide derivative having melanin-concentrating hormone receptor antagonism |
| ES2627848T3 (es) | 2008-06-04 | 2017-07-31 | Synergy Pharmaceuticals Inc. | Agonistas de la guanilato ciclasa útiles para el tratamiento de trastornos gastrointestinales, inflamación, cáncer y otros trastornos |
| AU2009261248A1 (en) | 2008-06-19 | 2009-12-23 | Banyu Pharmaceutical Co., Ltd. | Spirodiamine-diarylketoxime derivative |
| US8227628B2 (en) | 2008-07-09 | 2012-07-24 | Northwestern University | Method of synthesizing acetonide-protected catechol-containing compounds and intermediates produced therein |
| ES2624828T3 (es) | 2008-07-16 | 2017-07-17 | Synergy Pharmaceuticals Inc. | Agonistas de la guanilato ciclasa útiles para el tratamiento de trastornos gastrointestinales, inflamación, cáncer y otros |
| US20110124674A1 (en) | 2008-07-30 | 2011-05-26 | Hiroyuki Kishino | 5/5-or 5/6-membered condensed ring cycloalkylamine derivative |
| US8410284B2 (en) | 2008-10-22 | 2013-04-02 | Merck Sharp & Dohme Corp | Cyclic benzimidazole derivatives useful as anti-diabetic agents |
| WO2010051206A1 (en) | 2008-10-31 | 2010-05-06 | Merck Sharp & Dohme Corp. | Novel cyclic benzimidazole derivatives useful anti-diabetic agents |
| UA99555C2 (en) | 2008-11-12 | 2012-08-27 | Элджи Лайф Саенсез Лтд. | Melanocortin receptor agonists |
| JP5514831B2 (ja) | 2008-11-17 | 2014-06-04 | メルク・シャープ・アンド・ドーム・コーポレーション | 糖尿病の治療のための置換二環式アミン |
| WO2011011506A1 (en) | 2009-07-23 | 2011-01-27 | Schering Corporation | Spirocyclic oxazepine compounds as stearoyl-coenzyme a delta-9 desaturase inhibitors |
| CA2768577A1 (en) | 2009-07-23 | 2011-01-27 | Schering Corporation | Benzo-fused oxazepine compounds as stearoyl-coenzyme a delta-9 desaturase inhibitors |
| US8476227B2 (en) | 2010-01-22 | 2013-07-02 | Ethicon Endo-Surgery, Inc. | Methods of activating a melanocortin-4 receptor pathway in obese subjects |
| US9044606B2 (en) | 2010-01-22 | 2015-06-02 | Ethicon Endo-Surgery, Inc. | Methods and devices for activating brown adipose tissue using electrical energy |
| JP2013520502A (ja) | 2010-02-25 | 2013-06-06 | メルク・シャープ・エンド・ドーム・コーポレイション | 有用な抗糖尿病薬である新規な環状ベンズイミダゾール誘導体 |
| US8785634B2 (en) | 2010-04-26 | 2014-07-22 | Merck Sharp & Dohme Corp | Spiropiperidine prolylcarboxypeptidase inhibitors |
| WO2011143057A1 (en) | 2010-05-11 | 2011-11-17 | Merck Sharp & Dohme Corp. | Novel prolylcarboxypeptidase inhibitors |
| EP2579873A4 (en) | 2010-06-11 | 2013-11-27 | Merck Sharp & Dohme | NOVEL PROLYLCARBOXYPEPTIDASE HEMMER |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| CA2826649C (en) | 2011-02-25 | 2016-07-26 | Merck Sharp & Dohme Corp. | Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents |
| US20140045746A1 (en) | 2012-08-02 | 2014-02-13 | Merck Sharp & Dohme Corp. | Antidiabetic tricyclic compounds |
| JP2016516004A (ja) | 2013-02-22 | 2016-06-02 | メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． | 抗糖尿病二環式化合物 |
| WO2014139388A1 (en) | 2013-03-14 | 2014-09-18 | Merck Sharp & Dohme Corp. | Novel indole derivatives useful as anti-diabetic agents |
| US9708367B2 (en) | 2013-03-15 | 2017-07-18 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase and their uses |
| EP2968439A2 (en) | 2013-03-15 | 2016-01-20 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
| PL3004138T3 (pl) | 2013-06-05 | 2024-07-29 | Bausch Health Ireland Limited | Ultra-oczyszczeni agoniści peptydowi cyklazy guanylanowej C, sposób ich uzyskiwania i ich zastosowanie |
