PT2094658E - Compostos de tetra-hidrociclopenta[b]indole como moduladores do recetor de androgénio - Google Patents

Info

Publication number

PT2094658E

PT2094658E PT07844898T PT07844898T PT2094658E PT 2094658 E PT2094658 E PT 2094658E PT 07844898 T PT07844898 T PT 07844898T PT 07844898 T PT07844898 T PT 07844898T PT 2094658 E PT2094658 E PT 2094658E

Authority

PT

Portugal

Prior art keywords

cyano

cyclopenta

pyridin

tetrahydro

ylmethyl

Prior art date

2006-11-20

Links

• Espacenet
• Global Dossier
• Discuss

• IAZKTAKWBHQCGF-UHFFFAOYSA-N 1,2,3,3a-tetrahydrocyclopenta[b]indole Chemical class N1=C2C=CC=CC2=C2C1CCC2 IAZKTAKWBHQCGF-UHFFFAOYSA-N 0.000 title description 10
• 239000000849 selective androgen receptor modulator Substances 0.000 title description 7
• -1 hydroxy, amino Chemical group 0.000 claims description 214
• 150000001875 compounds Chemical class 0.000 claims description 169
• 150000003839 salts Chemical class 0.000 claims description 42
• 238000011282 treatment Methods 0.000 claims description 33
• 230000002829 reductive effect Effects 0.000 claims description 29
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 24
• 210000000988 bone and bone Anatomy 0.000 claims description 20
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
• 208000001132 Osteoporosis Diseases 0.000 claims description 18
• 208000029725 Metabolic bone disease Diseases 0.000 claims description 17
• 206010049088 Osteopenia Diseases 0.000 claims description 17
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
• 210000003205 muscle Anatomy 0.000 claims description 17
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 12
• 238000002560 therapeutic procedure Methods 0.000 claims description 12
• 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 claims description 12
• 229910052799 carbon Inorganic materials 0.000 claims description 11
• 125000001072 heteroaryl group Chemical group 0.000 claims description 10
• 125000001424 substituent group Chemical group 0.000 claims description 10
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
• 125000001246 bromo group Chemical group Br* 0.000 claims description 8
• 125000001153 fluoro group Chemical group F* 0.000 claims description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims description 8
• 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims description 8
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 7
• 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 7
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 7
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 7
• 125000004076 pyridyl group Chemical group 0.000 claims description 7
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 7
• 125000000335 thiazolyl group Chemical group 0.000 claims description 7
• 206010012205 Delayed puberty Diseases 0.000 claims description 6
• 206010058359 Hypogonadism Diseases 0.000 claims description 6
• 208000007502 anemia Diseases 0.000 claims description 6
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
• UHDCOVNPQFZHIG-KRWDZBQOSA-N tert-butyl n-[(2s)-7-cyano-4-(pyridin-2-ylmethyl)-2,3-dihydro-1h-cyclopenta[b]indol-2-yl]carbamate Chemical compound C([C@H](C1)NC(=O)OC(C)(C)C)C2=C1C1=CC(C#N)=CC=C1N2CC1=CC=CC=N1 UHDCOVNPQFZHIG-KRWDZBQOSA-N 0.000 claims description 6
• 208000010228 Erectile Dysfunction Diseases 0.000 claims description 5
• 206010057671 Female sexual dysfunction Diseases 0.000 claims description 5
• 206010024264 Lethargy Diseases 0.000 claims description 5
• 206010057672 Male sexual dysfunction Diseases 0.000 claims description 5
• 239000003085 diluting agent Substances 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 5
• 201000001881 impotence Diseases 0.000 claims description 5
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
• 208000001076 sarcopenia Diseases 0.000 claims description 5
• 125000000217 alkyl group Chemical group 0.000 claims description 4
• 230000007423 decrease Effects 0.000 claims description 4
• 125000001793 isothiazol-3-yl group Chemical group [H]C1=C([H])C(*)=NS1 0.000 claims description 4
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 4
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 4
• CFZPNDIMNLMLED-AWEZNQCLSA-N propan-2-yl n-[(2s)-7-cyano-4-(1,3-thiazol-5-ylmethyl)-2,3-dihydro-1h-cyclopenta[b]indol-2-yl]carbamate Chemical compound C([C@H](C1)NC(=O)OC(C)C)C2=C1C1=CC(C#N)=CC=C1N2CC1=CN=CS1 CFZPNDIMNLMLED-AWEZNQCLSA-N 0.000 claims description 3
• 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims description 2
• 229910052701 rubidium Inorganic materials 0.000 claims description 2
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
• JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical group F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims 1
• 108010081348 HRT1 protein Hairy Chemical group 0.000 claims 1
• 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims 1
• 235000009508 confectionery Nutrition 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 139
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 80
• 239000000203 mixture Substances 0.000 description 79
• 239000007787 solid Substances 0.000 description 72
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 65
• 239000000543 intermediate Substances 0.000 description 65
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
• 238000000034 method Methods 0.000 description 63
• 238000003756 stirring Methods 0.000 description 59
• 235000019439 ethyl acetate Nutrition 0.000 description 57
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 57
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 48
• 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 description 45
• 239000012141 concentrate Substances 0.000 description 42
• 235000008504 concentrate Nutrition 0.000 description 42
• 229910001868 water Inorganic materials 0.000 description 41
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 40
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 40
• 235000019441 ethanol Nutrition 0.000 description 36
• 238000006243 chemical reaction Methods 0.000 description 35
• 239000000047 product Substances 0.000 description 33
• 239000003098 androgen Substances 0.000 description 31
• 239000000741 silica gel Substances 0.000 description 29
• 229910002027 silica gel Inorganic materials 0.000 description 29
• 239000000243 solution Substances 0.000 description 29
• 230000000694 effects Effects 0.000 description 26
• 238000010992 reflux Methods 0.000 description 23
• 238000012360 testing method Methods 0.000 description 23
• 239000011541 reaction mixture Substances 0.000 description 22
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 20
• 239000000460 chlorine Substances 0.000 description 20
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 19
• 102100032187 Androgen receptor Human genes 0.000 description 18
• 108010080146 androgen receptors Proteins 0.000 description 18
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 18
• 239000002904 solvent Substances 0.000 description 18
• 241001465754 Metazoa Species 0.000 description 17
• 239000013461 intermediate chemical Substances 0.000 description 17
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
• 238000003556 assay Methods 0.000 description 15
• 238000001914 filtration Methods 0.000 description 15
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
• 238000009739 binding Methods 0.000 description 14
• 208000035475 disorder Diseases 0.000 description 14
• 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 13
• 241000700159 Rattus Species 0.000 description 13
• 230000027455 binding Effects 0.000 description 13
• 102000003998 progesterone receptors Human genes 0.000 description 13
• 108090000468 progesterone receptors Proteins 0.000 description 13
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
• 102000003676 Glucocorticoid Receptors Human genes 0.000 description 12
• 108090000079 Glucocorticoid Receptors Proteins 0.000 description 12
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 12
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
• 150000001412 amines Chemical class 0.000 description 12
• 239000003795 chemical substances by application Substances 0.000 description 12
• 239000003814 drug Substances 0.000 description 12
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 12
• 239000003921 oil Substances 0.000 description 12
• 235000019198 oils Nutrition 0.000 description 12
• 239000012044 organic layer Substances 0.000 description 12
• 238000005160 1H NMR spectroscopy Methods 0.000 description 11
