RU2669367C2 - Модуляторы натриевого канала для лечения боли - Google Patents

Info

Publication number

RU2669367C2

RU2669367C2 RU2015133310A RU2015133310A RU2669367C2 RU 2669367 C2 RU2669367 C2 RU 2669367C2 RU 2015133310 A RU2015133310 A RU 2015133310A RU 2015133310 A RU2015133310 A RU 2015133310A RU 2669367 C2 RU2669367 C2 RU 2669367C2

Authority

RU

Russia

Prior art keywords

chloro

sulfamoyl

compounds

propyl

pain

Prior art date

2013-03-15

Links

• Espacenet
• Global Dossier
• Discuss

• 208000002193 Pain Diseases 0.000 title claims abstract description 83
• 230000036407 pain Effects 0.000 title claims abstract description 76
• 102000018674 Sodium Channels Human genes 0.000 title claims abstract description 19
• 108010052164 Sodium Channels Proteins 0.000 title claims abstract description 19
• 238000011282 treatment Methods 0.000 title claims abstract description 11
• 150000001875 compounds Chemical class 0.000 claims abstract description 534
• -1 5-methyl-2-oxo-1,3-dioxol-4-yl Chemical group 0.000 claims abstract description 91
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 48
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 48
• 125000003118 aryl group Chemical group 0.000 claims abstract description 37
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 32
• 150000003839 salts Chemical class 0.000 claims abstract description 31
• 125000004076 pyridyl group Chemical group 0.000 claims abstract description 26
• 125000001424 substituent group Chemical group 0.000 claims abstract description 22
• 230000000694 effects Effects 0.000 claims abstract description 15
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
• 239000000126 substance Substances 0.000 claims abstract description 8
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 7
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 7
• 125000003226 pyrazolyl group Chemical group 0.000 claims abstract description 6
• IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 claims abstract description 5
• 238000000034 method Methods 0.000 claims description 101
• 239000000203 mixture Substances 0.000 claims description 70
• 238000012360 testing method Methods 0.000 claims description 64
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 36
• 125000001246 bromo group Chemical group Br* 0.000 claims description 26
• 108010053752 Voltage-Gated Sodium Channels Proteins 0.000 claims description 23
• 102000016913 Voltage-Gated Sodium Channels Human genes 0.000 claims description 23
• 125000000335 thiazolyl group Chemical group 0.000 claims description 23
• 230000004044 response Effects 0.000 claims description 22
• 229910052757 nitrogen Inorganic materials 0.000 claims description 20
• 125000005842 heteroatom Chemical group 0.000 claims description 17
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 16
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 16
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 15
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 15
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
• 229910052760 oxygen Inorganic materials 0.000 claims description 13
• 239000008194 pharmaceutical composition Substances 0.000 claims description 13
• 229910052717 sulfur Inorganic materials 0.000 claims description 13
• 230000001419 dependent effect Effects 0.000 claims description 12
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 12
• 208000004296 neuralgia Diseases 0.000 claims description 12
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 12
• 125000004516 1,2,4-thiadiazol-5-yl group Chemical group S1N=CN=C1* 0.000 claims description 11
• 208000021722 neuropathic pain Diseases 0.000 claims description 11
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
• 125000004434 sulfur atom Chemical group 0.000 claims description 11
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 9
• 230000005764 inhibitory process Effects 0.000 claims description 9
• RRFCFPIUKYXLDO-UHFFFAOYSA-N 3-[3-[5-chloro-2-[2-chloro-5-fluoro-4-(1,2,4-thiadiazol-5-ylsulfamoyl)phenoxy]phenyl]propylamino]propanoic acid Chemical compound OC(=O)CCNCCCC1=CC(Cl)=CC=C1OC1=CC(F)=C(S(=O)(=O)NC=2SN=CN=2)C=C1Cl RRFCFPIUKYXLDO-UHFFFAOYSA-N 0.000 claims description 8
• 208000004454 Hyperalgesia Diseases 0.000 claims description 8
• 239000003814 drug Substances 0.000 claims description 8
• 150000003053 piperidines Chemical group 0.000 claims description 8
• NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
• CCHQXXOVICLEOW-UHFFFAOYSA-N 2-[3-[5-chloro-2-[2-chloro-5-fluoro-4-(1,3-thiazol-4-ylsulfamoyl)phenoxy]phenyl]propylamino]acetic acid Chemical compound OC(=O)CNCCCC1=CC(Cl)=CC=C1OC1=CC(F)=C(S(=O)(=O)NC=2N=CSC=2)C=C1Cl CCHQXXOVICLEOW-UHFFFAOYSA-N 0.000 claims description 7
• 208000001294 Nociceptive Pain Diseases 0.000 claims description 7
• 230000003040 nociceptive effect Effects 0.000 claims description 7
• 208000011580 syndromic disease Diseases 0.000 claims description 7
• VDNXSICDYYQJEH-UHFFFAOYSA-N 1-[3-[5-chloro-2-[2-chloro-5-fluoro-4-(1,3-thiazol-4-ylsulfamoyl)phenoxy]phenyl]propyl]piperidine-4-carboxylic acid Chemical compound C1CC(C(=O)O)CCN1CCCC1=CC(Cl)=CC=C1OC1=CC(F)=C(S(=O)(=O)NC=2N=CSC=2)C=C1Cl VDNXSICDYYQJEH-UHFFFAOYSA-N 0.000 claims description 6
• AFIYUNZJZBVSBB-UHFFFAOYSA-N 2-[3-[5-chloro-2-[2-chloro-5-fluoro-4-(1,3-thiazol-2-ylsulfamoyl)phenoxy]phenyl]propylamino]acetic acid Chemical compound OC(=O)CNCCCC1=CC(Cl)=CC=C1OC1=CC(F)=C(S(=O)(=O)NC=2SC=CN=2)C=C1Cl AFIYUNZJZBVSBB-UHFFFAOYSA-N 0.000 claims description 6
• 208000001387 Causalgia Diseases 0.000 claims description 6
• 208000023890 Complex Regional Pain Syndromes Diseases 0.000 claims description 6
• 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 6
• 206010036376 Postherpetic Neuralgia Diseases 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 6
• 239000003112 inhibitor Substances 0.000 claims description 6
• 230000002981 neuropathic effect Effects 0.000 claims description 6
• 201000001119 neuropathy Diseases 0.000 claims description 6
• 230000007823 neuropathy Effects 0.000 claims description 6
• 208000033808 peripheral neuropathy Diseases 0.000 claims description 6
• 206010044652 trigeminal neuralgia Diseases 0.000 claims description 6
• AWOHJRVCJKXEPJ-UHFFFAOYSA-N 2-[acetyl-[3-[5-chloro-2-[2-chloro-5-fluoro-4-(1,3-thiazol-4-ylsulfamoyl)phenoxy]phenyl]propyl]amino]acetic acid Chemical compound OC(=O)CN(C(=O)C)CCCC1=CC(Cl)=CC=C1OC1=CC(F)=C(S(=O)(=O)NC=2N=CSC=2)C=C1Cl AWOHJRVCJKXEPJ-UHFFFAOYSA-N 0.000 claims description 5
• 230000006378 damage Effects 0.000 claims description 5
• 229940079593 drug Drugs 0.000 claims description 5
• 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims description 5
• 230000035945 sensitivity Effects 0.000 claims description 5
• 239000012453 solvate Substances 0.000 claims description 5
• YRBMLUDTYBOAQY-UHFFFAOYSA-N 1-[3-[5-chloro-2-[2-chloro-5-fluoro-4-(1,2,4-thiadiazol-5-ylsulfamoyl)phenoxy]phenyl]propyl]piperidine-4-carboxylic acid Chemical compound C1CC(C(=O)O)CCN1CCCC1=CC(Cl)=CC=C1OC1=CC(F)=C(S(=O)(=O)NC=2SN=CN=2)C=C1Cl YRBMLUDTYBOAQY-UHFFFAOYSA-N 0.000 claims description 4
• MGSFVZDDZXCGRW-UHFFFAOYSA-N 1-[3-[5-chloro-2-[2-chloro-5-fluoro-4-(1,3-thiazol-4-ylsulfamoyl)phenoxy]phenyl]propyl]piperidine-3-carboxylic acid Chemical compound C1C(C(=O)O)CCCN1CCCC1=CC(Cl)=CC=C1OC1=CC(F)=C(S(=O)(=O)NC=2N=CSC=2)C=C1Cl MGSFVZDDZXCGRW-UHFFFAOYSA-N 0.000 claims description 4
• PNNDFMDCGIONSI-UHFFFAOYSA-N 2-[1-[3-[5-chloro-2-[2-chloro-5-fluoro-4-(1,2,4-thiadiazol-5-ylsulfamoyl)phenoxy]phenyl]propyl]piperidin-4-yl]acetic acid Chemical compound C1CC(CC(=O)O)CCN1CCCC1=CC(Cl)=CC=C1OC1=CC(F)=C(S(=O)(=O)NC=2SN=CN=2)C=C1Cl PNNDFMDCGIONSI-UHFFFAOYSA-N 0.000 claims description 4
• LNZMKYCMCXMMRE-UHFFFAOYSA-N 2-[3-[2-[2-chloro-5-fluoro-4-(1,2,4-thiadiazol-5-ylsulfamoyl)phenoxy]phenyl]propylamino]acetic acid Chemical compound OC(=O)CNCCCC1=CC=CC=C1OC1=CC(F)=C(S(=O)(=O)NC=2SN=CN=2)C=C1Cl LNZMKYCMCXMMRE-UHFFFAOYSA-N 0.000 claims description 4
• LEHXCZNUWZNFJL-UHFFFAOYSA-N 2-[3-[5-chloro-2-[2,5-difluoro-4-(1,3-thiazol-2-ylsulfamoyl)phenoxy]phenyl]propylamino]acetic acid Chemical compound OC(=O)CNCCCC1=CC(Cl)=CC=C1OC1=CC(F)=C(S(=O)(=O)NC=2SC=CN=2)C=C1F LEHXCZNUWZNFJL-UHFFFAOYSA-N 0.000 claims description 4
• MYRXJVGNDDTXEV-UHFFFAOYSA-N 2-[3-[5-chloro-2-[2,5-difluoro-4-(1,3-thiazol-4-ylsulfamoyl)phenoxy]phenyl]propylamino]acetic acid Chemical compound OC(=O)CNCCCC1=CC(Cl)=CC=C1OC1=CC(F)=C(S(=O)(=O)NC=2N=CSC=2)C=C1F MYRXJVGNDDTXEV-UHFFFAOYSA-N 0.000 claims description 4
• DRVYUUZVFWRQMZ-UHFFFAOYSA-N 2-amino-4-[3-[5-chloro-2-[2-chloro-5-fluoro-4-(1,3-thiazol-4-ylsulfamoyl)phenoxy]phenyl]propylamino]butanoic acid Chemical compound OC(=O)C(N)CCNCCCC1=CC(Cl)=CC=C1OC1=CC(F)=C(S(=O)(=O)NC=2N=CSC=2)C=C1Cl DRVYUUZVFWRQMZ-UHFFFAOYSA-N 0.000 claims description 4
• OAPISBIIXJPSAF-UHFFFAOYSA-N 3-[3-[2-[2-chloro-5-fluoro-4-(1,3-thiazol-4-ylsulfamoyl)phenoxy]-5-fluorophenyl]propylamino]propanoic acid Chemical compound OC(=O)CCNCCCC1=CC(F)=CC=C1OC1=CC(F)=C(S(=O)(=O)NC=2N=CSC=2)C=C1Cl OAPISBIIXJPSAF-UHFFFAOYSA-N 0.000 claims description 4
• XNJXUSXGUDKONA-UHFFFAOYSA-N 3-[3-[5-chloro-2-[2,5-difluoro-4-(1,3-thiazol-4-ylsulfamoyl)phenoxy]phenyl]propylamino]propanoic acid Chemical compound OC(=O)CCNCCCC1=CC(Cl)=CC=C1OC1=CC(F)=C(S(=O)(=O)NC=2N=CSC=2)C=C1F XNJXUSXGUDKONA-UHFFFAOYSA-N 0.000 claims description 4
• TYNPLTLSAPMWIL-UHFFFAOYSA-N 3-[3-[5-chloro-2-[2-chloro-5-fluoro-4-(1,3-thiazol-2-ylsulfamoyl)phenoxy]phenyl]propylamino]propanoic acid Chemical compound OC(=O)CCNCCCC1=CC(Cl)=CC=C1OC1=CC(F)=C(S(=O)(=O)NC=2SC=CN=2)C=C1Cl TYNPLTLSAPMWIL-UHFFFAOYSA-N 0.000 claims description 4
• OPSIRGRDQKKTJS-UHFFFAOYSA-N 3-[3-[5-chloro-2-[2-chloro-5-fluoro-4-(1,3-thiazol-4-ylsulfamoyl)phenoxy]phenyl]propylamino]propanoic acid Chemical compound OC(=O)CCNCCCC1=CC(Cl)=CC=C1OC1=CC(F)=C(S(=O)(=O)NC=2N=CSC=2)C=C1Cl OPSIRGRDQKKTJS-UHFFFAOYSA-N 0.000 claims description 4
• LQIQUKQNKZJWLP-UHFFFAOYSA-N 3-[3-[5-chloro-2-[2-cyano-4-(1,3-thiazol-4-ylsulfamoyl)phenoxy]phenyl]propylamino]propanoic acid Chemical compound OC(=O)CCNCCCC1=CC(Cl)=CC=C1OC1=CC=C(S(=O)(=O)NC=2N=CSC=2)C=C1C#N LQIQUKQNKZJWLP-UHFFFAOYSA-N 0.000 claims description 4