| TR201807959T4 (tr) | 2013-07-22 | 2018-06-21 | Idorsia Pharmaceuticals Ltd | 1-(Piperazın-1-il)-2- ([1,2,4] triazol-1-il)-etanon türevleri. |
| WO2015051496A1 (en) | 2013-10-08 | 2015-04-16 | Merck Sharp & Dohme Corp. | Antidiabetic tricyclic compounds |
| AR099789A1 (es) | 2014-03-24 | 2016-08-17 | Actelion Pharmaceuticals Ltd | Derivados de 8-(piperazin-1-il)-1,2,3,4-tetrahidro-isoquinolina |
| BR112017003745A2 (pt) | 2014-08-29 | 2017-12-05 | Tes Pharma S R L | inibidores de semialdeído descarboxilase de ácido alfa-amino-beta-carboximucônico |
| US10092738B2 (en) | 2014-12-29 | 2018-10-09 | Ethicon Llc | Methods and devices for inhibiting nerves when activating brown adipose tissue |
| US10080884B2 (en) | 2014-12-29 | 2018-09-25 | Ethicon Llc | Methods and devices for activating brown adipose tissue using electrical energy |
| AR103399A1 (es) | 2015-01-15 | 2017-05-10 | Actelion Pharmaceuticals Ltd | Derivados de (r)-2-metil-piperazina como moduladores del receptor cxcr3 |
| RS58349B1 (sr) | 2015-01-15 | 2019-03-29 | Idorsia Pharmaceuticals Ltd | Hidroksialkil-piperazinski derivati kao modulatori cxcr3 receptora |
| AU2017342083A1 (en) | 2016-10-14 | 2019-04-11 | Tes Pharma S.R.L. | Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase |
| WO2018106518A1 (en) | 2016-12-06 | 2018-06-14 | Merck Sharp & Dohme Corp. | Antidiabetic heterocyclic compounds |
| WO2018118670A1 (en) | 2016-12-20 | 2018-06-28 | Merck Sharp & Dohme Corp. | Antidiabetic spirochroman compounds |
| KR102695210B1 (ko) * | 2018-06-05 | 2024-08-13 | 크리네틱스 파마슈티칼스, 인크. | 멜라노코르틴 아형-2 수용체(mc2r) 길항제 및 이의 용도 |
| EP3883930A1 (en) | 2018-11-20 | 2021-09-29 | Tes Pharma S.r.l. | Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase |
| WO2021039023A1 (ja) * | 2019-08-23 | 2021-03-04 | 持田製薬株式会社 | ヘテロシクリデンアセトアミド誘導体の製造方法 |
| MX2023004731A (es) * | 2020-10-29 | 2023-05-10 | Lg Chemical Ltd | Forma cristalina iv del compuesto agonista de receptor de melanocortina y metodo de preparacion para la misma. |
| CN116507615A (zh) * | 2020-10-29 | 2023-07-28 | 株式会社Lg化学 | 黑皮质素受体激动剂化合物的晶型i及其制备方法 |
| EP4219471A4 (en) * | 2020-10-29 | 2024-03-13 | Lg Chem, Ltd. | Amorphous melanocortin-4 receptor agonist |
| PE20240366A1 (es) * | 2020-10-29 | 2024-03-04 | Lg Chemical Ltd | Forma cristalina iii del compuesto agonista de receptor de melanocortina y metodo de preparacion para la misma |
| EP4219473A4 (en) * | 2020-10-29 | 2024-03-13 | Lg Chem, Ltd. | CRYSTAL TYPE II OF A MALANOCORTIN RECEPTOR AGONIST COMPOUND AND METHOD FOR THE PRODUCTION THEREOF |
| CA3202315A1 (en) * | 2020-12-22 | 2022-06-30 | Hee Dong Park | Use as selective agonist of malanocortin-4 receptor |
| TWI814185B (zh) * | 2020-12-22 | 2023-09-01 | 南韓商Ｌｇ化學股份有限公司 | 黑皮質素受體促效劑化合物之晶型ii及其製備方法 |
| TWI810757B (zh) * | 2020-12-22 | 2023-08-01 | 南韓商Ｌｇ化學股份有限公司 | 黑皮質素受體促效劑化合物的晶型ｉ及其製備方法 |
| JP2024501829A (ja) | 2020-12-22 | 2024-01-16 | エルジー・ケム・リミテッド | メラノコルチン受容体アゴニスト化合物の結晶形ｉｉｉおよびその製造方法 |
| TWI804170B (zh) * | 2021-01-21 | 2023-06-01 | 南韓商Ｌｇ化學股份有限公司 | 黑皮質素-4受體促效劑的用途 |
| TWI826938B (zh) * | 2021-02-26 | 2023-12-21 | 南韓商Ｌｇ化學股份有限公司 | 黑皮質素-4受體促效劑 |
| CN117255786A (zh) * | 2021-05-06 | 2023-12-19 | 株式会社Lg 化学 | 黑皮质素受体激动剂化合物的晶型vii及其制备方法 |
| KR102854595B1 (ko) * | 2021-05-06 | 2025-09-03 | 주식회사 엘지화학 | 멜라노코르틴 수용체 작용제 화합물의 결정형 v 및 이의 제조방법 |
| KR102854598B1 (ko) * | 2021-05-07 | 2025-09-03 | 주식회사 엘지화학 | 멜라노코르틴 수용체 작용제 화합물의 황산염의 결정형 및 이의 제조방법 |
| JP2024517271A (ja) * | 2021-05-07 | 2024-04-19 | エルジー・ケム・リミテッド | メラノコルチン受容体アゴニスト化合物の有機酸塩の結晶形ｉｖおよびその製造方法 |