• 210000004027 cell Anatomy 0.000 description 11
• 239000012043 crude product Substances 0.000 description 11
• 239000000706 filtrate Substances 0.000 description 11
• IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 11
• VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 10
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
• 108090000375 Mineralocorticoid Receptors Proteins 0.000 description 10
• 102100021316 Mineralocorticoid receptor Human genes 0.000 description 10
• MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 10
• 238000004587 chromatography analysis Methods 0.000 description 10
• 238000004128 high performance liquid chromatography Methods 0.000 description 10
• 239000000463 material Substances 0.000 description 10
• 229910052757 nitrogen Inorganic materials 0.000 description 10
• 239000002245 particle Substances 0.000 description 10
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
• 239000003981 vehicle Substances 0.000 description 10
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
• 239000000556 agonist Substances 0.000 description 9
• 230000015572 biosynthetic process Effects 0.000 description 9
• 238000002360 preparation method Methods 0.000 description 9
• 239000011734 sodium Substances 0.000 description 9
• 230000003637 steroidlike Effects 0.000 description 9
• 238000003786 synthesis reaction Methods 0.000 description 9
• 210000001519 tissue Anatomy 0.000 description 9
• CCCIJQPRIXGQOE-XWSJACJDSA-N 17beta-hydroxy-17-methylestra-4,9,11-trien-3-one Chemical compound C1CC2=CC(=O)CCC2=C2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C=C2 CCCIJQPRIXGQOE-XWSJACJDSA-N 0.000 description 8
• KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 8
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
• 229940030486 androgens Drugs 0.000 description 8
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 8
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
• 235000019341 magnesium sulphate Nutrition 0.000 description 8
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
• 210000001625 seminal vesicle Anatomy 0.000 description 8
• 238000010561 standard procedure Methods 0.000 description 8
• 239000007858 starting material Substances 0.000 description 8
• VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
• 201000010653 vesiculitis Diseases 0.000 description 8
• OZAIFHULBGXAKX-UHFFFAOYSA-N 2,2'-azo-bis-isobutyronitrile Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 7
• 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 7
• QTTMOCOWZLSYSV-QWAPEVOJSA-M equilin sodium sulfate Chemical compound [Na+].[O-]S(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4C3=CCC2=C1 QTTMOCOWZLSYSV-QWAPEVOJSA-M 0.000 description 7
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
• 239000012442 inert solvent Substances 0.000 description 7
• 239000013612 plasmid Substances 0.000 description 7
• 102000005962 receptors Human genes 0.000 description 7
• 108020003175 receptors Proteins 0.000 description 7
• 230000004044 response Effects 0.000 description 7
• 238000010898 silica gel chromatography Methods 0.000 description 7
• PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 6
• PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 6
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
• JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 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
• 239000002585 base Substances 0.000 description 6
• 229910000024 caesium carbonate Inorganic materials 0.000 description 6
• 239000003153 chemical reaction reagent Substances 0.000 description 6
• UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 6
• 239000000284 extract Substances 0.000 description 6
• 238000001727 in vivo Methods 0.000 description 6
• 239000010410 layer Substances 0.000 description 6
• 239000003446 ligand Substances 0.000 description 6
• AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
• 239000000523 sample Substances 0.000 description 6
• 229920006395 saturated elastomer Polymers 0.000 description 6
• 239000002002 slurry Substances 0.000 description 6
• 150000003431 steroids Chemical class 0.000 description 6
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 5
• 108060001084 Luciferase Proteins 0.000 description 5
• 239000005089 Luciferase Substances 0.000 description 5
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
• 150000001299 aldehydes Chemical class 0.000 description 5
• 230000001548 androgenic effect Effects 0.000 description 5
• 239000005557 antagonist Substances 0.000 description 5
• 239000012267 brine Substances 0.000 description 5
• 239000000872 buffer Substances 0.000 description 5
• BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 5
• 235000011089 carbon dioxide Nutrition 0.000 description 5
• 238000001816 cooling Methods 0.000 description 5
• 239000008367 deionised water Substances 0.000 description 5
• 229910021641 deionized water Inorganic materials 0.000 description 5
• 238000004090 dissolution Methods 0.000 description 5
• 239000003480 eluent Substances 0.000 description 5
• 238000011534 incubation Methods 0.000 description 5
• 239000002609 medium Substances 0.000 description 5
• 229910000027 potassium carbonate Inorganic materials 0.000 description 5
• IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 5
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
• 102000005969 steroid hormone receptors Human genes 0.000 description 5
• 230000000638 stimulation Effects 0.000 description 5
• 229960003604 testosterone Drugs 0.000 description 5
• 229940124597 therapeutic agent Drugs 0.000 description 5
• 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 5
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
• NBNLXVDIURVLAP-UHFFFAOYSA-N 2-(1,3-dioxoisoindol-2-yl)-1,2,3,4-tetrahydrocyclopenta[b]indole-7-carbonitrile Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CC(C2=CC(=CC=C2N2)C#N)=C2C1 NBNLXVDIURVLAP-UHFFFAOYSA-N 0.000 description 4
• RTIZJQCGWLDNKT-UHFFFAOYSA-N 2-(3-oxocyclopentyl)isoindole-1,3-dione Chemical compound C1C(=O)CCC1N1C(=O)C2=CC=CC=C2C1=O RTIZJQCGWLDNKT-UHFFFAOYSA-N 0.000 description 4
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
• OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
• 208000017667 Chronic Disease Diseases 0.000 description 4
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
• 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
• 102000007399 Nuclear hormone receptor Human genes 0.000 description 4
• 108020005497 Nuclear hormone receptor Proteins 0.000 description 4
• 235000019502 Orange oil Nutrition 0.000 description 4
• 108091027981 Response element Proteins 0.000 description 4
• 102000006601 Thymidine Kinase Human genes 0.000 description 4
• 108020004440 Thymidine kinase Proteins 0.000 description 4
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
• 230000001154 acute effect Effects 0.000 description 4
• 229960002478 aldosterone Drugs 0.000 description 4
• 230000001195 anabolic effect Effects 0.000 description 4
• 229910052794 bromium Inorganic materials 0.000 description 4
• 239000011575 calcium Substances 0.000 description 4
• 229910052791 calcium Inorganic materials 0.000 description 4
• 238000004296 chiral HPLC Methods 0.000 description 4
• FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 4
• 229960003957 dexamethasone Drugs 0.000 description 4
• 201000010099 disease Diseases 0.000 description 4
• 229940079593 drug Drugs 0.000 description 4
• 235000019253 formic acid Nutrition 0.000 description 4
• 230000005764 inhibitory process Effects 0.000 description 4
• DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 description 4
• 150000002825 nitriles Chemical class 0.000 description 4
• 239000010502 orange oil Substances 0.000 description 4
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
• 239000008177 pharmaceutical agent Substances 0.000 description 4
• 230000008569 process Effects 0.000 description 4
• 210000002307 prostate Anatomy 0.000 description 4
• 230000009467 reduction Effects 0.000 description 4
• 108010068072 salmon calcitonin Proteins 0.000 description 4
• 238000000926 separation method Methods 0.000 description 4
• 239000000126 substance Substances 0.000 description 4
• 239000000725 suspension Substances 0.000 description 4
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
• 210000000689 upper leg Anatomy 0.000 description 4
• NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 3
• AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 3
• NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 3
• ADYKBYXVMBDQQX-UHFFFAOYSA-N 2-(bromomethyl)-6-fluoropyridine Chemical compound FC1=CC=CC(CBr)=N1 ADYKBYXVMBDQQX-UHFFFAOYSA-N 0.000 description 3
• JQDNCGRNPYKRAO-UHFFFAOYSA-N 2-(bromomethyl)pyridine;hydron;bromide Chemical compound Br.BrCC1=CC=CC=N1 JQDNCGRNPYKRAO-UHFFFAOYSA-N 0.000 description 3
• ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical class OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 3
• OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 3
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
• OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 3
• 102000002260 Alkaline Phosphatase Human genes 0.000 description 3
• 108020004774 Alkaline Phosphatase Proteins 0.000 description 3
• 206010065687 Bone loss Diseases 0.000 description 3
• 241000701022 Cytomegalovirus Species 0.000 description 3
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
• 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
• 229910004809 Na2 SO4 Inorganic materials 0.000 description 3
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
• IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 description 3
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
• 238000000540 analysis of variance Methods 0.000 description 3
• WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 3
• SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
• 230000037182 bone density Effects 0.000 description 3
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
• 239000001768 carboxy methyl cellulose Substances 0.000 description 3
• 239000003054 catalyst Substances 0.000 description 3
• 229910052801 chlorine Inorganic materials 0.000 description 3
• 239000002299 complementary DNA Substances 0.000 description 3
• 230000003247 decreasing effect Effects 0.000 description 3
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 3
• 238000003821 enantio-separation Methods 0.000 description 3
• 150000002148 esters Chemical class 0.000 description 3
• 229940011871 estrogen Drugs 0.000 description 3
• 239000000262 estrogen Substances 0.000 description 3
• 239000012091 fetal bovine serum Substances 0.000 description 3
• 238000009472 formulation Methods 0.000 description 3
• 230000008717 functional decline Effects 0.000 description 3
• 239000003862 glucocorticoid Substances 0.000 description 3
• 150000004820 halides Chemical class 0.000 description 3
• XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 description 3
• 238000002347 injection Methods 0.000 description 3
• 239000007924 injection Substances 0.000 description 3
• 229910052500 inorganic mineral Inorganic materials 0.000 description 3
• 229940047889 isobutyramide Drugs 0.000 description 3
• 239000007788 liquid Substances 0.000 description 3
• 230000014759 maintenance of location Effects 0.000 description 3
• PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 3
• QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
• 235000010755 mineral Nutrition 0.000 description 3
• 239000011707 mineral Substances 0.000 description 3
• 108020004017 nuclear receptors Proteins 0.000 description 3
• 238000009806 oophorectomy Methods 0.000 description 3
• 239000003960 organic solvent Substances 0.000 description 3
• QOWOXBFFQOXPHM-UHFFFAOYSA-O oxo-[[1-[[4-(oxoazaniumylmethylidene)pyridin-1-yl]methyl]pyridin-4-ylidene]methyl]azanium;chloride Chemical compound [Cl-].C1=CC(=C[NH+]=O)C=CN1CN1C=CC(=C[NH+]=O)C=C1 QOWOXBFFQOXPHM-UHFFFAOYSA-O 0.000 description 3
• WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 3
• 230000036961 partial effect Effects 0.000 description 3
• 239000012071 phase Substances 0.000 description 3
• 239000002244 precipitate Substances 0.000 description 3
• QFFCYTLOTYIJMR-XMGTWHOFSA-N promegestone Chemical compound C1CC2=CC(=O)CCC2=C2[C@@H]1[C@@H]1CC[C@@](C(=O)CC)(C)[C@@]1(C)CC2 QFFCYTLOTYIJMR-XMGTWHOFSA-N 0.000 description 3
• 229960001584 promegestone Drugs 0.000 description 3
• 238000000159 protein binding assay Methods 0.000 description 3
• GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 3
• 238000012552 review Methods 0.000 description 3
• 238000002390 rotary evaporation Methods 0.000 description 3
• 239000000377 silicon dioxide Substances 0.000 description 3
• 108020003113 steroid hormone receptors Proteins 0.000 description 3
• 208000024891 symptom Diseases 0.000 description 3
• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
• 238000012546 transfer Methods 0.000 description 3
• IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 3
• 238000002604 ultrasonography Methods 0.000 description 3
• 238000011144 upstream manufacturing Methods 0.000 description 3
• 238000003828 vacuum filtration Methods 0.000 description 3
• DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 2
• PYGGEOFNOAVTCT-UHFFFAOYSA-N (2-chloro-1,3-thiazol-4-yl)methanol Chemical compound OCC1=CSC(Cl)=N1 PYGGEOFNOAVTCT-UHFFFAOYSA-N 0.000 description 2
• AOPGRNGCXGFSDS-NVJADKKVSA-N (2r)-2-amino-4-(1,2-thiazol-3-ylmethyl)-2,3-dihydro-1h-cyclopenta[b]indole-7-carbonitrile;dihydrochloride Chemical compound Cl.Cl.C([C@@H](C1)N)C2=C1C1=CC(C#N)=CC=C1N2CC=1C=CSN=1 AOPGRNGCXGFSDS-NVJADKKVSA-N 0.000 description 2
• ZSPJEGPBSALMHQ-LJQANCHMSA-N (2r)-7-cyano-2-(dimethylsulfamoylamino)-4-[[2-(1,3-dioxoisoindol-2-yl)pyridin-3-yl]methyl]-2,3-dihydro-1h-cyclopenta[b]indole Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1=NC=CC=C1CN1C2=CC=C(C#N)C=C2C2=C1C[C@H](NS(=O)(=O)N(C)C)C2 ZSPJEGPBSALMHQ-LJQANCHMSA-N 0.000 description 2
• UGVXXDSOHKIRJX-QMMMGPOBSA-N (2s)-2-amino-1,2,3,4-tetrahydrocyclopenta[b]indole-7-carbonitrile Chemical compound N1C2=CC=C(C#N)C=C2C2=C1C[C@@H](N)C2 UGVXXDSOHKIRJX-QMMMGPOBSA-N 0.000 description 2
• KJCSNXOBSSRNMM-UHFFFAOYSA-N (4,5-dichloro-1,2-thiazol-3-yl)methanol Chemical compound OCC1=NSC(Cl)=C1Cl KJCSNXOBSSRNMM-UHFFFAOYSA-N 0.000 description 2
• QMJGQJINYQEOMX-UHFFFAOYSA-N 1,2,3,3a-tetrahydrocyclopenta[b]indol-1-amine Chemical compound C1=CC=CC2=C3C(N)CCC3N=C21 QMJGQJINYQEOMX-UHFFFAOYSA-N 0.000 description 2
• HZDXFZHFEASSBM-UHFFFAOYSA-N 1,2,3,4-tetrahydrocyclopenta[b]indole Chemical class N1C2=CC=CC=C2C2=C1CCC2 HZDXFZHFEASSBM-UHFFFAOYSA-N 0.000 description 2
• GFTBMBHVZZFGCK-UHFFFAOYSA-N 1,2,5-thiadiazole-3-carboxylic acid Chemical compound OC(=O)C=1C=NSN=1 GFTBMBHVZZFGCK-UHFFFAOYSA-N 0.000 description 2
• YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 description 2
• WKBQQWDVVHGWDB-UHFFFAOYSA-N 1,3-thiazol-5-ylmethanol Chemical compound OCC1=CN=CS1 WKBQQWDVVHGWDB-UHFFFAOYSA-N 0.000 description 2
• WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 2
• OXQOBQJCDNLAPO-UHFFFAOYSA-N 2,3-Dimethylpyrazine Chemical compound CC1=NC=CN=C1C OXQOBQJCDNLAPO-UHFFFAOYSA-N 0.000 description 2
• LCZUOKDVTBMCMX-UHFFFAOYSA-N 2,5-Dimethylpyrazine Chemical compound CC1=CN=C(C)C=N1 LCZUOKDVTBMCMX-UHFFFAOYSA-N 0.000 description 2
• GGRXRGUIJQVNFR-UHFFFAOYSA-N 2-(1,3-dioxoisoindol-2-yl)-4-(pyridin-2-ylmethyl)-2,3-dihydro-1h-cyclopenta[b]indole-7-carbonitrile Chemical compound O=C1C2=CC=CC=C2C(=O)N1C(C1)CC2=C1C1=CC(C#N)=CC=C1N2CC1=CC=CC=N1 GGRXRGUIJQVNFR-UHFFFAOYSA-N 0.000 description 2
• KUHSAAHTEMAJTF-UHFFFAOYSA-N 2-(difluoromethyl)pyridine Chemical compound FC(F)C1=CC=CC=N1 KUHSAAHTEMAJTF-UHFFFAOYSA-N 0.000 description 2
• PZQWWGXBCQGCFF-UHFFFAOYSA-N 2-[3-(bromomethyl)pyridin-2-yl]isoindole-1,3-dione Chemical compound BrCC1=CC=CN=C1N1C(=O)C2=CC=CC=C2C1=O PZQWWGXBCQGCFF-UHFFFAOYSA-N 0.000 description 2
• UGVXXDSOHKIRJX-UHFFFAOYSA-N 2-amino-1,2,3,4-tetrahydrocyclopenta[b]indole-7-carbonitrile Chemical compound N1C2=CC=C(C#N)C=C2C2=C1CC(N)C2 UGVXXDSOHKIRJX-UHFFFAOYSA-N 0.000 description 2
• RZFPCSFJQKFSRB-UHFFFAOYSA-N 2-amino-4-(pyridin-2-ylmethyl)-2,3-dihydro-1h-cyclopenta[b]indole-7-carbonitrile;hydrochloride Chemical compound Cl.C1C(N)CC2=C1C1=CC(C#N)=CC=C1N2CC1=CC=CC=N1 RZFPCSFJQKFSRB-UHFFFAOYSA-N 0.000 description 2
• RJAGYZDHDFAFKV-UHFFFAOYSA-N 2-amino-4-[(6-fluoropyridin-2-yl)methyl]-2,3-dihydro-1h-cyclopenta[b]indole-7-carbonitrile Chemical compound C1C(N)CC2=C1C1=CC(C#N)=CC=C1N2CC1=CC=CC(F)=N1 RJAGYZDHDFAFKV-UHFFFAOYSA-N 0.000 description 2
• WOTIUKDGJBXFLG-UHFFFAOYSA-N 3-methyl-1,2-thiazole Chemical compound CC=1C=CSN=1 WOTIUKDGJBXFLG-UHFFFAOYSA-N 0.000 description 2
• XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl Phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 2
• XSVSPKKXQGNHMD-UHFFFAOYSA-N 5-bromo-3-methyl-1,2-thiazole Chemical compound CC=1C=C(Br)SN=1 XSVSPKKXQGNHMD-UHFFFAOYSA-N 0.000 description 2
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
• CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 description 2
• 229920002307 Dextran Polymers 0.000 description 2
• 241000283073 Equus caballus Species 0.000 description 2
• 238000006783 Fischer indole synthesis reaction Methods 0.000 description 2
• KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 2
• 101001135770 Homo sapiens Parathyroid hormone Proteins 0.000 description 2
• 101001135995 Homo sapiens Probable peptidyl-tRNA hydrolase Proteins 0.000 description 2
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
• 239000005909 Kieselgur Substances 0.000 description 2
• 239000002841 Lewis acid Substances 0.000 description 2
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
• 229910017917 NH4 Cl Inorganic materials 0.000 description 2
• IMONTRJLAWHYGT-ZCPXKWAGSA-N Norethindrone Acetate Chemical compound C1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@](C#C)(OC(=O)C)[C@@]1(C)CC2 IMONTRJLAWHYGT-ZCPXKWAGSA-N 0.000 description 2
• OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
• RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
• 102000007066 Prostate-Specific Antigen Human genes 0.000 description 2
• 108010072866 Prostate-Specific Antigen Proteins 0.000 description 2
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
• NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
• 108700008625 Reporter Genes Proteins 0.000 description 2
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
• 108010085012 Steroid Receptors Proteins 0.000 description 2
• 108010049264 Teriparatide Proteins 0.000 description 2
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
• OZPWNCNLFBVVEN-RFYLDXRNSA-N [(6s,8r,9s,10r,13s,14s,17r)-17-acetyl-6,10,13-trimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-17-yl] acetate;[(9s,13s,14s)-13-methyl-17-oxo-9,11,12,14,15,16-hexahydro-6h-cyclopenta[a]phenanthren-3-yl] hydrogen sulfate;[(8r,9 Chemical compound OS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1.OS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4C3=CCC2=C1.OS(=O)(=O)OC1=CC=C2C(CC[C@]3([C@H]4CCC3=O)C)=C4C=CC2=C1.C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 OZPWNCNLFBVVEN-RFYLDXRNSA-N 0.000 description 2
• KYIKRXIYLAGAKQ-UHFFFAOYSA-N abcn Chemical compound C1CCCCC1(C#N)N=NC1(C#N)CCCCC1 KYIKRXIYLAGAKQ-UHFFFAOYSA-N 0.000 description 2
• 238000010521 absorption reaction Methods 0.000 description 2
• DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
• 230000002378 acidificating effect Effects 0.000 description 2
• 229940037127 actonel Drugs 0.000 description 2
• 150000001298 alcohols Chemical class 0.000 description 2
• 125000001931 aliphatic group Chemical group 0.000 description 2
• 230000029936 alkylation Effects 0.000 description 2
• 238000005804 alkylation reaction Methods 0.000 description 2
• 150000001408 amides Chemical class 0.000 description 2
• 238000009165 androgen replacement therapy Methods 0.000 description 2
• 238000010171 animal model Methods 0.000 description 2
• 239000002518 antifoaming agent Substances 0.000 description 2
• 239000007864 aqueous solution Substances 0.000 description 2
• 230000002146 bilateral effect Effects 0.000 description 2
• 229960003773 calcitonin (salmon synthetic) Drugs 0.000 description 2
• 125000004432 carbon atom Chemical group C* 0.000 description 2
• 229940062399 cenestin Drugs 0.000 description 2
• 229940108922 climara Drugs 0.000 description 2
• 238000004440 column chromatography Methods 0.000 description 2
• 238000002648 combination therapy Methods 0.000 description 2
• 229940068850 combipatch Drugs 0.000 description 2
• 239000013058 crude material Substances 0.000 description 2
• 230000007812 deficiency Effects 0.000 description 2
• 238000010511 deprotection reaction Methods 0.000 description 2
• ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical compound OC(=O)OC(O)=O ZFTFAPZRGNKQPU-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
• 238000004821 distillation Methods 0.000 description 2
• VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 2
• 239000002934 diuretic Substances 0.000 description 2
• 229940030606 diuretics Drugs 0.000 description 2
• 230000002255 enzymatic effect Effects 0.000 description 2
• 229940074117 estraderm Drugs 0.000 description 2
• 229960005309 estradiol Drugs 0.000 description 2
• 229930182833 estradiol Natural products 0.000 description 2
• JKKFKPJIXZFSSB-CBZIJGRNSA-N estrone 3-sulfate Chemical compound OS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 JKKFKPJIXZFSSB-CBZIJGRNSA-N 0.000 description 2
• HZEQBCVBILBTEP-ZFINNJDLSA-N estropipate Chemical compound C1CNCCN1.OS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 HZEQBCVBILBTEP-ZFINNJDLSA-N 0.000 description 2
• KTGUPAFUVGHOQS-UHFFFAOYSA-N ethyl 2-amino-5-methyl-1,3-thiazole-4-carboxylate Chemical compound CCOC(=O)C=1N=C(N)SC=1C KTGUPAFUVGHOQS-UHFFFAOYSA-N 0.000 description 2
• GILVNZWYCBUGMT-UHFFFAOYSA-N ethyl 2-chloro-1,3-thiazole-4-carboxylate Chemical compound CCOC(=O)C1=CSC(Cl)=N1 GILVNZWYCBUGMT-UHFFFAOYSA-N 0.000 description 2
• SNOLCJGSEPTCMD-UHFFFAOYSA-N ethyl 5-methyl-1,3-thiazole-4-carboxylate Chemical compound CCOC(=O)C=1N=CSC=1C SNOLCJGSEPTCMD-UHFFFAOYSA-N 0.000 description 2
• 125000004494 ethyl ester group Chemical group 0.000 description 2
• 229940085363 evista Drugs 0.000 description 2
• 229940006346 femhrt Drugs 0.000 description 2
• 229940053641 forteo Drugs 0.000 description 2
• 229940001490 fosamax Drugs 0.000 description 2
• 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
• 238000010438 heat treatment Methods 0.000 description 2
• 125000000623 heterocyclic group Chemical group 0.000 description 2
• 102000058004 human PTH Human genes 0.000 description 2
• 239000004615 ingredient Substances 0.000 description 2
• JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 2
• WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 2
• 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 2
• 210000003734 kidney Anatomy 0.000 description 2
• 150000007517 lewis acids Chemical class 0.000 description 2
• 238000004519 manufacturing process Methods 0.000 description 2
• 229940101513 menest Drugs 0.000 description 2
• CAWHJQAVHZEVTJ-UHFFFAOYSA-N methylpyrazine Chemical compound CC1=CN=CC=N1 CAWHJQAVHZEVTJ-UHFFFAOYSA-N 0.000 description 2
• 229940101566 miacalcin Drugs 0.000 description 2
• 239000002395 mineralocorticoid Substances 0.000 description 2
• 239000012452 mother liquor Substances 0.000 description 2
• 229910000069 nitrogen hydride Inorganic materials 0.000 description 2
• 229960000417 norgestimate Drugs 0.000 description 2
• KIQQMECNKUGGKA-NMYWJIRASA-N norgestimate Chemical compound O/N=C/1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(OC(C)=O)C#C)[C@@H]4[C@@H]3CCC2=C\1 KIQQMECNKUGGKA-NMYWJIRASA-N 0.000 description 2
• 229940099990 ogen Drugs 0.000 description 2
• 238000011474 orchiectomy Methods 0.000 description 2
• 150000002894 organic compounds Chemical class 0.000 description 2
• 239000004031 partial agonist Substances 0.000 description 2
• 230000037361 pathway Effects 0.000 description 2
• 229910052698 phosphorus Inorganic materials 0.000 description 2
• 239000011574 phosphorus Substances 0.000 description 2
• 125000005543 phthalimide group Chemical group 0.000 description 2
• 230000036470 plasma concentration Effects 0.000 description 2
• 229920000728 polyester Polymers 0.000 description 2
• 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
• 229920000053 polysorbate 80 Polymers 0.000 description 2
• 239000013641 positive control Substances 0.000 description 2
• 229940063238 premarin Drugs 0.000 description 2
• 238000011552 rat model Methods 0.000 description 2
• 238000001525 receptor binding assay Methods 0.000 description 2
• 229940095743 selective estrogen receptor modulator Drugs 0.000 description 2
• 239000000333 selective estrogen receptor modulator Substances 0.000 description 2
• HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 2
• 235000017557 sodium bicarbonate Nutrition 0.000 description 2
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
• 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
• 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
• 229910000104 sodium hydride Inorganic materials 0.000 description 2
• 239000012312 sodium hydride Substances 0.000 description 2
• 229910052938 sodium sulfate Inorganic materials 0.000 description 2
• 235000011152 sodium sulphate Nutrition 0.000 description 2
• 239000001433 sodium tartrate Substances 0.000 description 2
• 229960002167 sodium tartrate Drugs 0.000 description 2
• 235000011004 sodium tartrates Nutrition 0.000 description 2
• 239000012453 solvate Substances 0.000 description 2
• 239000003270 steroid hormone Substances 0.000 description 2
• 238000010254 subcutaneous injection Methods 0.000 description 2
• 239000007929 subcutaneous injection Substances 0.000 description 2
• KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
• 229950009390 symclosene Drugs 0.000 description 2
• 239000006188 syrup Substances 0.000 description 2
• 235000020357 syrup Nutrition 0.000 description 2
• OGBMKVWORPGQRR-UMXFMPSGSA-N teriparatide Chemical compound C([C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)[C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 OGBMKVWORPGQRR-UMXFMPSGSA-N 0.000 description 2
• XDPAXRFBCFDZRH-UHFFFAOYSA-N tert-butyl n-[7-cyano-4-(1,2-thiazol-3-ylmethyl)-2,3-dihydro-1h-cyclopenta[b]indol-2-yl]carbamate Chemical compound C1C(NC(=O)OC(C)(C)C)CC2=C1C1=CC(C#N)=CC=C1N2CC=1C=CSN=1 XDPAXRFBCFDZRH-UHFFFAOYSA-N 0.000 description 2
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
• 238000004809 thin layer chromatography Methods 0.000 description 2
• 238000000825 ultraviolet detection Methods 0.000 description 2
• 230000003612 virological effect Effects 0.000 description 2
• 229940053743 vivelle Drugs 0.000 description 2
• 238000005303 weighing Methods 0.000 description 2
• JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
• FBYURPJSXWRIGY-OAHLLOKOSA-N (2r)-4-[(2-aminopyridin-3-yl)methyl]-7-cyano-2-(dimethylsulfamoylamino)-2,3-dihydro-1h-cyclopenta[b]indole Chemical compound C([C@@H](C1)NS(=O)(=O)N(C)C)C2=C1C1=CC(C#N)=CC=C1N2CC1=CC=CN=C1N FBYURPJSXWRIGY-OAHLLOKOSA-N 0.000 description 1
• NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
• ZRTGHKVPFXNDHE-UHFFFAOYSA-N (3-methyl-1,2-thiazol-5-yl)azanium;chloride Chemical compound [Cl-].CC=1C=C([NH3+])SN=1 ZRTGHKVPFXNDHE-UHFFFAOYSA-N 0.000 description 1
• WLNWBRRUSXTXME-UHFFFAOYSA-N (7-cyano-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl)carbamic acid Chemical compound N1C2=CC=C(C#N)C=C2C2=C1CC(NC(=O)O)C2 WLNWBRRUSXTXME-UHFFFAOYSA-N 0.000 description 1
• GEONECATAKDDLT-JDSZYESASA-N (8r,9s,13s,14s,17r)-17-ethynyl-13-methyl-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthrene-3,17-diol;[(8r,9s,10r,13s,14s,17r)-17-ethynyl-13-methyl-3-oxo-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl] acetate Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1.C1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@](C#C)(OC(=O)C)[C@@]1(C)CC2 GEONECATAKDDLT-JDSZYESASA-N 0.000 description 1
• SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
• AICZEPAZLXWVES-UHFFFAOYSA-N 1,2,5-thiadiazol-3-ylmethanol Chemical compound OCC=1C=NSN=1 AICZEPAZLXWVES-UHFFFAOYSA-N 0.000 description 1
• KAVUJQDUTPJHRQ-UHFFFAOYSA-N 1,2,5-thiadiazol-3-ylmethyl methanesulfonate Chemical compound CS(=O)(=O)OCC=1C=NSN=1 KAVUJQDUTPJHRQ-UHFFFAOYSA-N 0.000 description 1
• JNHDLNXNYPLBMJ-UHFFFAOYSA-N 1,3-thiazol-2-ylmethanol Chemical compound OCC1=NC=CS1 JNHDLNXNYPLBMJ-UHFFFAOYSA-N 0.000 description 1
• ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-UHFFFAOYSA-N 0.000 description 1
• IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 description 1
• NTUHBYLZRBVHRS-UHFFFAOYSA-N 1h-indole-7-carbonitrile Chemical compound N#CC1=CC=CC2=C1NC=C2 NTUHBYLZRBVHRS-UHFFFAOYSA-N 0.000 description 1
• ORBSDNKEGRKTKU-UHFFFAOYSA-N 1h-indole-7-carbonitrile;hydrochloride Chemical compound Cl.N#CC1=CC=CC2=C1NC=C2 ORBSDNKEGRKTKU-UHFFFAOYSA-N 0.000 description 1
• XKLNOVWDVMWTOB-UHFFFAOYSA-N 2,3,4,9-tetrahydro-1h-carbazole Chemical class N1C2=CC=CC=C2C2=C1CCCC2 XKLNOVWDVMWTOB-UHFFFAOYSA-N 0.000 description 1
• KGLPWQKSKUVKMJ-UHFFFAOYSA-N 2,3-dihydrophthalazine-1,4-dione Chemical compound C1=CC=C2C(=O)NNC(=O)C2=C1 KGLPWQKSKUVKMJ-UHFFFAOYSA-N 0.000 description 1
• 239000001934 2,5-dimethylpyrazine Substances 0.000 description 1
• JYSWJYZWSPYQGZ-UHFFFAOYSA-N 2-(bromomethyl)-6-(difluoromethyl)pyridine Chemical compound FC(F)C1=CC=CC(CBr)=N1 JYSWJYZWSPYQGZ-UHFFFAOYSA-N 0.000 description 1
• YEZLFBCEZYSGQC-UHFFFAOYSA-N 2-(bromomethyl)pyridin-1-ium-3-ol;bromide Chemical compound Br.OC1=CC=CN=C1CBr YEZLFBCEZYSGQC-UHFFFAOYSA-N 0.000 description 1
• ZHAKAIBZKYHXJS-UHFFFAOYSA-N 2-(chloromethyl)-1,3-thiazole Chemical compound ClCC1=NC=CS1 ZHAKAIBZKYHXJS-UHFFFAOYSA-N 0.000 description 1
• HQYGCYJUSJWSBU-UHFFFAOYSA-N 2-(chloromethyl)-3-methylpyrazine Chemical compound CC1=NC=CN=C1CCl HQYGCYJUSJWSBU-UHFFFAOYSA-N 0.000 description 1
• QUEDRKKLXVSNPQ-UHFFFAOYSA-N 2-(difluoromethyl)-6-methylpyridine Chemical compound CC1=CC=CC(C(F)F)=N1 QUEDRKKLXVSNPQ-UHFFFAOYSA-N 0.000 description 1
• JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
• ATHVRPQAKNQENL-CYBMUJFWSA-N 2-[[(2r)-7-cyano-2-(dimethylsulfamoylamino)-2,3-dihydro-1h-cyclopenta[b]indol-4-yl]methyl]-1,3-thiazole Chemical compound C([C@@H](C1)NS(=O)(=O)N(C)C)C2=C1C1=CC(C#N)=CC=C1N2CC1=NC=CS1 ATHVRPQAKNQENL-CYBMUJFWSA-N 0.000 description 1
• AAFKKZAJPJKSNG-UHFFFAOYSA-N 2-amino-4-(pyridin-2-ylmethyl)-2,3-dihydro-1h-cyclopenta[b]indole-7-carbonitrile Chemical compound C1C(N)CC2=C1C1=CC(C#N)=CC=C1N2CC1=CC=CC=N1 AAFKKZAJPJKSNG-UHFFFAOYSA-N 0.000 description 1
• SOHDPICLICFSOP-UHFFFAOYSA-N 2-bromo-6-methylpyridine Chemical compound CC1=CC=CC(Br)=N1 SOHDPICLICFSOP-UHFFFAOYSA-N 0.000 description 1
• YQGZWZWIEBRCJW-UHFFFAOYSA-N 2-chloro-3-(chloromethyl)pyrazine Chemical compound ClCC1=NC=CN=C1Cl YQGZWZWIEBRCJW-UHFFFAOYSA-N 0.000 description 1
• WZHWPZQQPWKEAV-UHFFFAOYSA-N 2-chloro-3-methylpyrazine Chemical compound CC1=NC=CN=C1Cl WZHWPZQQPWKEAV-UHFFFAOYSA-N 0.000 description 1
• QELZCGMVHLQNSO-UHFFFAOYSA-N 2-chloro-4-(chloromethyl)pyridine Chemical compound ClCC1=CC=NC(Cl)=C1 QELZCGMVHLQNSO-UHFFFAOYSA-N 0.000 description 1
• MZVSTDHRRYQFGI-UHFFFAOYSA-N 2-chloro-4-methylpyridine Chemical compound CC1=CC=NC(Cl)=C1 MZVSTDHRRYQFGI-UHFFFAOYSA-N 0.000 description 1
• CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 1
• APOYTRAZFJURPB-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)-n-(trifluoro-$l^{4}-sulfanyl)ethanamine Chemical compound COCCN(S(F)(F)F)CCOC APOYTRAZFJURPB-UHFFFAOYSA-N 0.000 description 1
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
• VZWOXDYRBDIHMA-UHFFFAOYSA-N 2-methyl-1,3-thiazole Chemical compound CC1=NC=CS1 VZWOXDYRBDIHMA-UHFFFAOYSA-N 0.000 description 1
• ZNGINKJHQQQORD-UHFFFAOYSA-N 2-trimethylsilylethanol Chemical compound C[Si](C)(C)CCO ZNGINKJHQQQORD-UHFFFAOYSA-N 0.000 description 1
• ARLSJNLOYBFYTO-UHFFFAOYSA-N 3,3a-dihydro-2H-cyclopenta[g]indol-1-amine Chemical compound C1CN(C2=C3C=CC=C3C=CC21)N ARLSJNLOYBFYTO-UHFFFAOYSA-N 0.000 description 1
• FVJGRFFQOBEQSX-UHFFFAOYSA-N 3-(bromomethyl)-1,2-thiazole Chemical compound BrCC=1C=CSN=1 FVJGRFFQOBEQSX-UHFFFAOYSA-N 0.000 description 1
• TWCGCUQPXQOQCA-UHFFFAOYSA-N 3-(chloromethyl)pyridazine Chemical compound ClCC1=CC=CN=N1 TWCGCUQPXQOQCA-UHFFFAOYSA-N 0.000 description 1
• AHRVHKYJVUKSST-UHFFFAOYSA-N 3-[7-cyano-4-[(6-fluoropyridin-2-yl)methyl]-2,3-dihydro-1h-cyclopenta[b]indol-2-yl]-1,1-dimethylurea Chemical compound C1C(NC(=O)N(C)C)CC2=C1C1=CC(C#N)=CC=C1N2CC1=CC=CC(F)=N1 AHRVHKYJVUKSST-UHFFFAOYSA-N 0.000 description 1
• MXDRPNGTQDRKQM-UHFFFAOYSA-N 3-methylpyridazine Chemical compound CC1=CC=CN=N1 MXDRPNGTQDRKQM-UHFFFAOYSA-N 0.000 description 1
• RGDQRXPEZUNWHX-UHFFFAOYSA-N 3-methylpyridin-2-amine Chemical compound CC1=CC=CN=C1N RGDQRXPEZUNWHX-UHFFFAOYSA-N 0.000 description 1
• UZJQAAGBFSYATG-CYBMUJFWSA-N 4-[[(2r)-7-cyano-2-(dimethylsulfamoylamino)-2,3-dihydro-1h-cyclopenta[b]indol-4-yl]methyl]-1,3-thiazole Chemical compound C([C@@H](C1)NS(=O)(=O)N(C)C)C2=C1C1=CC(C#N)=CC=C1N2CC1=CSC=N1 UZJQAAGBFSYATG-CYBMUJFWSA-N 0.000 description 1
• FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
• UXDLLFIRCVPPQP-UHFFFAOYSA-N 4-hydrazinylbenzonitrile;hydrochloride Chemical compound [Cl-].[NH3+]NC1=CC=C(C#N)C=C1 UXDLLFIRCVPPQP-UHFFFAOYSA-N 0.000 description 1
• XFXKCFDTGLPELQ-CYBMUJFWSA-N 5-[[(2r)-7-cyano-2-(dimethylsulfamoylamino)-2,3-dihydro-1h-cyclopenta[b]indol-4-yl]methyl]-1,3-thiazole Chemical compound C([C@@H](C1)NS(=O)(=O)N(C)C)C2=C1C1=CC(C#N)=CC=C1N2CC1=CN=CS1 XFXKCFDTGLPELQ-CYBMUJFWSA-N 0.000 description 1
• IDMQAOSTCQJAQL-ZDUSSCGKSA-N 5-[[(2s)-7-cyano-2-(propan-2-yloxycarbonylamino)-2,3-dihydro-1h-cyclopenta[b]indol-4-yl]methyl]-1,3-thiazole-4-carboxylic acid Chemical compound C([C@H](C1)NC(=O)OC(C)C)C2=C1C1=CC(C#N)=CC=C1N2CC=1SC=NC=1C(O)=O IDMQAOSTCQJAQL-ZDUSSCGKSA-N 0.000 description 1
• UQMHBWOPZJAIQP-UHFFFAOYSA-N 5-bromo-3-(bromomethyl)-1,2-thiazole Chemical compound BrCC=1C=C(Br)SN=1 UQMHBWOPZJAIQP-UHFFFAOYSA-N 0.000 description 1
• ODHCTXKNWHHXJC-GSVOUGTGSA-N 5-oxo-D-proline Chemical compound OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 description 1
• AHISYUZBWDSPQL-UHFFFAOYSA-N 6-methylpyridine-2-carbaldehyde Chemical compound CC1=CC=CC(C=O)=N1 AHISYUZBWDSPQL-UHFFFAOYSA-N 0.000 description 1
• 229910018507 Al—Ni Inorganic materials 0.000 description 1
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
• 206010002261 Androgen deficiency Diseases 0.000 description 1
• 108010039627 Aprotinin Proteins 0.000 description 1
• 239000004342 Benzoyl peroxide Substances 0.000 description 1
• OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
• 229940122361 Bisphosphonate Drugs 0.000 description 1
• 208000006386 Bone Resorption Diseases 0.000 description 1
• 241000283690 Bos taurus Species 0.000 description 1
• 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
• QRDIOXLCSJXGPQ-UHFFFAOYSA-N C(C)(C)OC(NC1CC2=C(N(C=3C=CC(=CC2=3)C#N)CC2=NSC(=C2)Br)C1)=O Chemical compound C(C)(C)OC(NC1CC2=C(N(C=3C=CC(=CC2=3)C#N)CC2=NSC(=C2)Br)C1)=O QRDIOXLCSJXGPQ-UHFFFAOYSA-N 0.000 description 1
• GWKVRFDPILIQGI-UHFFFAOYSA-N C(C)OC(NC1CC2=C(N(C=3C=CC(=CC2=3)C#N)CC2=NC=CN=C2)C1)=O Chemical compound C(C)OC(NC1CC2=C(N(C=3C=CC(=CC2=3)C#N)CC2=NC=CN=C2)C1)=O GWKVRFDPILIQGI-UHFFFAOYSA-N 0.000 description 1
• IXRMYHMIPHCTPR-NSHDSACASA-N C1[C@@H](CC2=C1C3=C(N2CC4=NC=CN=C4Cl)C=CC(=C3)C#N)NC(=O)O Chemical compound C1[C@@H](CC2=C1C3=C(N2CC4=NC=CN=C4Cl)C=CC(=C3)C#N)NC(=O)O IXRMYHMIPHCTPR-NSHDSACASA-N 0.000 description 1
• 108060001064 Calcitonin Proteins 0.000 description 1
• 102000055006 Calcitonin Human genes 0.000 description 1
• 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
• 208000024172 Cardiovascular disease Diseases 0.000 description 1
• 241000282693 Cercopithecidae Species 0.000 description 1
• 241001000171 Chira Species 0.000 description 1
• 101710178035 Chorismate synthase 2 Proteins 0.000 description 1
• 102000029816 Collagenase Human genes 0.000 description 1
• 108060005980 Collagenase Proteins 0.000 description 1
• BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical compound O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 description 1
• 101710152694 Cysteine synthase 2 Proteins 0.000 description 1
• GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
• LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
• YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 1
• 108010065556 Drug Receptors Proteins 0.000 description 1
• 102000013138 Drug Receptors Human genes 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
• 241000282326 Felis catus Species 0.000 description 1
• 230000005526 G1 to G0 transition Effects 0.000 description 1
• 229910004373 HOAc Inorganic materials 0.000 description 1
• 206010019851 Hepatotoxicity Diseases 0.000 description 1
• 206010020112 Hirsutism Diseases 0.000 description 1
• 101000926939 Homo sapiens Glucocorticoid receptor Proteins 0.000 description 1
• 101001071608 Homo sapiens Glutathione reductase, mitochondrial Proteins 0.000 description 1
• 101000615613 Homo sapiens Mineralocorticoid receptor Proteins 0.000 description 1
• 101000685982 Homo sapiens NAD(+) hydrolase SARM1 Proteins 0.000 description 1
• 101000574060 Homo sapiens Progesterone receptor Proteins 0.000 description 1
• 101000738977 Homo sapiens Reverse transcriptase/ribonuclease H Proteins 0.000 description 1
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
• GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 description 1
• 239000012448 Lithium borohydride Substances 0.000 description 1
• 102100023356 NAD(+) hydrolase SARM1 Human genes 0.000 description 1
• ZKSYPTBBNIPWMR-UHFFFAOYSA-N NC1CC2=C(N(C=3C=CC(=CC23)C#N)CC2=NC=CN=C2)C1 Chemical compound NC1CC2=C(N(C=3C=CC(=CC23)C#N)CC2=NC=CN=C2)C1 ZKSYPTBBNIPWMR-UHFFFAOYSA-N 0.000 description 1
• 238000005481 NMR spectroscopy Methods 0.000 description 1
• FQGIVPFMVGLAGP-SNVBAGLBSA-N N[C@@H]1CC2=C(N(C=3C=CC(=CC23)C#N)CC2=NSN=C2)C1 Chemical compound N[C@@H]1CC2=C(N(C=3C=CC(=CC23)C#N)CC2=NSN=C2)C1 FQGIVPFMVGLAGP-SNVBAGLBSA-N 0.000 description 1
• XGYZXUDDZZFNQW-LLVKDONJSA-N N[C@@H]1CC2=C(N(C=3C=CC(=CC23)C#N)CC=2N=CSC2)C1 Chemical compound N[C@@H]1CC2=C(N(C=3C=CC(=CC23)C#N)CC=2N=CSC2)C1 XGYZXUDDZZFNQW-LLVKDONJSA-N 0.000 description 1
• HESHSNINBMHMAO-LLVKDONJSA-N N[C@@H]1CC2=C(N(C=3C=CC(=CC23)C#N)CC=2SC=CN2)C1 Chemical compound N[C@@H]1CC2=C(N(C=3C=CC(=CC23)C#N)CC=2SC=CN2)C1 HESHSNINBMHMAO-LLVKDONJSA-N 0.000 description 1
• BKMAFXRYNLRHCM-LLVKDONJSA-N N[C@@H]1CC2=C(N(C=3C=CC(=CC2=3)C#N)CC2=CN=CS2)C1 Chemical compound N[C@@H]1CC2=C(N(C=3C=CC(=CC2=3)C#N)CC2=CN=CS2)C1 BKMAFXRYNLRHCM-LLVKDONJSA-N 0.000 description 1
• 238000011887 Necropsy Methods 0.000 description 1
• 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
• 108091028043 Nucleic acid sequence Proteins 0.000 description 1
• 206010030247 Oestrogen deficiency Diseases 0.000 description 1
• 108090000445 Parathyroid hormone Proteins 0.000 description 1
• 102000003982 Parathyroid hormone Human genes 0.000 description 1
• 241001494479 Pecora Species 0.000 description 1
• 241000009328 Perro Species 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
• 239000004743 Polypropylene Substances 0.000 description 1
• XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
• 206010060862 Prostate cancer Diseases 0.000 description 1
• 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
• OEYVFRVNVPKHQQ-UHFFFAOYSA-N Pyrimidin-4-yl-Methanol Chemical compound OCC1=CC=NC=N1 OEYVFRVNVPKHQQ-UHFFFAOYSA-N 0.000 description 1
• 241000700157 Rattus norvegicus Species 0.000 description 1
• 201000001880 Sexual dysfunction Diseases 0.000 description 1
• DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
• 241000282898 Sus scrofa Species 0.000 description 1
• 239000007983 Tris buffer Substances 0.000 description 1
• 206010047486 Virilism Diseases 0.000 description 1
• 229930003316 Vitamin D Natural products 0.000 description 1
• QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
• 238000002441 X-ray diffraction Methods 0.000 description 1
• NAUDKYVGHCCLOT-LAQCMFAESA-N [(8r,9s,10r,13s,14s,17r)-17-ethynyl-13-methyl-3-oxo-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl] acetate;(8r,9s,13s,14s,17s)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1.C1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@](C#C)(OC(=O)C)[C@@]1(C)CC2 NAUDKYVGHCCLOT-LAQCMFAESA-N 0.000 description 1
• KQXZVSQCMVKMBK-UHFFFAOYSA-N [4-(trifluoromethoxy)phenyl]hydrazine;hydrochloride Chemical compound Cl.NNC1=CC=C(OC(F)(F)F)C=C1 KQXZVSQCMVKMBK-UHFFFAOYSA-N 0.000 description 1
• 229960000583 acetic acid Drugs 0.000 description 1
• 239000002253 acid Substances 0.000 description 1
• ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 1
• 230000032683 aging Effects 0.000 description 1
• 229940062527 alendronate Drugs 0.000 description 1
• 125000003545 alkoxy group Chemical group 0.000 description 1
• 150000001347 alkyl bromides Chemical class 0.000 description 1
• 150000001348 alkyl chlorides Chemical class 0.000 description 1
• 150000001350 alkyl halides Chemical class 0.000 description 1
• 230000002152 alkylating effect Effects 0.000 description 1
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
• 230000003042 antagnostic effect Effects 0.000 description 1
• 239000000010 aprotic solvent Substances 0.000 description 1
• 229960004405 aprotinin Drugs 0.000 description 1
• 239000012131 assay buffer Substances 0.000 description 1
• 230000009286 beneficial effect Effects 0.000 description 1
• 235000019400 benzoyl peroxide Nutrition 0.000 description 1
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
• 238000004166 bioassay Methods 0.000 description 1
• 230000033228 biological regulation Effects 0.000 description 1
• AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
• 150000004663 bisphosphonates Chemical class 0.000 description 1
• 230000037396 body weight Effects 0.000 description 1
• 238000009835 boiling Methods 0.000 description 1
• 230000024279 bone resorption Effects 0.000 description 1
• 230000031709 bromination Effects 0.000 description 1
• 238000005893 bromination reaction Methods 0.000 description 1
• 244000309464 bull Species 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
• 239000006227 byproduct Substances 0.000 description 1
• 229960004015 calcitonin Drugs 0.000 description 1
• 229960005069 calcium Drugs 0.000 description 1
• 239000002775 capsule Substances 0.000 description 1
• 239000004202 carbamide Substances 0.000 description 1
• 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
• 150000001733 carboxylic acid esters Chemical class 0.000 description 1
• 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
• 230000015556 catabolic process Effects 0.000 description 1
• 230000001413 cellular effect Effects 0.000 description 1
• 230000008859 change Effects 0.000 description 1
• 239000003610 charcoal Substances 0.000 description 1
• 150000005829 chemical entities Chemical class 0.000 description 1
• 239000003638 chemical reducing agent Substances 0.000 description 1
• 238000005660 chlorination reaction Methods 0.000 description 1
• 230000001684 chronic effect Effects 0.000 description 1
• 229960002424 collagenase Drugs 0.000 description 1
• 239000012230 colorless oil Substances 0.000 description 1
• 229940035811 conjugated estrogen Drugs 0.000 description 1
• 238000010276 construction Methods 0.000 description 1
• 238000007796 conventional method Methods 0.000 description 1
• DLTBAYKGXREKMW-UHFFFAOYSA-N cyclopropanesulfonic acid Chemical compound OS(=O)(=O)C1CC1 DLTBAYKGXREKMW-UHFFFAOYSA-N 0.000 description 1
• 238000006731 degradation reaction Methods 0.000 description 1
• 229940075894 denatured ethanol Drugs 0.000 description 1
• 238000011161 development Methods 0.000 description 1
• 230000018109 developmental process Effects 0.000 description 1
• 206010012601 diabetes mellitus Diseases 0.000 description 1
• 238000003745 diagnosis Methods 0.000 description 1
• 239000012973 diazabicyclooctane Substances 0.000 description 1
• MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
• 239000006185 dispersion Substances 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
• 238000001035 drying Methods 0.000 description 1
• 238000002296 dynamic light scattering Methods 0.000 description 1
• 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 1
• 238000005516 engineering process Methods 0.000 description 1
• 210000002745 epiphysis Anatomy 0.000 description 1
• DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
• PNWIKDRAYAABHN-UHFFFAOYSA-N ethyl 5-(bromomethyl)-1,3-thiazole-4-carboxylate Chemical compound CCOC(=O)C=1N=CSC=1CBr PNWIKDRAYAABHN-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
• 230000005713 exacerbation Effects 0.000 description 1
• 230000029142 excretion Effects 0.000 description 1
• 206010016256 fatigue Diseases 0.000 description 1
• 230000035558 fertility Effects 0.000 description 1
• 239000012065 filter cake Substances 0.000 description 1
• 239000012530 fluid Substances 0.000 description 1
• 229940091249 fluoride supplement Drugs 0.000 description 1
• 229910052731 fluorine Inorganic materials 0.000 description 1
• 235000013305 food Nutrition 0.000 description 1
• 238000010575 fractional recrystallization Methods 0.000 description 1
• 239000012458 free base Substances 0.000 description 1
• 238000002825 functional assay Methods 0.000 description 1
• 230000014509 gene expression Effects 0.000 description 1
• 210000004392 genitalia Anatomy 0.000 description 1
• 239000012362 glacial acetic acid Substances 0.000 description 1
• 238000000227 grinding Methods 0.000 description 1
• 230000012010 growth Effects 0.000 description 1
• 230000003779 hair growth Effects 0.000 description 1
• 125000005843 halogen group Chemical group 0.000 description 1
• 230000036541 health Effects 0.000 description 1
• 230000007686 hepatotoxicity Effects 0.000 description 1
• 231100000304 hepatotoxicity Toxicity 0.000 description 1
• 229940088597 hormone Drugs 0.000 description 1
• 239000005556 hormone Substances 0.000 description 1
• 238000002657 hormone replacement therapy Methods 0.000 description 1
• 239000001257 hydrogen Substances 0.000 description 1
• 229910052739 hydrogen Inorganic materials 0.000 description 1
• SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 1
• 239000012535 impurity Substances 0.000 description 1
• 238000000338 in vitro Methods 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
• 230000002401 inhibitory effect Effects 0.000 description 1
• ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
• 239000003999 initiator Substances 0.000 description 1
• 239000002198 insoluble material Substances 0.000 description 1
• 229910052740 iodine Inorganic materials 0.000 description 1
• 239000011630 iodine Substances 0.000 description 1
• PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
• OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 1
• 238000002955 isolation Methods 0.000 description 1
• 238000002356 laser light scattering Methods 0.000 description 1
• GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
• 108010052968 leupeptin Proteins 0.000 description 1
• 230000000670 limiting effect Effects 0.000 description 1
• 210000004185 liver Anatomy 0.000 description 1
• 239000006166 lysate Substances 0.000 description 1
• 230000001356 masculinizing effect Effects 0.000 description 1
• 238000010907 mechanical stirring Methods 0.000 description 1
• 230000001404 mediated effect Effects 0.000 description 1
• 238000002483 medication Methods 0.000 description 1
• 229960002985 medroxyprogesterone acetate Drugs 0.000 description 1
• 230000004060 metabolic process Effects 0.000 description 1
• 229910052987 metal hydride Inorganic materials 0.000 description 1
• 150000004681 metal hydrides Chemical class 0.000 description 1
• 229940098779 methanesulfonic acid Drugs 0.000 description 1
• CICHVVTYUVANBB-UHFFFAOYSA-N methyl 4,5-dichloro-1,2-thiazole-3-carboxylate Chemical compound COC(=O)C1=NSC(Cl)=C1Cl CICHVVTYUVANBB-UHFFFAOYSA-N 0.000 description 1
• 229920000609 methyl cellulose Polymers 0.000 description 1
• 239000001923 methylcellulose Substances 0.000 description 1
• 238000003801 milling Methods 0.000 description 1
• 230000004048 modification Effects 0.000 description 1
• 238000012986 modification Methods 0.000 description 1
• 239000002808 molecular sieve Substances 0.000 description 1
• 150000004682 monohydrates Chemical class 0.000 description 1
• 230000003387 muscular Effects 0.000 description 1
• 210000003098 myoblast Anatomy 0.000 description 1
• PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
• JFCHSQDLLFJHOA-UHFFFAOYSA-N n,n-dimethylsulfamoyl chloride Chemical compound CN(C)S(Cl)(=O)=O JFCHSQDLLFJHOA-UHFFFAOYSA-N 0.000 description 1
• LRWJAPFTGFXQSL-UHFFFAOYSA-N n-(7-cyano-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl)-2-methylpropanamide Chemical compound N1C2=CC=C(C#N)C=C2C2=C1CC(NC(=O)C(C)C)C2 LRWJAPFTGFXQSL-UHFFFAOYSA-N 0.000 description 1
• GWODIHIRPBVVCY-GFCCVEGCSA-N n-[(2r)-7-(methoxyiminomethyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl]-2,2-dimethylpropanamide Chemical compound C12=CC(C=NOC)=CC=C2NC2=C1C[C@@H](NC(=O)C(C)(C)C)C2 GWODIHIRPBVVCY-GFCCVEGCSA-N 0.000 description 1
• YGBMUOWWXBNHHD-INIZCTEOSA-N n-[(2s)-7-cyano-4-[(6-fluoropyridin-2-yl)methyl]-2,3-dihydro-1h-cyclopenta[b]indol-2-yl]-2-methylpropanamide Chemical compound C([C@H](C1)NC(=O)C(C)C)C2=C1C1=CC(C#N)=CC=C1N2CC1=CC=CC(F)=N1 YGBMUOWWXBNHHD-INIZCTEOSA-N 0.000 description 1
• ZPPDXYYRKANUOI-UHFFFAOYSA-N n-[7-(methoxyiminomethyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl]-2-methylpropanamide Chemical compound C12=CC(C=NOC)=CC=C2NC2=C1CC(NC(=O)C(C)C)C2 ZPPDXYYRKANUOI-UHFFFAOYSA-N 0.000 description 1
• YGBMUOWWXBNHHD-UHFFFAOYSA-N n-[7-cyano-4-[(6-fluoropyridin-2-yl)methyl]-2,3-dihydro-1h-cyclopenta[b]indol-2-yl]-2-methylpropanamide Chemical compound C1C(NC(=O)C(C)C)CC2=C1C1=CC(C#N)=CC=C1N2CC1=CC=CC(F)=N1 YGBMUOWWXBNHHD-UHFFFAOYSA-N 0.000 description 1
• 239000006070 nanosuspension Substances 0.000 description 1
• 239000013642 negative control Substances 0.000 description 1
• PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
• 239000012299 nitrogen atmosphere Substances 0.000 description 1
• 230000009871 nonspecific binding Effects 0.000 description 1
• 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
• 230000003287 optical effect Effects 0.000 description 1
• 238000005457 optimization Methods 0.000 description 1
• 150000007530 organic bases Chemical class 0.000 description 1
• 239000012074 organic phase Substances 0.000 description 1
• 230000001350 orogenic effect Effects 0.000 description 1
• 210000000963 osteoblast Anatomy 0.000 description 1
• 150000002923 oximes Chemical class 0.000 description 1
• 125000004430 oxygen atom Chemical group O* 0.000 description 1
• 229940046231 pamidronate Drugs 0.000 description 1
• 239000000199 parathyroid hormone Substances 0.000 description 1
• 229960001319 parathyroid hormone Drugs 0.000 description 1
• 238000007911 parenteral administration Methods 0.000 description 1
• 238000010951 particle size reduction Methods 0.000 description 1
• 210000003899 penis Anatomy 0.000 description 1
• 230000000144 pharmacologic effect Effects 0.000 description 1
• HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
• 229940067157 phenylhydrazine Drugs 0.000 description 1
• XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
• 230000035790 physiological processes and functions Effects 0.000 description 1
• 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
• 229920001155 polypropylene Polymers 0.000 description 1
• 229940068968 polysorbate 80 Drugs 0.000 description 1
• 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 1
• 229910000105 potassium hydride Inorganic materials 0.000 description 1
• NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
• 230000003389 potentiating effect Effects 0.000 description 1
• 230000002265 prevention Effects 0.000 description 1
• 239000000186 progesterone Substances 0.000 description 1
• 229960003387 progesterone Drugs 0.000 description 1
• 239000000583 progesterone congener Substances 0.000 description 1
• 230000002035 prolonged effect Effects 0.000 description 1
• PHVMCWNVJBLADG-NSHDSACASA-N propan-2-yl n-[(2s)-7-cyano-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl]carbamate Chemical compound N1C2=CC=C(C#N)C=C2C2=C1C[C@@H](NC(=O)OC(C)C)C2 PHVMCWNVJBLADG-NSHDSACASA-N 0.000 description 1
• ADLCPMYHZWQMCZ-KRWDZBQOSA-N propan-2-yl n-[(2s)-7-formyl-4-(pyridin-2-ylmethyl)-2,3-dihydro-1h-cyclopenta[b]indol-2-yl]carbamate Chemical compound C([C@H](C1)NC(=O)OC(C)C)C2=C1C1=CC(C=O)=CC=C1N2CC1=CC=CC=N1 ADLCPMYHZWQMCZ-KRWDZBQOSA-N 0.000 description 1
• IHIWYQYVBNODSV-UHFFFAOYSA-N propan-2-yl n-[7-cyano-4-(pyridin-2-ylmethyl)-2,3-dihydro-1h-cyclopenta[b]indol-2-yl]carbamate Chemical compound C1C(NC(=O)OC(C)C)CC2=C1C1=CC(C#N)=CC=C1N2CC1=CC=CC=N1 IHIWYQYVBNODSV-UHFFFAOYSA-N 0.000 description 1
• BWENMPIYGWONFR-UHFFFAOYSA-N propan-2-yl n-[7-cyano-4-(pyrimidin-4-ylmethyl)-2,3-dihydro-1h-cyclopenta[b]indol-2-yl]carbamate Chemical compound C1C(NC(=O)OC(C)C)CC2=C1C1=CC(C#N)=CC=C1N2CC1=CC=NC=N1 BWENMPIYGWONFR-UHFFFAOYSA-N 0.000 description 1
• CWWNTLISFFCQSK-UHFFFAOYSA-N propan-2-yl n-[7-cyano-4-[(6-fluoropyridin-2-yl)methyl]-2,3-dihydro-1h-cyclopenta[b]indol-2-yl]carbamate Chemical compound C1C(NC(=O)OC(C)C)CC2=C1C1=CC(C#N)=CC=C1N2CC1=CC=CC(F)=N1 CWWNTLISFFCQSK-UHFFFAOYSA-N 0.000 description 1
• 230000000069 prophylactic effect Effects 0.000 description 1
• 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
• 208000023958 prostate neoplasm Diseases 0.000 description 1
• 125000006239 protecting group Chemical group 0.000 description 1
• 108090000623 proteins and genes Proteins 0.000 description 1
• 239000003586 protic polar solvent Substances 0.000 description 1
• 238000000746 purification Methods 0.000 description 1
• 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
• HZGCZRCZOMANHK-UHFFFAOYSA-N pyrimidin-2-ylmethanol Chemical compound OCC1=NC=CC=N1 HZGCZRCZOMANHK-UHFFFAOYSA-N 0.000 description 1
• 238000010791 quenching Methods 0.000 description 1
• 230000006340 racemization Effects 0.000 description 1
• 150000003254 radicals Chemical class 0.000 description 1
• 229960004622 raloxifene Drugs 0.000 description 1
• 239000002994 raw material Substances 0.000 description 1
• 230000009257 reactivity Effects 0.000 description 1
• 230000001850 reproductive effect Effects 0.000 description 1
• 238000011160 research Methods 0.000 description 1
• 238000012827 research and development Methods 0.000 description 1
• 229940089617 risedronate Drugs 0.000 description 1
• 210000004706 scrotum Anatomy 0.000 description 1
• 238000002398 sedimentation field-flow fractionation Methods 0.000 description 1
• 231100000872 sexual dysfunction Toxicity 0.000 description 1
• 230000001568 sexual effect Effects 0.000 description 1
• 238000004088 simulation Methods 0.000 description 1
• 229910052708 sodium Inorganic materials 0.000 description 1
• URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
• WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
• 235000017550 sodium carbonate Nutrition 0.000 description 1
• 229910000029 sodium carbonate Inorganic materials 0.000 description 1
• 239000011780 sodium chloride Substances 0.000 description 1
• 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
• 210000004872 soft tissue Anatomy 0.000 description 1
• 239000011877 solvent mixture Substances 0.000 description 1
• 238000000527 sonication Methods 0.000 description 1
• 241000894007 species Species 0.000 description 1
• 238000013223 sprague-dawley female rat Methods 0.000 description 1
• 238000013222 sprague-dawley male rat Methods 0.000 description 1
• 239000007921 spray Substances 0.000 description 1
• 229910001220 stainless steel Inorganic materials 0.000 description 1
• 239000010935 stainless steel Substances 0.000 description 1
• 230000000707 stereoselective effect Effects 0.000 description 1
• 238000006467 substitution reaction Methods 0.000 description 1
• 239000000758 substrate Substances 0.000 description 1
• 229960002317 succinimide Drugs 0.000 description 1
• NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 1
• QAHVHSLSRLSVGS-UHFFFAOYSA-N sulfamoyl chloride Chemical compound NS(Cl)(=O)=O QAHVHSLSRLSVGS-UHFFFAOYSA-N 0.000 description 1
• 229940124530 sulfonamide Drugs 0.000 description 1
• 150000003456 sulfonamides Chemical class 0.000 description 1
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
• YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
• 238000001356 surgical procedure Methods 0.000 description 1
• 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 1
• LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical class CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
• WQCGDEQLNYULRY-UHFFFAOYSA-N tert-butyl n-(7-cyano-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl)carbamate Chemical compound N1C2=CC=C(C#N)C=C2C2=C1CC(NC(=O)OC(C)(C)C)C2 WQCGDEQLNYULRY-UHFFFAOYSA-N 0.000 description 1
• WQCGDEQLNYULRY-LLVKDONJSA-N tert-butyl n-[(2r)-7-cyano-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl]carbamate Chemical compound N1C2=CC=C(C#N)C=C2C2=C1C[C@H](NC(=O)OC(C)(C)C)C2 WQCGDEQLNYULRY-LLVKDONJSA-N 0.000 description 1
• XDPAXRFBCFDZRH-OAHLLOKOSA-N tert-butyl n-[(2r)-7-cyano-4-(1,2-thiazol-3-ylmethyl)-2,3-dihydro-1h-cyclopenta[b]indol-2-yl]carbamate Chemical compound C([C@@H](C1)NC(=O)OC(C)(C)C)C2=C1C1=CC(C#N)=CC=C1N2CC=1C=CSN=1 XDPAXRFBCFDZRH-OAHLLOKOSA-N 0.000 description 1
• FHHKQFJHKLKWFQ-LLVKDONJSA-N tert-butyl n-[(2r)-7-formyl-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl]carbamate Chemical compound N1C2=CC=C(C=O)C=C2C2=C1C[C@H](NC(=O)OC(C)(C)C)C2 FHHKQFJHKLKWFQ-LLVKDONJSA-N 0.000 description 1
• UHDCOVNPQFZHIG-UHFFFAOYSA-N tert-butyl n-[7-cyano-4-(pyridin-2-ylmethyl)-2,3-dihydro-1h-cyclopenta[b]indol-2-yl]carbamate Chemical compound C1C(NC(=O)OC(C)(C)C)CC2=C1C1=CC(C#N)=CC=C1N2CC1=CC=CC=N1 UHDCOVNPQFZHIG-UHFFFAOYSA-N 0.000 description 1
• 238000004154 testing of material Methods 0.000 description 1
• 210000001550 testis Anatomy 0.000 description 1
• CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
• 230000001225 therapeutic effect Effects 0.000 description 1
• 210000002303 tibia Anatomy 0.000 description 1
• 238000013518 transcription Methods 0.000 description 1
• 230000035897 transcription Effects 0.000 description 1
• 239000012096 transfection reagent Substances 0.000 description 1
• 230000009466 transformation Effects 0.000 description 1
• 238000000844 transformation Methods 0.000 description 1
• LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
• 238000001665 trituration Methods 0.000 description 1
• WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
• 229910052721 tungsten Inorganic materials 0.000 description 1
• 239000010937 tungsten Substances 0.000 description 1
• 229930003231 vitamin Natural products 0.000 description 1
• 235000013343 vitamin Nutrition 0.000 description 1
• 239000011782 vitamin Substances 0.000 description 1
• 229940088594 vitamin Drugs 0.000 description 1
• 235000019166 vitamin D Nutrition 0.000 description 1
• 239000011710 vitamin D Substances 0.000 description 1
• 150000003710 vitamin D derivatives Chemical class 0.000 description 1
• 229940046008 vitamin d Drugs 0.000 description 1
• 150000003722 vitamin derivatives Chemical class 0.000 description 1
• 230000036642 wellbeing Effects 0.000 description 1
• 238000001238 wet grinding Methods 0.000 description 1
• 239000011592 zinc chloride Substances 0.000 description 1
• 235000005074 zinc chloride Nutrition 0.000 description 1