• IKJLFRFPNWRJQY-UHFFFAOYSA-N 4-amino-1-[3-[5-chloro-2-[2-chloro-5-fluoro-4-(1,3-thiazol-4-ylsulfamoyl)phenoxy]phenyl]propyl]piperidine-4-carboxylic acid Chemical compound C1CC(N)(C(O)=O)CCN1CCCC1=CC(Cl)=CC=C1OC1=CC(F)=C(S(=O)(=O)NC=2N=CSC=2)C=C1Cl IKJLFRFPNWRJQY-UHFFFAOYSA-N 0.000 claims description 4
• 208000001640 Fibromyalgia Diseases 0.000 claims description 4
• 206010019233 Headaches Diseases 0.000 claims description 4
• 206010065390 Inflammatory pain Diseases 0.000 claims description 4
• 208000004550 Postoperative Pain Diseases 0.000 claims description 4
• 231100000869 headache Toxicity 0.000 claims description 4
• 208000009935 visceral pain Diseases 0.000 claims description 4
• YXDPLLFMUMFORJ-UHFFFAOYSA-N 2-[3-[5-chloro-2-[2-chloro-5-fluoro-4-(1,3-thiazol-4-ylsulfamoyl)phenoxy]phenyl]propylamino]-n-methylacetamide Chemical compound CNC(=O)CNCCCC1=CC(Cl)=CC=C1OC1=CC(F)=C(S(=O)(=O)NC=2N=CSC=2)C=C1Cl YXDPLLFMUMFORJ-UHFFFAOYSA-N 0.000 claims description 3
• 206010003694 Atrophy Diseases 0.000 claims description 3
• 206010003840 Autonomic nervous system imbalance Diseases 0.000 claims description 3
• 206010058019 Cancer Pain Diseases 0.000 claims description 3
• 208000009043 Chemical Burns Diseases 0.000 claims description 3
• 208000018380 Chemical injury Diseases 0.000 claims description 3
• 206010008874 Chronic Fatigue Syndrome Diseases 0.000 claims description 3
• 208000000094 Chronic Pain Diseases 0.000 claims description 3
• 208000013586 Complex regional pain syndrome type 1 Diseases 0.000 claims description 3
• 208000034656 Contusions Diseases 0.000 claims description 3
• 206010020843 Hyperthermia Diseases 0.000 claims description 3
• 206010061218 Inflammation Diseases 0.000 claims description 3
• 208000019695 Migraine disease Diseases 0.000 claims description 3
• LKJPYSCBVHEWIU-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CS(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-UHFFFAOYSA-N 0.000 claims description 3
• 208000004983 Phantom Limb Diseases 0.000 claims description 3
• 206010056238 Phantom pain Diseases 0.000 claims description 3
• 206010037779 Radiculopathy Diseases 0.000 claims description 3
• 201000001947 Reflex Sympathetic Dystrophy Diseases 0.000 claims description 3
• 208000000491 Tendinopathy Diseases 0.000 claims description 3
• 206010043255 Tendonitis Diseases 0.000 claims description 3
• 206010053615 Thermal burn Diseases 0.000 claims description 3
• 201000008907 algoneurodystrophy Diseases 0.000 claims description 3
• 206010053552 allodynia Diseases 0.000 claims description 3
• 230000037444 atrophy Effects 0.000 claims description 3
• 230000001363 autoimmune Effects 0.000 claims description 3
• 210000000988 bone and bone Anatomy 0.000 claims description 3
• 208000034526 bruise Diseases 0.000 claims description 3
• 208000014439 complex regional pain syndrome type 2 Diseases 0.000 claims description 3
• 238000002845 discoloration Methods 0.000 claims description 3
• 230000036031 hyperthermia Effects 0.000 claims description 3
• 230000002631 hypothermal effect Effects 0.000 claims description 3
• 230000000642 iatrogenic effect Effects 0.000 claims description 3
• 230000004054 inflammatory process Effects 0.000 claims description 3
• 208000014674 injury Diseases 0.000 claims description 3
• 238000001990 intravenous administration Methods 0.000 claims description 3
• 206010027599 migraine Diseases 0.000 claims description 3
• 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 claims description 3
• 201000008482 osteoarthritis Diseases 0.000 claims description 3
• 208000005877 painful neuropathy Diseases 0.000 claims description 3
• 230000002265 prevention Effects 0.000 claims description 3
• 230000011514 reflex Effects 0.000 claims description 3
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
• 238000007920 subcutaneous administration Methods 0.000 claims description 3
• 201000004415 tendinitis Diseases 0.000 claims description 3
• 206010064012 Central pain syndrome Diseases 0.000 claims description 2
• 208000027418 Wounds and injury Diseases 0.000 claims description 2
• 210000000278 spinal cord Anatomy 0.000 claims description 2
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 128
• 239000011541 reaction mixture Substances 0.000 description 93
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 85
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 73
• 239000000243 solution Substances 0.000 description 70
• 239000000047 product Substances 0.000 description 65
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 64
• 239000012071 phase Substances 0.000 description 50
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
• 238000006243 chemical reaction Methods 0.000 description 45
• 235000019439 ethyl acetate Nutrition 0.000 description 43
• 238000002360 preparation method Methods 0.000 description 43
• 239000012043 crude product Substances 0.000 description 40
• 230000015572 biosynthetic process Effects 0.000 description 37
• 239000000543 intermediate Substances 0.000 description 36
• 238000003786 synthesis reaction Methods 0.000 description 36
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 35
• 239000007787 solid Substances 0.000 description 35
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
• 210000004027 cell Anatomy 0.000 description 32
• 238000001704 evaporation Methods 0.000 description 28
• 230000008020 evaporation Effects 0.000 description 28
• OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 26
• 238000005160 1H NMR spectroscopy Methods 0.000 description 25
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 25
• 229910052938 sodium sulfate Inorganic materials 0.000 description 25
• 235000011152 sodium sulphate Nutrition 0.000 description 25
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
• 239000012267 brine Substances 0.000 description 23
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 22
• 239000000284 extract Substances 0.000 description 20
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 20
• 241001465754 Metazoa Species 0.000 description 19
• OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 19
• QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 18
• 238000010898 silica gel chromatography Methods 0.000 description 18
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 17
• 238000007792 addition Methods 0.000 description 16
• 210000003041 ligament Anatomy 0.000 description 16
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 15
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
• 230000037396 body weight Effects 0.000 description 14
• 239000010410 layer Substances 0.000 description 14
• 125000004432 carbon atom Chemical group C* 0.000 description 13
• KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 description 13
• 239000002253 acid Substances 0.000 description 12
• 238000004458 analytical method Methods 0.000 description 12
• UZCXPYDBYUEZCV-UHFFFAOYSA-N methyl 3-aminopropanoate Chemical compound COC(=O)CCN UZCXPYDBYUEZCV-UHFFFAOYSA-N 0.000 description 12
• 238000002953 preparative HPLC Methods 0.000 description 12
• 239000003826 tablet Substances 0.000 description 12
• 241000700159 Rattus Species 0.000 description 11
• 229910021529 ammonia Inorganic materials 0.000 description 11
• 125000004429 atom Chemical group 0.000 description 11
• 210000004379 membrane Anatomy 0.000 description 11
• 239000012528 membrane Substances 0.000 description 11
• 239000002244 precipitate Substances 0.000 description 11
• 238000002211 ultraviolet spectrum Methods 0.000 description 11
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 10
• 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 10
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
• 210000002683 foot Anatomy 0.000 description 10
• 235000019253 formic acid Nutrition 0.000 description 10
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
• 239000002775 capsule Substances 0.000 description 9
• 210000000548 hind-foot Anatomy 0.000 description 9
• 229910052739 hydrogen Inorganic materials 0.000 description 9
• 239000007788 liquid Substances 0.000 description 9
• 238000003756 stirring Methods 0.000 description 9
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 8
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
• 229940125904 compound 1 Drugs 0.000 description 8
• XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 8
• 238000004128 high performance liquid chromatography Methods 0.000 description 8
• 239000000463 material Substances 0.000 description 8
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
• 230000009467 reduction Effects 0.000 description 8
• 238000006722 reduction reaction Methods 0.000 description 8
• WQUXRPSUESZMDU-UHFFFAOYSA-N tert-butyl n-(5-chloro-2,4-difluorophenyl)sulfonyl-n-(1,3-thiazol-4-yl)carbamate Chemical compound C=1C(Cl)=C(F)C=C(F)C=1S(=O)(=O)N(C(=O)OC(C)(C)C)C1=CSC=N1 WQUXRPSUESZMDU-UHFFFAOYSA-N 0.000 description 8
• 239000003981 vehicle Substances 0.000 description 8
• FUGKCSRLAQKUHG-UHFFFAOYSA-N 5-chloro-2-hydroxybenzaldehyde Chemical compound OC1=CC=C(Cl)C=C1C=O FUGKCSRLAQKUHG-UHFFFAOYSA-N 0.000 description 7
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 7
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
• 229920002472 Starch Polymers 0.000 description 7
• 229910002091 carbon monoxide Inorganic materials 0.000 description 7
• 230000008859 change Effects 0.000 description 7
• 235000019698 starch Nutrition 0.000 description 7
• 239000003643 water by type Substances 0.000 description 7
• 125000004400 (C1-C12) alkyl group Chemical group 0.000 description 6
• 125000006545 (C1-C9) alkyl group Chemical group 0.000 description 6
• 125000006325 2-propenyl amino group Chemical group [H]C([H])=C([H])C([H])([H])N([H])* 0.000 description 6
• HJYWKHWXPBTFRZ-UHFFFAOYSA-N 3-[[4-[5-chloro-2-[2-chloro-5-fluoro-4-(1,2,4-thiadiazol-5-ylsulfamoyl)phenoxy]phenyl]pyridine-2-carbonyl]amino]propanoic acid Chemical compound C1=NC(C(=O)NCCC(=O)O)=CC(C=2C(=CC=C(Cl)C=2)OC=2C(=CC(=C(F)C=2)S(=O)(=O)NC=2SN=CN=2)Cl)=C1 HJYWKHWXPBTFRZ-UHFFFAOYSA-N 0.000 description 6
• 108091006146 Channels Proteins 0.000 description 6
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
• FVECELJHCSPHKY-UHFFFAOYSA-N Veratridine Natural products C1=C(OC)C(OC)=CC=C1C(=O)OC1C2(O)OC34CC5(O)C(CN6C(CCC(C)C6)C6(C)O)C6(O)C(O)CC5(O)C4CCC2C3(C)CC1 FVECELJHCSPHKY-UHFFFAOYSA-N 0.000 description 6
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
• 150000003840 hydrochlorides Chemical class 0.000 description 6
• 239000001257 hydrogen Substances 0.000 description 6
• 230000000155 isotopic effect Effects 0.000 description 6
• 239000012299 nitrogen atmosphere Substances 0.000 description 6
• 108090000623 proteins and genes Proteins 0.000 description 6
• 239000002795 scorpion venom Substances 0.000 description 6
• 239000012265 solid product Substances 0.000 description 6
• 239000002904 solvent Substances 0.000 description 6
• 239000008107 starch Substances 0.000 description 6
• FVECELJHCSPHKY-JLSHOZRYSA-N veratridine Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)O[C@@H]1[C@@]2(O)O[C@]34C[C@@]5(O)[C@H](CN6[C@@H](CC[C@H](C)C6)[C@@]6(C)O)[C@]6(O)[C@@H](O)C[C@@]5(O)[C@@H]4CC[C@H]2[C@]3(C)CC1 FVECELJHCSPHKY-JLSHOZRYSA-N 0.000 description 6
• DVVLVVNKFYXUCM-UHFFFAOYSA-N 2-[[4-[5-chloro-2-[2-chloro-5-fluoro-4-(1,2,4-thiadiazol-5-ylsulfamoyl)phenoxy]phenyl]pyridine-2-carbonyl]amino]acetic acid Chemical compound C1=NC(C(=O)NCC(=O)O)=CC(C=2C(=CC=C(Cl)C=2)OC=2C(=CC(=C(F)C=2)S(=O)(=O)NC=2SN=CN=2)Cl)=C1 DVVLVVNKFYXUCM-UHFFFAOYSA-N 0.000 description 5
• TWBSLXPPYNMYNJ-UHFFFAOYSA-N 3-(5-chloro-2-hydroxyphenyl)prop-2-enal Chemical compound OC1=CC=C(Cl)C=C1C=CC=O TWBSLXPPYNMYNJ-UHFFFAOYSA-N 0.000 description 5
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
• 102000004328 Cytochrome P-450 CYP3A Human genes 0.000 description 5
• 108010081668 Cytochrome P-450 CYP3A Proteins 0.000 description 5
• 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 5
• 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 5
• 101000654386 Homo sapiens Sodium channel protein type 9 subunit alpha Proteins 0.000 description 5
• 238000003556 assay Methods 0.000 description 5
• 239000000460 chlorine Substances 0.000 description 5
• 229910052801 chlorine Inorganic materials 0.000 description 5
• 239000003085 diluting agent Substances 0.000 description 5
• 239000008187 granular material Substances 0.000 description 5
• 239000005457 ice water Substances 0.000 description 5
• 238000000338 in vitro Methods 0.000 description 5
• 230000002779 inactivation Effects 0.000 description 5
• 210000002414 leg Anatomy 0.000 description 5
• 210000003205 muscle Anatomy 0.000 description 5
• 239000000546 pharmaceutical excipient Substances 0.000 description 5
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
• 239000000843 powder Substances 0.000 description 5
• 210000003497 sciatic nerve Anatomy 0.000 description 5
• 239000012279 sodium borohydride Substances 0.000 description 5
• 229910000033 sodium borohydride Inorganic materials 0.000 description 5
• 125000006568 (C4-C7) heterocycloalkyl group Chemical group 0.000 description 4
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
• CQCAYWAIRTVXIY-UHFFFAOYSA-N 2-(triphenyl-$l^{5}-phosphanylidene)acetaldehyde Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC=O)C1=CC=CC=C1 CQCAYWAIRTVXIY-UHFFFAOYSA-N 0.000 description 4
• QXDYIMFUBBMMFL-UHFFFAOYSA-N 2-[[4-[5-chloro-2-[2-chloro-5-fluoro-4-(1,2,4-thiadiazol-5-ylsulfamoyl)phenoxy]phenyl]pyridine-2-carbonyl]amino]propanoic acid Chemical compound C1=NC(C(=O)NC(C)C(O)=O)=CC(C=2C(=CC=C(Cl)C=2)OC=2C(=CC(=C(F)C=2)S(=O)(=O)NC=2SN=CN=2)Cl)=C1 QXDYIMFUBBMMFL-UHFFFAOYSA-N 0.000 description 4
• PAFAJPNNWKLONU-UHFFFAOYSA-N 5-chloro-n-[(2,4-dimethoxyphenyl)methyl]-2,4-difluoro-n-(1,2,4-thiadiazol-5-yl)benzenesulfonamide Chemical compound COC1=CC(OC)=CC=C1CN(S(=O)(=O)C=1C(=CC(F)=C(Cl)C=1)F)C1=NC=NS1 PAFAJPNNWKLONU-UHFFFAOYSA-N 0.000 description 4
• KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 4
• FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
• 125000000041 C6-C10 aryl group Chemical group 0.000 description 4
• 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 4
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
• 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 4
• 229930195725 Mannitol Natural products 0.000 description 4
• 206010028347 Muscle twitching Diseases 0.000 description 4
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
• 102100031367 Sodium channel protein type 9 subunit alpha Human genes 0.000 description 4
• 229910052770 Uranium Inorganic materials 0.000 description 4
• 150000007513 acids Chemical class 0.000 description 4
• 230000004913 activation Effects 0.000 description 4
• 208000005298 acute pain Diseases 0.000 description 4
• 239000007864 aqueous solution Substances 0.000 description 4
• 239000012131 assay buffer Substances 0.000 description 4
• 239000011230 binding agent Substances 0.000 description 4
• ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
• 238000004113 cell culture Methods 0.000 description 4
• 230000036461 convulsion Effects 0.000 description 4
• 238000010511 deprotection reaction Methods 0.000 description 4
• 238000005516 engineering process Methods 0.000 description 4
• 239000000706 filtrate Substances 0.000 description 4
• 239000011521 glass Substances 0.000 description 4
• 239000007924 injection Substances 0.000 description 4
• 238000002347 injection Methods 0.000 description 4
• 239000008101 lactose Substances 0.000 description 4
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
• 239000000314 lubricant Substances 0.000 description 4
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
• 235000019341 magnesium sulphate Nutrition 0.000 description 4
• 239000000594 mannitol Substances 0.000 description 4
• 235000010355 mannitol Nutrition 0.000 description 4
• 238000001819 mass spectrum Methods 0.000 description 4
• 229910052751 metal Inorganic materials 0.000 description 4
• 239000002184 metal Substances 0.000 description 4
• BAHGCYPLANVVBV-UHFFFAOYSA-N methyl 2-[3-(5-chloro-2-hydroxyphenyl)propylamino]acetate Chemical compound COC(=O)CNCCCC1=CC(Cl)=CC=C1O BAHGCYPLANVVBV-UHFFFAOYSA-N 0.000 description 4
• NHBPMXVRNXAHDI-UHFFFAOYSA-N methyl 2-[3-[5-chloro-2-[2-chloro-5-fluoro-4-[(2-methylpropan-2-yl)oxycarbonyl-(1,3-thiazol-4-yl)sulfamoyl]phenoxy]phenyl]propylamino]acetate Chemical compound COC(=O)CNCCCC1=CC(Cl)=CC=C1OC1=CC(F)=C(S(=O)(=O)N(C(=O)OC(C)(C)C)C=2N=CSC=2)C=C1Cl NHBPMXVRNXAHDI-UHFFFAOYSA-N 0.000 description 4
• 229920000609 methyl cellulose Polymers 0.000 description 4
• 235000010981 methylcellulose Nutrition 0.000 description 4
• 239000001923 methylcellulose Substances 0.000 description 4
• DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 4
• 239000012044 organic layer Substances 0.000 description 4
• 230000036470 plasma concentration Effects 0.000 description 4
• 229920001223 polyethylene glycol Polymers 0.000 description 4
• 229910000027 potassium carbonate Inorganic materials 0.000 description 4
• 235000019260 propionic acid Nutrition 0.000 description 4
• 238000010992 reflux Methods 0.000 description 4
• 239000011734 sodium Substances 0.000 description 4
• 239000011780 sodium chloride Substances 0.000 description 4
• 235000000346 sugar Nutrition 0.000 description 4
• 229940124530 sulfonamide Drugs 0.000 description 4
• 239000000829 suppository Substances 0.000 description 4
• 239000000725 suspension Substances 0.000 description 4
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 3
• TWBSLXPPYNMYNJ-OWOJBTEDSA-N (e)-3-(5-chloro-2-hydroxyphenyl)prop-2-enal Chemical compound OC1=CC=C(Cl)C=C1\C=C\C=O TWBSLXPPYNMYNJ-OWOJBTEDSA-N 0.000 description 3
• JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
• JLSMERLIZSAYDJ-UHFFFAOYSA-N 3-[[4-[5-chloro-2-[2,5-difluoro-4-(1,2,4-thiadiazol-5-ylsulfamoyl)phenoxy]phenyl]pyridine-2-carbonyl]amino]propanoic acid Chemical compound C1=NC(C(=O)NCCC(=O)O)=CC(C=2C(=CC=C(Cl)C=2)OC=2C(=CC(=C(F)C=2)S(=O)(=O)NC=2SN=CN=2)F)=C1 JLSMERLIZSAYDJ-UHFFFAOYSA-N 0.000 description 3
• UQMLKNGBGPTQDK-UHFFFAOYSA-N 4-[[4-[5-chloro-2-[2-chloro-5-fluoro-4-(1,2,4-thiadiazol-5-ylsulfamoyl)phenoxy]phenyl]pyridine-2-carbonyl]amino]butanoic acid Chemical compound C1=NC(C(=O)NCCCC(=O)O)=CC(C=2C(=CC=C(Cl)C=2)OC=2C(=CC(=C(F)C=2)S(=O)(=O)NC=2SN=CN=2)Cl)=C1 UQMLKNGBGPTQDK-UHFFFAOYSA-N 0.000 description 3
• KXKLYWDAUBSKGO-UHFFFAOYSA-N 5-[[4-[5-chloro-2-[2-chloro-5-fluoro-4-(1,2,4-thiadiazol-5-ylsulfamoyl)phenoxy]phenyl]pyridine-2-carbonyl]amino]pentanoic acid Chemical compound C1=NC(C(=O)NCCCCC(=O)O)=CC(C=2C(=CC=C(Cl)C=2)OC=2C(=CC(=C(F)C=2)S(=O)(=O)NC=2SN=CN=2)Cl)=C1 KXKLYWDAUBSKGO-UHFFFAOYSA-N 0.000 description 3
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
• 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 3
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
• 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 3
• 239000007995 HEPES buffer Substances 0.000 description 3
• 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 3
• 102000004310 Ion Channels Human genes 0.000 description 3
• 108090000862 Ion Channels Proteins 0.000 description 3
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
• 239000002202 Polyethylene glycol Substances 0.000 description 3
• XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
• 229930006000 Sucrose Natural products 0.000 description 3
• 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 3
• 238000006069 Suzuki reaction reaction Methods 0.000 description 3
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
• 230000002378 acidificating effect Effects 0.000 description 3
• 235000010443 alginic acid Nutrition 0.000 description 3
• 229920000615 alginic acid Polymers 0.000 description 3
• 125000003277 amino group Chemical group 0.000 description 3
• 239000008346 aqueous phase Substances 0.000 description 3
• 239000000872 buffer Substances 0.000 description 3
• 239000001506 calcium phosphate Substances 0.000 description 3
• 235000011010 calcium phosphates Nutrition 0.000 description 3
• 239000001913 cellulose Substances 0.000 description 3
• 235000010980 cellulose Nutrition 0.000 description 3
• 229920002678 cellulose Polymers 0.000 description 3
• 239000003153 chemical reaction reagent Substances 0.000 description 3
• 238000004090 dissolution Methods 0.000 description 3
• 238000009826 distribution Methods 0.000 description 3
• 239000002552 dosage form Substances 0.000 description 3
• 239000000975 dye Substances 0.000 description 3
• 201000011384 erythromelalgia Diseases 0.000 description 3
• PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 3
• 238000002474 experimental method Methods 0.000 description 3
• 210000003414 extremity Anatomy 0.000 description 3
• 239000011737 fluorine Substances 0.000 description 3
• 229910052731 fluorine Inorganic materials 0.000 description 3
• WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 3
• 230000006870 function Effects 0.000 description 3
• 239000008103 glucose Substances 0.000 description 3
• 125000001072 heteroaryl group Chemical group 0.000 description 3
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
• 238000007912 intraperitoneal administration Methods 0.000 description 3
• 239000007928 intraperitoneal injection Substances 0.000 description 3
• 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 3
• GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 3
• 210000003141 lower extremity Anatomy 0.000 description 3
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
• 230000035772 mutation Effects 0.000 description 3
• 231100000252 nontoxic Toxicity 0.000 description 3
• 230000003000 nontoxic effect Effects 0.000 description 3
• 229920003023 plastic Polymers 0.000 description 3
• 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
• 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
• 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
• 239000013641 positive control Substances 0.000 description 3
• 102000004169 proteins and genes Human genes 0.000 description 3
• 125000006413 ring segment Chemical group 0.000 description 3
• 239000000523 sample Substances 0.000 description 3
• 229910052708 sodium Inorganic materials 0.000 description 3
• 229910000104 sodium hydride Inorganic materials 0.000 description 3
• 230000000638 stimulation Effects 0.000 description 3
• 239000011550 stock solution Substances 0.000 description 3
• 239000005720 sucrose Substances 0.000 description 3
• 125000000565 sulfonamide group Chemical group 0.000 description 3
• 238000001356 surgical procedure Methods 0.000 description 3
• 239000000454 talc Substances 0.000 description 3
• 229910052623 talc Inorganic materials 0.000 description 3
• 235000012222 talc Nutrition 0.000 description 3
• 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 3
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
• 238000004724 ultra fast liquid chromatography Methods 0.000 description 3
• 239000001993 wax Substances 0.000 description 3
• YJZMFZSDIHXCFD-AWEZNQCLSA-N (2s)-4-[3-(5-chloro-2-hydroxyphenyl)propylamino]-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CCNCCCC1=CC(Cl)=CC=C1O YJZMFZSDIHXCFD-AWEZNQCLSA-N 0.000 description 2
• LGKPWPQFWDNQHR-QHCPKHFHSA-N (2s)-4-[3-[5-chloro-2-[2-chloro-5-fluoro-4-[(2-methylpropan-2-yl)oxycarbonyl-(1,3-thiazol-4-yl)sulfamoyl]phenoxy]phenyl]propylamino]-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CCNCCCC1=CC(Cl)=CC=C1OC1=CC(F)=C(S(=O)(=O)N(C(=O)OC(C)(C)C)C=2N=CSC=2)C=C1Cl LGKPWPQFWDNQHR-QHCPKHFHSA-N 0.000 description 2
• MDCPCLPRWLKUIQ-LURJTMIESA-N (2s)-4-azaniumyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoate Chemical compound CC(C)(C)OC(=O)N[C@H](C([O-])=O)CC[NH3+] MDCPCLPRWLKUIQ-LURJTMIESA-N 0.000 description 2
• GGZASRFCRAZNPO-UHFFFAOYSA-N (5-chloro-2-hydroxyphenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=CC=C1O GGZASRFCRAZNPO-UHFFFAOYSA-N 0.000 description 2
• VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 2
• ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
• QHTTWLKEGVPADB-UHFFFAOYSA-N 2-(5-chloro-2-methoxyphenyl)-3-oxopropanenitrile Chemical compound COC1=CC=C(Cl)C=C1C(C=O)C#N QHTTWLKEGVPADB-UHFFFAOYSA-N 0.000 description 2
• YVPGMOIUQBMWLU-UHFFFAOYSA-N 2-(5-chloro-2-methoxyphenyl)acetonitrile Chemical compound COC1=CC=C(Cl)C=C1CC#N YVPGMOIUQBMWLU-UHFFFAOYSA-N 0.000 description 2
• HRVUGNRBTFVKBF-UHFFFAOYSA-N 2-[3-[5-chloro-2-[2-chloro-5-fluoro-4-[(2-methylpropan-2-yl)oxycarbonyl-(1,3-thiazol-4-yl)sulfamoyl]phenoxy]phenyl]propylamino]acetic acid Chemical compound C=1C(Cl)=C(OC=2C(=CC(Cl)=CC=2)CCCNCC(O)=O)C=C(F)C=1S(=O)(=O)N(C(=O)OC(C)(C)C)C1=CSC=N1 HRVUGNRBTFVKBF-UHFFFAOYSA-N 0.000 description 2
• SRQAAJVKYHUNEV-UHFFFAOYSA-N 2-[[6-[5-chloro-2-[2-chloro-5-fluoro-4-(1,2,4-thiadiazol-5-ylsulfamoyl)phenoxy]phenyl]pyridine-2-carbonyl]amino]acetic acid Chemical compound OC(=O)CNC(=O)C1=CC=CC(C=2C(=CC=C(Cl)C=2)OC=2C(=CC(=C(F)C=2)S(=O)(=O)NC=2SN=CN=2)Cl)=N1 SRQAAJVKYHUNEV-UHFFFAOYSA-N 0.000 description 2
• SUVCAHAMFIRFTH-UHFFFAOYSA-N 3-(5-chloro-2-methoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine Chemical compound ClC=1C=CC(=C(C=1)C=1C=NN2C=1NCCC2)OC SUVCAHAMFIRFTH-UHFFFAOYSA-N 0.000 description 2
• LLUODYKHIAENQP-UHFFFAOYSA-N 4-(5-chloro-2-hydroxyphenyl)pyridine-2-carbonitrile Chemical compound OC1=CC=C(Cl)C=C1C1=CC=NC(C#N)=C1 LLUODYKHIAENQP-UHFFFAOYSA-N 0.000 description 2
• LYLPVSGTPVOUOT-UHFFFAOYSA-N 4-(5-chloro-2-hydroxyphenyl)pyridine-2-carboxylic acid Chemical compound OC(=O)c1cc(ccn1)-c1cc(Cl)ccc1O LYLPVSGTPVOUOT-UHFFFAOYSA-N 0.000 description 2
• DDWSNPFRYQBQJQ-UHFFFAOYSA-N 4-(5-chloro-2-methoxyphenyl)-1h-pyrazol-5-amine Chemical compound COC1=CC=C(Cl)C=C1C1=C(N)NN=C1 DDWSNPFRYQBQJQ-UHFFFAOYSA-N 0.000 description 2
• SPTBGFAZEIVQNR-UHFFFAOYSA-N 4-chloro-2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)phenol Chemical compound ClC1=CC(=C(C=C1)O)C=1C=NN2C1NCCC2 SPTBGFAZEIVQNR-UHFFFAOYSA-N 0.000 description 2
• UWRGQGVLSLNMLG-UHFFFAOYSA-N 4-chloro-2-(chloromethyl)-1-methoxybenzene Chemical compound COC1=CC=C(Cl)C=C1CCl UWRGQGVLSLNMLG-UHFFFAOYSA-N 0.000 description 2
• HXTWDGGMXZXOIV-UHFFFAOYSA-N 5-chloro-2-methoxybenzaldehyde Chemical compound COC1=CC=C(Cl)C=C1C=O HXTWDGGMXZXOIV-UHFFFAOYSA-N 0.000 description 2
• QYLAOPBJCZYQMP-UHFFFAOYSA-N 5-chloro-4-[4-chloro-2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-2-fluoro-N-(1,3-thiazol-4-yl)benzenesulfonamide Chemical compound Fc1cc(Oc2ccc(Cl)cc2-c2cnn3CCCNc23)c(Cl)cc1S(=O)(=O)Nc1cscn1 QYLAOPBJCZYQMP-UHFFFAOYSA-N 0.000 description 2
• HJKGDCXPISYNCT-UHFFFAOYSA-N 5-chloro-n-[(2,4-dimethoxyphenyl)methyl]-2,4-difluoro-n-(1,3-thiazol-2-yl)benzenesulfonamide Chemical compound COC1=CC(OC)=CC=C1CN(S(=O)(=O)C=1C(=CC(F)=C(Cl)C=1)F)C1=NC=CS1 HJKGDCXPISYNCT-UHFFFAOYSA-N 0.000 description 2
• LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
• QGZKDVFQNNGYKY-OUBTZVSYSA-N Ammonia-15N Chemical compound [15NH3] QGZKDVFQNNGYKY-OUBTZVSYSA-N 0.000 description 2
• USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
• 239000005695 Ammonium acetate Substances 0.000 description 2
• 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
• YBYSFJAQLCLZRW-UHFFFAOYSA-N CC(=O)N(CCCc1cc(Cl)ccc1Oc1cc(F)c(cc1Cl)S(=O)(=O)N(C(=O)OC(C)(C)C)c1cscn1)CC(O)=O Chemical compound CC(=O)N(CCCc1cc(Cl)ccc1Oc1cc(F)c(cc1Cl)S(=O)(=O)N(C(=O)OC(C)(C)C)c1cscn1)CC(O)=O YBYSFJAQLCLZRW-UHFFFAOYSA-N 0.000 description 2
• VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
• OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 description 2
• 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
• QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
• 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
• 102000004190 Enzymes Human genes 0.000 description 2
• 108090000790 Enzymes Proteins 0.000 description 2
• 239000001856 Ethyl cellulose Substances 0.000 description 2
• ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
• 229930091371 Fructose Natural products 0.000 description 2
• 239000005715 Fructose Substances 0.000 description 2
• RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
• 108010010803 Gelatin Proteins 0.000 description 2
• DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
• ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
• FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
• NMMIHXMBOZYNET-UHFFFAOYSA-N Methyl picolinate Chemical compound COC(=O)C1=CC=CC=N1 NMMIHXMBOZYNET-UHFFFAOYSA-N 0.000 description 2
• MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
• ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
• 208000027520 Somatoform disease Diseases 0.000 description 2
• HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
• 150000001408 amides Chemical class 0.000 description 2
• 235000019257 ammonium acetate Nutrition 0.000 description 2
• 229940043376 ammonium acetate Drugs 0.000 description 2
• VJDDAARZIFHSQY-UHFFFAOYSA-N basic black 2 Chemical compound [Cl-].C=1C2=[N+](C=3C=CC=CC=3)C3=CC(N(CC)CC)=CC=C3N=C2C=CC=1NN=C1C=CC(=O)C=C1 VJDDAARZIFHSQY-UHFFFAOYSA-N 0.000 description 2
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
• 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 2
• UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
• 229910000389 calcium phosphate Inorganic materials 0.000 description 2
• 239000001768 carboxy methyl cellulose Substances 0.000 description 2
• 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
• 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
• 239000003054 catalyst Substances 0.000 description 2
• 239000003795 chemical substances by application Substances 0.000 description 2
• 239000007910 chewable tablet Substances 0.000 description 2
• 235000019868 cocoa butter Nutrition 0.000 description 2
• 229940110456 cocoa butter Drugs 0.000 description 2
• 238000004440 column chromatography Methods 0.000 description 2
• 229910052805 deuterium Inorganic materials 0.000 description 2
• FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
• 239000007884 disintegrant Substances 0.000 description 2
• 235000019325 ethyl cellulose Nutrition 0.000 description 2
• 229920001249 ethyl cellulose Polymers 0.000 description 2
• 210000003195 fascia Anatomy 0.000 description 2
• 239000012091 fetal bovine serum Substances 0.000 description 2
• 238000011049 filling Methods 0.000 description 2
• 239000000796 flavoring agent Substances 0.000 description 2
• 235000013305 food Nutrition 0.000 description 2
• 239000008273 gelatin Substances 0.000 description 2
• 229920000159 gelatin Polymers 0.000 description 2
• 235000019322 gelatine Nutrition 0.000 description 2
• 235000011852 gelatine desserts Nutrition 0.000 description 2
• ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
• 229960001269 glycine hydrochloride Drugs 0.000 description 2
• UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
• 150000002367 halogens Chemical group 0.000 description 2
• 238000010438 heat treatment Methods 0.000 description 2
• CBCIHIVRDWLAME-UHFFFAOYSA-N hexanitrodiphenylamine Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC([N+]([O-])=O)=C1NC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O CBCIHIVRDWLAME-UHFFFAOYSA-N 0.000 description 2
• 238000000099 in vitro assay Methods 0.000 description 2
• 238000011534 incubation Methods 0.000 description 2
• QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 2
• YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
• 229910052749 magnesium Inorganic materials 0.000 description 2
• 235000019359 magnesium stearate Nutrition 0.000 description 2
• 239000002609 medium Substances 0.000 description 2
• 238000002779 membrane potential assay Methods 0.000 description 2
• GILKOXUKDOJPNC-NSCUHMNNSA-N methyl 2-[[(e)-3-(5-chloro-2-hydroxyphenyl)prop-2-enyl]amino]acetate Chemical compound COC(=O)CNC\C=C\C1=CC(Cl)=CC=C1O GILKOXUKDOJPNC-NSCUHMNNSA-N 0.000 description 2
• PMZCASKHZXWSET-UHFFFAOYSA-N methyl 3-[3-(5-chloro-2-hydroxyphenyl)propylamino]propanoate Chemical compound COC(=O)CCNCCCc1cc(Cl)ccc1O PMZCASKHZXWSET-UHFFFAOYSA-N 0.000 description 2
• ODTRUGQOTBMPAM-UHFFFAOYSA-N methyl 3-[[4-(5-chloro-2-hydroxyphenyl)pyridine-2-carbonyl]amino]propanoate Chemical compound ClC=1C=CC(=C(C1)C1=CC(=NC=C1)C(=O)NCCC(=O)OC)O ODTRUGQOTBMPAM-UHFFFAOYSA-N 0.000 description 2
• RZVWBASHHLFBJF-UHFFFAOYSA-N methyl piperidine-4-carboxylate Chemical compound COC(=O)C1CCNCC1 RZVWBASHHLFBJF-UHFFFAOYSA-N 0.000 description 2
• LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
• 150000007522 mineralic acids Chemical class 0.000 description 2
• 239000003068 molecular probe Substances 0.000 description 2
• 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
• 125000001624 naphthyl group Chemical group 0.000 description 2
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
• 150000007524 organic acids Chemical class 0.000 description 2
• 235000005985 organic acids Nutrition 0.000 description 2
• 208000027753 pain disease Diseases 0.000 description 2
• 230000001314 paroxysmal effect Effects 0.000 description 2
• 230000000144 pharmacologic effect Effects 0.000 description 2
• 239000002504 physiological saline solution Substances 0.000 description 2
• IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 2
• 238000001556 precipitation Methods 0.000 description 2
• QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
• 238000010926 purge Methods 0.000 description 2
• 238000000746 purification Methods 0.000 description 2
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
• 125000000168 pyrrolyl group Chemical group 0.000 description 2
• 230000002285 radioactive effect Effects 0.000 description 2
• 229920005989 resin Polymers 0.000 description 2
• 239000011347 resin Substances 0.000 description 2
• SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 2
• 229920006395 saturated elastomer Polymers 0.000 description 2
• 239000000741 silica gel Substances 0.000 description 2
• 229910002027 silica gel Inorganic materials 0.000 description 2
• 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 2
• 239000012312 sodium hydride Substances 0.000 description 2
• 229910001415 sodium ion Inorganic materials 0.000 description 2
• 239000007790 solid phase Substances 0.000 description 2
• 239000000758 substrate Substances 0.000 description 2
• 150000008163 sugars Chemical class 0.000 description 2
• 150000003456 sulfonamides Chemical class 0.000 description 2
• 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 2
• YTNVYYKULGJICS-UHFFFAOYSA-N tert-butyl N-[5-chloro-4-[4-chloro-2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-2-fluorophenyl]sulfonyl-N-(1,3-thiazol-4-yl)carbamate Chemical compound ClC=1C(=CC(=C(C1)S(=O)(=O)N(C(OC(C)(C)C)=O)C=1N=CSC1)F)OC1=C(C=C(C=C1)Cl)C=1C=NN2C1NCCC2 YTNVYYKULGJICS-UHFFFAOYSA-N 0.000 description 2
• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
• 229940124597 therapeutic agent Drugs 0.000 description 2
• 238000004809 thin layer chromatography Methods 0.000 description 2
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
• 230000000451 tissue damage Effects 0.000 description 2
• 231100000827 tissue damage Toxicity 0.000 description 2
• 230000000699 topical effect Effects 0.000 description 2
• 238000001665 trituration Methods 0.000 description 2
• 229910052725 zinc Inorganic materials 0.000 description 2
• 239000011701 zinc Substances 0.000 description 2
• NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
• UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-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
• SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
• XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 1
• DRVYUUZVFWRQMZ-KRWDZBQOSA-N (2S)-2-amino-4-[3-[5-chloro-2-[2-chloro-5-fluoro-4-(1,3-thiazol-4-ylsulfamoyl)phenoxy]phenyl]propylamino]butanoic acid Chemical compound N[C@@H](CCNCCCC1=C(OC2=C(Cl)C=C(C(F)=C2)S(=O)(=O)NC2=CSC=N2)C=CC(Cl)=C1)C(O)=O DRVYUUZVFWRQMZ-KRWDZBQOSA-N 0.000 description 1
• GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
• VLPIATFUUWWMKC-SNVBAGLBSA-N (2r)-1-(2,6-dimethylphenoxy)propan-2-amine Chemical compound C[C@@H](N)COC1=C(C)C=CC=C1C VLPIATFUUWWMKC-SNVBAGLBSA-N 0.000 description 1
• 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 1
• IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
• FMBVAOHFMSQDGT-UHFFFAOYSA-N (5-chloro-2-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(Cl)C=C1B(O)O FMBVAOHFMSQDGT-UHFFFAOYSA-N 0.000 description 1
• GFCZAZVHUMJMJN-UHFFFAOYSA-N (5-chloro-2-methoxyphenyl)methanol Chemical compound COC1=CC=C(Cl)C=C1CO GFCZAZVHUMJMJN-UHFFFAOYSA-N 0.000 description 1
• 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 description 1
• 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
• BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
• OUFKPMUEFRPJCA-UHFFFAOYSA-N 1,3-thiazol-4-yl carbamate Chemical compound NC(=O)OC1=CSC=N1 OUFKPMUEFRPJCA-UHFFFAOYSA-N 0.000 description 1
• KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
• WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-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
• UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
• LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 description 1
• 125000006183 2,4-dimethyl benzyl group Chemical group [H]C1=C(C([H])=C(C(=C1[H])C([H])([H])*)C([H])([H])[H])C([H])([H])[H] 0.000 description 1
• FVLJCJMQFVCVMM-UHFFFAOYSA-N 2-[3-[5-chloro-2-[2-chloro-5-fluoro-4-(1,3-thiazol-2-ylsulfamoyl)phenoxy]phenyl]propyl-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]amino]acetic acid Chemical compound Cc1oc(=O)oc1CN(CCCc1cc(Cl)ccc1Oc1cc(F)c(cc1Cl)S(=O)(=O)Nc1nccs1)CC(O)=O FVLJCJMQFVCVMM-UHFFFAOYSA-N 0.000 description 1
• HKBJKKBTMCBLDY-UHFFFAOYSA-N 2-[3-[5-chloro-2-[2-chloro-5-fluoro-4-(1,3-thiazol-2-ylsulfamoyl)phenoxy]phenyl]propyl-[1-(2-methylpropanoyloxy)ethoxycarbonyl]amino]acetic acid Chemical compound CC(C)C(=O)OC(C)OC(=O)N(CCCc1cc(Cl)ccc1Oc1cc(F)c(cc1Cl)S(=O)(=O)Nc1nccs1)CC(O)=O HKBJKKBTMCBLDY-UHFFFAOYSA-N 0.000 description 1
• RBWHPUWZFKHHPD-UHFFFAOYSA-N 2-[3-[5-chloro-2-[2-chloro-5-fluoro-4-(1,3-thiazol-2-ylsulfamoyl)phenoxy]phenyl]propyl-ethoxycarbonylamino]acetic acid Chemical compound CCOC(=O)N(CCCc1cc(Cl)ccc1Oc1cc(F)c(cc1Cl)S(=O)(=O)Nc1nccs1)CC(O)=O RBWHPUWZFKHHPD-UHFFFAOYSA-N 0.000 description 1
• UUYDPHCMCYSNAY-UHFFFAOYSA-N 2-amino-n-methylacetamide Chemical compound CNC(=O)CN UUYDPHCMCYSNAY-UHFFFAOYSA-N 0.000 description 1
• SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 1
• 125000005916 2-methylpentyl group Chemical group 0.000 description 1
• KSDMMCFWQWBVBW-UHFFFAOYSA-N 2-sulfanylbenzaldehyde Chemical compound SC1=CC=CC=C1C=O KSDMMCFWQWBVBW-UHFFFAOYSA-N 0.000 description 1
• QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
• PLYGKZUBMYQKJH-UHFFFAOYSA-N 3-[3-(5-chloro-2-hydroxyphenyl)propylamino]propanamide Chemical compound NC(=O)CCNCCCC1=CC(Cl)=CC=C1O PLYGKZUBMYQKJH-UHFFFAOYSA-N 0.000 description 1
• 125000005917 3-methylpentyl group Chemical group 0.000 description 1
• WCKQPPQRFNHPRJ-UHFFFAOYSA-N 4-[[4-(dimethylamino)phenyl]diazenyl]benzoic acid Chemical compound C1=CC(N(C)C)=CC=C1N=NC1=CC=C(C(O)=O)C=C1 WCKQPPQRFNHPRJ-UHFFFAOYSA-N 0.000 description 1
• GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 1
• DYEZRXLVZMZHQT-UHFFFAOYSA-N 4-chloropyridine-2-carbonitrile Chemical compound ClC1=CC=NC(C#N)=C1 DYEZRXLVZMZHQT-UHFFFAOYSA-N 0.000 description 1
• VVNYDCGZZSTUBC-UHFFFAOYSA-N 5-amino-2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxopentanoic acid Chemical compound CC(C)(C)OC(=O)NC(C(O)=O)CCC(N)=O VVNYDCGZZSTUBC-UHFFFAOYSA-N 0.000 description 1
• FDUBQNUDZOGOFE-UHFFFAOYSA-N 5-fluoro-2-hydroxybenzaldehyde Chemical compound OC1=CC=C(F)C=C1C=O FDUBQNUDZOGOFE-UHFFFAOYSA-N 0.000 description 1
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
• 208000004998 Abdominal Pain Diseases 0.000 description 1
• 206010000087 Abdominal pain upper Diseases 0.000 description 1
• 244000215068 Acacia senegal Species 0.000 description 1
• 229930024421 Adenine Natural products 0.000 description 1
• GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
• 229920001817 Agar Polymers 0.000 description 1
• 239000005995 Aluminium silicate Substances 0.000 description 1
• 244000144725 Amygdalus communis Species 0.000 description 1
• 235000011437 Amygdalus communis Nutrition 0.000 description 1
• 206010002091 Anaesthesia Diseases 0.000 description 1
• 208000006820 Arthralgia Diseases 0.000 description 1
• 206010003591 Ataxia Diseases 0.000 description 1
• 239000005711 Benzoic acid Substances 0.000 description 1
• 206010004637 Bile duct stone Diseases 0.000 description 1
• COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
• JBHGKSKBWBTEEO-UHFFFAOYSA-N CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(Cl)cc2CCCNCCC(O)=O)cc1F Chemical compound CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(Cl)cc2CCCNCCC(O)=O)cc1F JBHGKSKBWBTEEO-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
• BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 1
• JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
• OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
• OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
• 241000207199 Citrus Species 0.000 description 1
• IQDMMPULOSVLIL-UHFFFAOYSA-N ClC=1C=CC(=C(C1)C1=CC(=NC=C1)C(=O)NCCC(=O)O)OC1=C(C=C(C(=C1)F)S(N(C1=NC=NS1)CC1=C(C=C(C=C1)OC)OC)(=O)=O)Cl Chemical compound ClC=1C=CC(=C(C1)C1=CC(=NC=C1)C(=O)NCCC(=O)O)OC1=C(C=C(C(=C1)F)S(N(C1=NC=NS1)CC1=C(C=C(C=C1)OC)OC)(=O)=O)Cl IQDMMPULOSVLIL-UHFFFAOYSA-N 0.000 description 1
• 206010010904 Convulsion Diseases 0.000 description 1
• 229920002261 Corn starch Polymers 0.000 description 1
• FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
• FBPFZTCFMRRESA-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
• NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
• 206010052804 Drug tolerance Diseases 0.000 description 1
• QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
• PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
• 241000282326 Felis catus Species 0.000 description 1
• 239000004471 Glycine Substances 0.000 description 1
• 229920002907 Guar gum Polymers 0.000 description 1
• 229920000084 Gum arabic Polymers 0.000 description 1
• 101000694017 Homo sapiens Sodium channel protein type 5 subunit alpha Proteins 0.000 description 1
• 238000006130 Horner-Wadsworth-Emmons olefination reaction Methods 0.000 description 1
• 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 1
• 206010020751 Hypersensitivity Diseases 0.000 description 1
• PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
• 208000000913 Kidney Calculi Diseases 0.000 description 1
• KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
• 241000239270 Leiurus quinquestriatus quinquestriatus Species 0.000 description 1
• 240000007472 Leucaena leucocephala Species 0.000 description 1
• 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
• NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
• WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
• 239000004472 Lysine Substances 0.000 description 1
• KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
• 241000124008 Mammalia Species 0.000 description 1
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
• 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
• 241000699670 Mus sp. Species 0.000 description 1
• 208000007101 Muscle Cramp Diseases 0.000 description 1
• HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-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
• 238000005481 NMR spectroscopy Methods 0.000 description 1
• 206010029148 Nephrolithiasis Diseases 0.000 description 1
• 208000028389 Nerve injury Diseases 0.000 description 1
• IJNODFMGORTGDR-UHFFFAOYSA-N OC(=O)CCNCCCc1cc(Cl)ccc1O Chemical compound OC(=O)CCNCCCc1cc(Cl)ccc1O IJNODFMGORTGDR-UHFFFAOYSA-N 0.000 description 1
• 206010030113 Oedema Diseases 0.000 description 1
• 229920002319 Poly(methyl acrylate) Polymers 0.000 description 1
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
• 208000037674 Primary erythromelalgia Diseases 0.000 description 1
• 102000001708 Protein Isoforms Human genes 0.000 description 1
• 108010029485 Protein Isoforms Proteins 0.000 description 1
• 229920001131 Pulp (paper) Polymers 0.000 description 1
• 239000007868 Raney catalyst Substances 0.000 description 1
• 229910000564 Raney nickel Inorganic materials 0.000 description 1
• NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
• 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
• 206010038678 Respiratory depression Diseases 0.000 description 1
• UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
• DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
• 102100027198 Sodium channel protein type 5 subunit alpha Human genes 0.000 description 1
• DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
• 206010041349 Somnolence Diseases 0.000 description 1
• 235000021355 Stearic acid Nutrition 0.000 description 1
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
• NINIDFKCEFEMDL-AKLPVKDBSA-N Sulfur-35 Chemical compound [35S] NINIDFKCEFEMDL-AKLPVKDBSA-N 0.000 description 1
• FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
• YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
• GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
• 102000004142 Trypsin Human genes 0.000 description 1
• 108090000631 Trypsin Proteins 0.000 description 1
• 101710099833 Venom protein Proteins 0.000 description 1
• 206010053692 Wound complication Diseases 0.000 description 1
• 240000008042 Zea mays Species 0.000 description 1
• 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
• 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
• LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
• MXZNUGFCDVAXLG-CHWSQXEVSA-N [(2S)-1-[(2R)-3-methyl-2-(pyridine-4-carbonylamino)butanoyl]pyrrolidin-2-yl]boronic acid Chemical compound CC(C)[C@@H](NC(=O)c1ccncc1)C(=O)N1CCC[C@@H]1B(O)O MXZNUGFCDVAXLG-CHWSQXEVSA-N 0.000 description 1
• IYUKFAFDFHZKPI-AENDTGMFSA-N [(2r)-1-methoxy-1-oxopropan-2-yl]azanium;chloride Chemical compound Cl.COC(=O)[C@@H](C)N IYUKFAFDFHZKPI-AENDTGMFSA-N 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
• PNDPGZBMCMUPRI-XXSWNUTMSA-N [125I][125I] Chemical compound [125I][125I] PNDPGZBMCMUPRI-XXSWNUTMSA-N 0.000 description 1
• ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 1
• 206010000059 abdominal discomfort Diseases 0.000 description 1
• 239000006096 absorbing agent Substances 0.000 description 1
• 235000010489 acacia gum Nutrition 0.000 description 1
• 239000000205 acacia gum Substances 0.000 description 1
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
• 230000001154 acute effect Effects 0.000 description 1
• 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
• 239000000654 additive Substances 0.000 description 1
• 229960000643 adenine Drugs 0.000 description 1
• 239000008272 agar Substances 0.000 description 1
• 235000010419 agar Nutrition 0.000 description 1
• 239000000556 agonist Substances 0.000 description 1
• 150000001299 aldehydes Chemical class 0.000 description 1
• 239000000783 alginic acid Substances 0.000 description 1
• 229960001126 alginic acid Drugs 0.000 description 1
• 150000004781 alginic acids Chemical class 0.000 description 1
• 150000001335 aliphatic alkanes Chemical class 0.000 description 1
• 208000026935 allergic disease Diseases 0.000 description 1
• 235000020224 almond Nutrition 0.000 description 1
• 229910052782 aluminium Inorganic materials 0.000 description 1
• XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
• 235000012211 aluminium silicate Nutrition 0.000 description 1
• CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
• 229940063655 aluminum stearate Drugs 0.000 description 1
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
• 235000019270 ammonium chloride Nutrition 0.000 description 1
• 230000037005 anaesthesia Effects 0.000 description 1
• 238000010171 animal model Methods 0.000 description 1
• 210000003423 ankle Anatomy 0.000 description 1
• 230000001093 anti-cancer Effects 0.000 description 1
• 230000003110 anti-inflammatory effect Effects 0.000 description 1
• 235000015197 apple juice Nutrition 0.000 description 1
• 206010003246 arthritis Diseases 0.000 description 1
• XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
• 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 description 1
• 230000006399 behavior Effects 0.000 description 1
• 238000009227 behaviour therapy Methods 0.000 description 1
• 230000003542 behavioural effect Effects 0.000 description 1
• 239000000440 bentonite Substances 0.000 description 1
• 229910000278 bentonite Inorganic materials 0.000 description 1
• 235000012216 bentonite Nutrition 0.000 description 1
• SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
• JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
• 150000007962 benzene acetonitriles Chemical class 0.000 description 1
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
• 235000010233 benzoic acid Nutrition 0.000 description 1
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
• 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 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
• 229940000635 beta-alanine Drugs 0.000 description 1
• 125000002619 bicyclic group Chemical group 0.000 description 1
• 210000000013 bile duct Anatomy 0.000 description 1
• 239000001045 blue dye Substances 0.000 description 1
• 210000004556 brain Anatomy 0.000 description 1
• 229960003150 bupivacaine Drugs 0.000 description 1
• 239000011575 calcium Substances 0.000 description 1
• 229910052791 calcium Inorganic materials 0.000 description 1
• 229910000019 calcium carbonate Inorganic materials 0.000 description 1
• 235000010216 calcium carbonate Nutrition 0.000 description 1
• FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
• 239000001354 calcium citrate Substances 0.000 description 1
• CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
• 235000013539 calcium stearate Nutrition 0.000 description 1
• 239000008116 calcium stearate Substances 0.000 description 1
• OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Inorganic materials [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
• 125000002837 carbocyclic group Chemical group 0.000 description 1
• 229910052799 carbon Inorganic materials 0.000 description 1
• 150000001721 carbon Chemical group 0.000 description 1
• 150000001722 carbon compounds Chemical class 0.000 description 1
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
• 239000003729 cation exchange resin Substances 0.000 description 1
• 229940023913 cation exchange resins Drugs 0.000 description 1
• 210000000170 cell membrane Anatomy 0.000 description 1
• 235000013339 cereals Nutrition 0.000 description 1
• KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
• VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
• 229960002023 chloroprocaine Drugs 0.000 description 1
• OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
• 229960001231 choline Drugs 0.000 description 1
• 229960004106 citric acid Drugs 0.000 description 1
• 235000020971 citrus fruits Nutrition 0.000 description 1
• 239000011248 coating agent Substances 0.000 description 1
• 238000000576 coating method Methods 0.000 description 1
• 239000005515 coenzyme Substances 0.000 description 1
• 229940125773 compound 10 Drugs 0.000 description 1
• 229940125797 compound 12 Drugs 0.000 description 1
• 229940126543 compound 14 Drugs 0.000 description 1
• 229940125758 compound 15 Drugs 0.000 description 1
• 229940126142 compound 16 Drugs 0.000 description 1
• 229940125782 compound 2 Drugs 0.000 description 1
• 229940125810 compound 20 Drugs 0.000 description 1
• 229940126086 compound 21 Drugs 0.000 description 1
• 229940126208 compound 22 Drugs 0.000 description 1
• 229940125833 compound 23 Drugs 0.000 description 1
• 229940125961 compound 24 Drugs 0.000 description 1
• 229940125846 compound 25 Drugs 0.000 description 1
• 229940127204 compound 29 Drugs 0.000 description 1
• 229940126214 compound 3 Drugs 0.000 description 1
• 229940125877 compound 31 Drugs 0.000 description 1
• 229940125898 compound 5 Drugs 0.000 description 1
• 239000012050 conventional carrier Substances 0.000 description 1
• 238000001816 cooling Methods 0.000 description 1
• 235000005822 corn Nutrition 0.000 description 1
• 125000006165 cyclic alkyl group Chemical group 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
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
• 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([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
• 235000013365 dairy product Nutrition 0.000 description 1
• 238000007405 data analysis Methods 0.000 description 1
• 230000009849 deactivation Effects 0.000 description 1
• 238000006298 dechlorination reaction Methods 0.000 description 1
• 239000008367 deionised water Substances 0.000 description 1
• 229910021641 deionized water Inorganic materials 0.000 description 1
• 230000003111 delayed effect Effects 0.000 description 1
• 230000002999 depolarising effect Effects 0.000 description 1
• 206010012601 diabetes mellitus Diseases 0.000 description 1
• 229940039227 diagnostic agent Drugs 0.000 description 1
• 239000000032 diagnostic agent Substances 0.000 description 1
• 125000002720 diazolyl group Chemical group 0.000 description 1
• ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
• 229940043237 diethanolamine Drugs 0.000 description 1
• BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
• 238000007907 direct compression Methods 0.000 description 1
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
• XCFVSYWEMCQEOH-UHFFFAOYSA-L disodium 4-amino-5-hydroxy-3-[(4-nitrophenyl)diazenyl]naphthalene-2,7-disulfonate Chemical compound [Na+].[Na+].NC1=C(C(=CC2=CC(=CC(=C12)O)S(=O)(=O)[O-])S(=O)(=O)[O-])N=NC1=CC=C(C=C1)[N+](=O)[O-] XCFVSYWEMCQEOH-UHFFFAOYSA-L 0.000 description 1
• SDIXRDNYIMOKSG-UHFFFAOYSA-L disodium methyl arsenate Chemical compound [Na+].[Na+].C[As]([O-])([O-])=O SDIXRDNYIMOKSG-UHFFFAOYSA-L 0.000 description 1
• 208000035475 disorder Diseases 0.000 description 1
• 239000002270 dispersing agent 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
• MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
• 229940043264 dodecyl sulfate Drugs 0.000 description 1
• 229940000406 drug candidate Drugs 0.000 description 1
• 230000036267 drug metabolism Effects 0.000 description 1
• 238000007908 dry granulation Methods 0.000 description 1
• 230000004064 dysfunction Effects 0.000 description 1
• 210000005069 ears Anatomy 0.000 description 1
• 150000002148 esters Chemical class 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
• 229940012017 ethylenediamine Drugs 0.000 description 1
• 238000011156 evaluation Methods 0.000 description 1
• 230000005284 excitation Effects 0.000 description 1
• 235000019634 flavors Nutrition 0.000 description 1
• 235000013312 flour Nutrition 0.000 description 1
• 238000000684 flow cytometry Methods 0.000 description 1
• 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
• 239000007850 fluorescent dye Substances 0.000 description 1
• 235000013355 food flavoring agent Nutrition 0.000 description 1
• 238000009472 formulation Methods 0.000 description 1
• 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
• 125000000524 functional group Chemical group 0.000 description 1
• 125000002541 furyl group Chemical group 0.000 description 1
• 230000002496 gastric effect Effects 0.000 description 1
• 238000007429 general method Methods 0.000 description 1
• 235000001727 glucose Nutrition 0.000 description 1
• 229960002449 glycine Drugs 0.000 description 1
• 239000001963 growth medium Substances 0.000 description 1
• JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
• 235000010417 guar gum Nutrition 0.000 description 1
• 239000000665 guar gum Substances 0.000 description 1
• 229960002154 guar gum Drugs 0.000 description 1
• 230000026781 habituation Effects 0.000 description 1
• LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 1
• 230000023597 hemostasis Effects 0.000 description 1
• 238000013537 high throughput screening Methods 0.000 description 1
• IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
• 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
• 230000007062 hydrolysis Effects 0.000 description 1
• 238000006460 hydrolysis reaction Methods 0.000 description 1
• DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 description 1
• COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 1
• IYUKFAFDFHZKPI-UHFFFAOYSA-N hydron;methyl 2-aminopropanoate;chloride Chemical compound Cl.COC(=O)C(C)N IYUKFAFDFHZKPI-UHFFFAOYSA-N 0.000 description 1
• XPGRZDJXVKFLHQ-UHFFFAOYSA-N hydron;methyl 3-aminopropanoate;chloride Chemical compound Cl.COC(=O)CCN XPGRZDJXVKFLHQ-UHFFFAOYSA-N 0.000 description 1
• 239000001341 hydroxy propyl starch Substances 0.000 description 1
• 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
• 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
• 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
• 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
• 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
• 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
• 230000009610 hypersensitivity Effects 0.000 description 1
• 239000012216 imaging agent Substances 0.000 description 1
• 125000002883 imidazolyl group Chemical group 0.000 description 1
• 238000001727 in vivo Methods 0.000 description 1
• 238000011503 in vivo imaging Methods 0.000 description 1
• 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
• 125000001041 indolyl group Chemical group 0.000 description 1
• 230000002757 inflammatory effect Effects 0.000 description 1
• 150000007529 inorganic bases Chemical class 0.000 description 1
• 230000003993 interaction Effects 0.000 description 1
• XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
• 229940006461 iodide ion Drugs 0.000 description 1
• 229910052740 iodine Inorganic materials 0.000 description 1
• 239000011630 iodine Substances 0.000 description 1
• 229940044173 iodine-125 Drugs 0.000 description 1
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
• 239000002085 irritant Substances 0.000 description 1
• 231100000021 irritant Toxicity 0.000 description 1
• 229960002725 isoflurane Drugs 0.000 description 1
• 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
• 238000002955 isolation Methods 0.000 description 1
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
• 125000000842 isoxazolyl group Chemical group 0.000 description 1
• ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
• NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
• 229960004125 ketoconazole Drugs 0.000 description 1
• 210000003292 kidney cell Anatomy 0.000 description 1
• 229960004194 lidocaine Drugs 0.000 description 1
• 229910052744 lithium Inorganic materials 0.000 description 1
• 239000012280 lithium aluminium hydride Substances 0.000 description 1
• 239000012160 loading buffer Substances 0.000 description 1
• 230000007774 longterm Effects 0.000 description 1
• 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
• 239000007937 lozenge Substances 0.000 description 1
• 239000011777 magnesium Substances 0.000 description 1
• 238000007898 magnetic cell sorting Methods 0.000 description 1
• 238000002826 magnetic-activated cell sorting Methods 0.000 description 1
• 238000004519 manufacturing process Methods 0.000 description 1
• 230000007246 mechanism Effects 0.000 description 1
• 229960003194 meglumine Drugs 0.000 description 1
• 238000002844 melting Methods 0.000 description 1
• 230000008018 melting Effects 0.000 description 1
• 230000028161 membrane depolarization Effects 0.000 description 1
• 229940041616 menthol Drugs 0.000 description 1
• 230000004060 metabolic process Effects 0.000 description 1
• UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
• IYUKFAFDFHZKPI-DFWYDOINSA-N methyl (2s)-2-aminopropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@H](C)N IYUKFAFDFHZKPI-DFWYDOINSA-N 0.000 description 1
• BROIUCFVOBWBER-UHFFFAOYSA-N methyl 2-[acetyl-[3-[5-chloro-2-[2-chloro-5-fluoro-4-[(2-methylpropan-2-yl)oxycarbonyl-(1,3-thiazol-4-yl)sulfamoyl]phenoxy]phenyl]propyl]amino]acetate Chemical compound COC(=O)CN(C(C)=O)CCCC1=CC(Cl)=CC=C1OC1=CC(F)=C(S(=O)(=O)N(C(=O)OC(C)(C)C)C=2N=CSC=2)C=C1Cl BROIUCFVOBWBER-UHFFFAOYSA-N 0.000 description 1
• VOUIHMBRJVKANW-UHFFFAOYSA-N methyl 2-piperidin-4-ylacetate Chemical compound COC(=O)CC1CCNCC1 VOUIHMBRJVKANW-UHFFFAOYSA-N 0.000 description 1
• XWBFIPVPQLAHMA-UHFFFAOYSA-N methyl 4-[(2-methylpropan-2-yl)oxycarbonylamino]piperidine-4-carboxylate Chemical compound CC(C)(C)OC(=O)NC1(C(=O)OC)CCNCC1 XWBFIPVPQLAHMA-UHFFFAOYSA-N 0.000 description 1
• KVQGGLZHHFGHPU-UHFFFAOYSA-N methyl 4-aminobutanoate Chemical compound COC(=O)CCCN KVQGGLZHHFGHPU-UHFFFAOYSA-N 0.000 description 1
• 150000004702 methyl esters Chemical class 0.000 description 1
• 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
• HNBDRPTVWVGKBR-UHFFFAOYSA-N methyl pentanoate Chemical compound CCCCC(=O)OC HNBDRPTVWVGKBR-UHFFFAOYSA-N 0.000 description 1
• BCDBHIAXYFPJCT-UHFFFAOYSA-N methyl piperidine-3-carboxylate Chemical compound COC(=O)C1CCCNC1 BCDBHIAXYFPJCT-UHFFFAOYSA-N 0.000 description 1
• 229960002216 methylparaben Drugs 0.000 description 1
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
• 229960003404 mexiletine Drugs 0.000 description 1
• 239000003094 microcapsule Substances 0.000 description 1
• 229940016286 microcrystalline cellulose Drugs 0.000 description 1
• 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
• 239000008108 microcrystalline cellulose Substances 0.000 description 1
• 238000002156 mixing Methods 0.000 description 1
• 125000002950 monocyclic group Chemical group 0.000 description 1
• 125000002757 morpholinyl group Chemical group 0.000 description 1
• 210000004400 mucous membrane Anatomy 0.000 description 1
• 210000003097 mucus Anatomy 0.000 description 1
• 210000000663 muscle cell Anatomy 0.000 description 1
• WHVAGQIOVODUCH-UHFFFAOYSA-N n-[(2,4-dimethoxyphenyl)methyl]-2,4,5-trifluoro-n-(1,2,4-thiadiazol-5-yl)benzenesulfonamide Chemical compound COC1=CC(OC)=CC=C1CN(S(=O)(=O)C=1C(=CC(F)=C(F)C=1)F)C1=NC=NS1 WHVAGQIOVODUCH-UHFFFAOYSA-N 0.000 description 1
• 239000000025 natural resin Substances 0.000 description 1
• 210000005036 nerve Anatomy 0.000 description 1
• 230000008764 nerve damage Effects 0.000 description 1
• 230000002314 neuroinflammatory effect Effects 0.000 description 1
• 210000002569 neuron Anatomy 0.000 description 1
• PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
• 210000000929 nociceptor Anatomy 0.000 description 1
• 108091008700 nociceptors Proteins 0.000 description 1
• 150000007523 nucleic acids Chemical class 0.000 description 1
• 102000039446 nucleic acids Human genes 0.000 description 1
• 108020004707 nucleic acids Proteins 0.000 description 1
• QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
• OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
• 239000003921 oil Substances 0.000 description 1
• 235000019198 oils Nutrition 0.000 description 1
• 230000003287 optical effect Effects 0.000 description 1
• 235000015205 orange juice Nutrition 0.000 description 1
• 150000007530 organic bases Chemical class 0.000 description 1
• 239000012074 organic phase Substances 0.000 description 1
• 125000002971 oxazolyl group Chemical group 0.000 description 1
• 230000004783 oxidative metabolism Effects 0.000 description 1
• 239000001301 oxygen Substances 0.000 description 1
• 125000005440 p-toluyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C(*)=O)C([H])([H])[H] 0.000 description 1
• 230000037040 pain threshold Effects 0.000 description 1
• 229910052763 palladium Inorganic materials 0.000 description 1
• NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 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 description 1
• 238000007911 parenteral administration Methods 0.000 description 1
• 239000003182 parenteral nutrition solution Substances 0.000 description 1
• 230000001575 pathological effect Effects 0.000 description 1
• 230000007310 pathophysiology Effects 0.000 description 1
• 235000019271 petrolatum Nutrition 0.000 description 1
• WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
• 239000006187 pill Substances 0.000 description 1
• 125000004193 piperazinyl group Chemical group 0.000 description 1
• 239000004033 plastic Substances 0.000 description 1
• 239000011591 potassium Substances 0.000 description 1
• 229910052700 potassium Inorganic materials 0.000 description 1
• 229920001592 potato starch Polymers 0.000 description 1
• 229920003124 powdered cellulose Polymers 0.000 description 1
• 235000019814 powdered cellulose Nutrition 0.000 description 1
• 239000003755 preservative agent Substances 0.000 description 1
• 230000002335 preservative effect Effects 0.000 description 1
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
• 208000017692 primary erythermalgia Diseases 0.000 description 1
• 229960004919 procaine Drugs 0.000 description 1
• MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
• 230000002035 prolonged effect Effects 0.000 description 1
• 238000011321 prophylaxis Methods 0.000 description 1
• QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
• 125000006308 propyl amino group Chemical group 0.000 description 1
• 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
• 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
• 229960003415 propylparaben Drugs 0.000 description 1
• 125000006239 protecting group Chemical group 0.000 description 1
• 239000003223 protective agent Substances 0.000 description 1
• 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
• 125000003373 pyrazinyl group Chemical group 0.000 description 1
• 150000003217 pyrazoles Chemical class 0.000 description 1
• 125000002098 pyridazinyl group Chemical group 0.000 description 1
• 150000003222 pyridines Chemical class 0.000 description 1
• HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
• 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
• 125000006085 pyrrolopyridyl group Chemical group 0.000 description 1
• 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
• 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
• 238000011084 recovery Methods 0.000 description 1
• 238000006268 reductive amination reaction Methods 0.000 description 1
• 230000002829 reductive effect Effects 0.000 description 1
• 238000011160 research Methods 0.000 description 1
• 239000012047 saturated solution Substances 0.000 description 1
• 210000001044 sensory neuron Anatomy 0.000 description 1
• 230000020341 sensory perception of pain Effects 0.000 description 1
• 238000013207 serial dilution Methods 0.000 description 1
• 210000002966 serum Anatomy 0.000 description 1
• RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
• 235000012239 silicon dioxide Nutrition 0.000 description 1
• 238000004088 simulation Methods 0.000 description 1
• WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
• 235000010234 sodium benzoate Nutrition 0.000 description 1
• 239000004299 sodium benzoate Substances 0.000 description 1
• 229960003885 sodium benzoate Drugs 0.000 description 1
• 235000017557 sodium bicarbonate Nutrition 0.000 description 1
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
• 229940001607 sodium bisulfite Drugs 0.000 description 1
• 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
• 239000003378 sodium channel stimulating agent Substances 0.000 description 1
• 239000001509 sodium citrate Substances 0.000 description 1
• NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
• QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
• 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
• 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
• 235000010268 sodium methyl p-hydroxybenzoate Nutrition 0.000 description 1
• 239000000600 sorbitol Substances 0.000 description 1
• 235000010356 sorbitol Nutrition 0.000 description 1
• 208000020431 spinal cord injury Diseases 0.000 description 1
• 230000002269 spontaneous effect Effects 0.000 description 1
• 238000013222 sprague-dawley male rat Methods 0.000 description 1
• 239000003381 stabilizer Substances 0.000 description 1
• 238000010561 standard procedure Methods 0.000 description 1
• 239000008117 stearic acid Substances 0.000 description 1
• 210000002784 stomach Anatomy 0.000 description 1
• 239000011593 sulfur Substances 0.000 description 1
• 239000002511 suppository base Substances 0.000 description 1
• 239000000375 suspending agent Substances 0.000 description 1
• 239000000057 synthetic resin Substances 0.000 description 1
• 229920003002 synthetic resin Polymers 0.000 description 1
• 239000006188 syrup Substances 0.000 description 1
• 235000020357 syrup Nutrition 0.000 description 1
• 239000007916 tablet composition Substances 0.000 description 1
• 239000007885 tablet disintegrant Substances 0.000 description 1
• 235000002906 tartaric acid Nutrition 0.000 description 1
• 239000011975 tartaric acid Substances 0.000 description 1
• 238000003419 tautomerization reaction Methods 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
• 238000010998 test method Methods 0.000 description 1
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
• 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
• 125000003831 tetrazolyl group Chemical group 0.000 description 1
• 125000001544 thienyl group Chemical group 0.000 description 1
• 125000003396 thiol group Chemical group [H]S* 0.000 description 1
• 150000003573 thiols Chemical class 0.000 description 1
• 239000003106 tissue adhesive Substances 0.000 description 1
• 238000011200 topical administration Methods 0.000 description 1
• 230000008733 trauma Effects 0.000 description 1
• 125000001425 triazolyl group Chemical group 0.000 description 1
• 235000013337 tricalcium citrate Nutrition 0.000 description 1
• 229910052722 tritium Inorganic materials 0.000 description 1
• 239000012588 trypsin Substances 0.000 description 1
• 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
• 210000000689 upper leg Anatomy 0.000 description 1
• 230000003442 weekly effect Effects 0.000 description 1
• 238000005550 wet granulation Methods 0.000 description 1
• 239000003871 white petrolatum Substances 0.000 description 1
• 229940075420 xanthine Drugs 0.000 description 1