| US20240239769A1 (en) * | 2021-05-07 | 2024-07-18 | Lg Chem, Ltd. | Co-crystal of melanocortin receptor agonist compound and vanillin and method for preparing same |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SK282166B6 (sk) | 1992-12-11 | 2001-11-06 | Merck & Co., Inc. | Spiropiperidínové deriváty, spôsob ich výroby a farmaceutický prostriedok s ich obsahom |
| US6127381A (en) | 1998-04-28 | 2000-10-03 | Basu; Amaresh | Isoquinoline compound melanocortin receptor ligands and methods of using same |
| US6294534B1 (en) * | 1998-06-11 | 2001-09-25 | Merck & Co., Inc. | Spiropiperidine derivatives as melanocortin receptor agonists |
| AU742425B2 (en) * | 1998-06-11 | 2002-01-03 | Merck & Co., Inc. | Spiropiperidine derivatives as melanocortin receptor agonists |
| WO2000074679A1 (en) | 1999-06-04 | 2000-12-14 | Merck & Co., Inc. | Substituted piperidines as melanocortin-4 receptor agonists |
| JP2003527444A (ja) * | 2000-03-23 | 2003-09-16 | メルク エンド カムパニー インコーポレーテッド | メラノコルチン受容体アゴニストとして作用するスピロピペリジン誘導体 |
| CA2403686C (en) * | 2000-03-23 | 2010-01-26 | Merck & Co., Inc. | Substituted piperidines as melanocortin receptor agonists |
| JP2004506687A (ja) * | 2000-08-23 | 2004-03-04 | メルク エンド カムパニー インコーポレーテッド | メラノコルチン受容体作働薬としての置換ピペリジン類 |
| JP2004523530A (ja) | 2001-01-23 | 2004-08-05 | イーライ・リリー・アンド・カンパニー | メラノコルチン受容体アゴニストとしてのピペラジンおよびピペリジン誘導体 |
| EP1358163A1 (en) | 2001-01-23 | 2003-11-05 | Eli Lilly And Company | Melanocortin receptor agonists |
| EP1363898A4 (en) | 2001-03-02 | 2004-12-08 | Bristol Myers Squibb Co | COMPOUNDS SUITABLE AS MODULATORS OF MELANOCORTIN RECEPTORS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
-
2002
- 2002-01-23 CA CA002433025A patent/CA2433025A1/en not_active Abandoned
- 2002-01-23 WO PCT/US2002/000516 patent/WO2002059107A1/en not_active Ceased
- 2002-01-23 US US10/466,249 patent/US7157463B2/en not_active Expired - Fee Related
- 2002-01-23 EP EP02701923A patent/EP1368339A1/en not_active Withdrawn
- 2002-01-23 JP JP2002559409A patent/JP2004521117A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JP2004521117A (ja) | 2004-07-15 |
| WO2002059107A1 (en) | 2002-08-01 |
| WO2002059107A8 (en) | 2003-11-06 |
| US20040058936A1 (en) | 2004-03-25 |
| EP1368339A1 (en) | 2003-12-10 |
| US7157463B2 (en) | 2007-01-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1368340B1 (en) | Piperazine derivatives as melanocortin receptor agonists | |
| US7157463B2 (en) | Substituted piperidines/piperazines as melanocortin receptor agonists | |
| EP1469851B1 (en) | Melanocortin receptor agonists | |
| US7169777B2 (en) | Melanocortin receptor agonists | |
| US6350760B1 (en) | Substituted piperidines as melanocortin-4 receptor agonists | |
| US6294534B1 (en) | Spiropiperidine derivatives as melanocortin receptor agonists | |
| JP2004524297A5 (enExample) | ||
| CA2403631A1 (en) | Spiropiperidine derivatives as melanocortin receptor agonists | |
| EP1460069A1 (en) | Substituted cyclohexyl and piperidinyl derivatives as melanocortin-4 receptor modulators | |
| AU2002235323A1 (en) | Substituted piperidines/piperazines as melanocortin receptor agonists | |
| AU2002235322A1 (en) | Piperazine- and piperidine-derivatives as melanocortin receptor agonists | |
| AU2002246969A1 (en) | Melanocortin receptor agonists | |
| AU2003202852A1 (en) | Melanocortin receptor agonists | |
| AU2002235324A1 (en) | Melanocortin receptor agonists |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |