JP2011522839A - 性的不能の治療用のメラノコルチンレセプタ特異的ペプチド - Google Patents
性的不能の治療用のメラノコルチンレセプタ特異的ペプチド Download PDFInfo
- Publication number
- JP2011522839A JP2011522839A JP2011512730A JP2011512730A JP2011522839A JP 2011522839 A JP2011522839 A JP 2011522839A JP 2011512730 A JP2011512730 A JP 2011512730A JP 2011512730 A JP2011512730 A JP 2011512730A JP 2011522839 A JP2011522839 A JP 2011522839A
- Authority
- JP
- Japan
- Prior art keywords
- peptide
- peptides
- cyclic peptide
- arg
- cyclic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 134
- 102000004378 Melanocortin Receptors Human genes 0.000 title claims abstract description 29
- 108090000950 Melanocortin Receptors Proteins 0.000 title claims abstract description 29
- 201000001881 impotence Diseases 0.000 title claims abstract description 29
- 108010069514 Cyclic Peptides Proteins 0.000 claims abstract description 104
- 102000001189 Cyclic Peptides Human genes 0.000 claims abstract description 104
- 238000000034 method Methods 0.000 claims abstract description 59
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 33
- 201000010099 disease Diseases 0.000 claims abstract description 28
- 208000010228 Erectile Dysfunction Diseases 0.000 claims abstract description 22
- 208000011580 syndromic disease Diseases 0.000 claims abstract description 8
- 230000001404 mediated effect Effects 0.000 claims abstract description 5
- 108010021436 Type 4 Melanocortin Receptor Proteins 0.000 claims description 39
- 102000008316 Type 4 Melanocortin Receptor Human genes 0.000 claims description 39
- 230000001568 sexual effect Effects 0.000 claims description 34
- 239000003814 drug Substances 0.000 claims description 28
- 229940079593 drug Drugs 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 18
- 206010057671 Female sexual dysfunction Diseases 0.000 claims description 10
- 230000004913 activation Effects 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 7
- 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 claims description 3
- 210000000664 rectum Anatomy 0.000 claims description 2
- 210000003708 urethra Anatomy 0.000 claims description 2
- 210000001215 vagina Anatomy 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 229940127557 pharmaceutical product Drugs 0.000 claims 1
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 64
- 239000000203 mixture Substances 0.000 abstract description 58
- 238000009472 formulation Methods 0.000 abstract description 23
- 239000000336 melanocortin receptor agonist Substances 0.000 abstract description 4
- 230000036299 sexual function Effects 0.000 abstract description 4
- 201000001880 Sexual dysfunction Diseases 0.000 abstract description 3
- 231100000872 sexual dysfunction Toxicity 0.000 abstract description 3
- 229940117029 Melanocortin receptor agonist Drugs 0.000 abstract description 2
- 230000004064 dysfunction Effects 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 38
- 150000001875 compounds Chemical class 0.000 description 37
- -1 Cyclic lactam Chemical class 0.000 description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 31
- UAHFGYDRQSXQEB-LEBBXHLNSA-N afamelanotide Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(N)=O)NC(=O)[C@H](CO)NC(C)=O)C1=CC=C(O)C=C1 UAHFGYDRQSXQEB-LEBBXHLNSA-N 0.000 description 25
- 150000001413 amino acids Chemical group 0.000 description 24
- 108700034262 4-Nle-7-Phe-alpha- MSH Proteins 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 23
- 239000000556 agonist Substances 0.000 description 22
- 108010021428 Type 1 Melanocortin Receptor Proteins 0.000 description 19
- 102000008314 Type 1 Melanocortin Receptor Human genes 0.000 description 19
- 235000001014 amino acid Nutrition 0.000 description 19
- 230000027455 binding Effects 0.000 description 19
- 125000006239 protecting group Chemical group 0.000 description 19
- 230000000694 effects Effects 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 17
- 238000004458 analytical method Methods 0.000 description 17
- 239000002552 dosage form Substances 0.000 description 17
- 241000700159 Rattus Species 0.000 description 16
- 108010021433 Type 3 Melanocortin Receptor Proteins 0.000 description 16
- 102000008318 Type 3 Melanocortin Receptor Human genes 0.000 description 16
- 108010088565 Melanocortin 5 receptor Proteins 0.000 description 15
- 102000030612 Melanocortin 5 receptor Human genes 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 239000011347 resin Substances 0.000 description 14
- 229920005989 resin Polymers 0.000 description 14
- 239000003795 chemical substances by application Substances 0.000 description 13
- 102000005962 receptors Human genes 0.000 description 13
- 108020003175 receptors Proteins 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000003755 preservative agent Substances 0.000 description 12
- 239000003826 tablet Substances 0.000 description 12
- 230000018052 penile erection Effects 0.000 description 11
- 239000000651 prodrug Substances 0.000 description 11
- 229940002612 prodrug Drugs 0.000 description 11
- 230000002269 spontaneous effect Effects 0.000 description 11
- 125000003277 amino group Chemical group 0.000 description 10
- 239000000872 buffer Substances 0.000 description 10
- 239000002775 capsule Substances 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 239000002702 enteric coating Substances 0.000 description 10
- 238000009505 enteric coating Methods 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- WHNFPRLDDSXQCL-UAZQEYIDSA-N α-msh Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(N)=O)NC(=O)[C@H](CO)NC(C)=O)C1=CC=C(O)C=C1 WHNFPRLDDSXQCL-UAZQEYIDSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 239000000546 pharmaceutical excipient Substances 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- 238000010532 solid phase synthesis reaction Methods 0.000 description 9
- 238000010254 subcutaneous injection Methods 0.000 description 9
- 239000007929 subcutaneous injection Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 238000002648 combination therapy Methods 0.000 description 8
- 229940088597 hormone Drugs 0.000 description 8
- 239000005556 hormone Substances 0.000 description 8
- 102400000740 Melanocyte-stimulating hormone alpha Human genes 0.000 description 7
- 101710200814 Melanotropin alpha Proteins 0.000 description 7
- 239000000654 additive Substances 0.000 description 7
- 230000006957 competitive inhibition Effects 0.000 description 7
- 230000005714 functional activity Effects 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- 229920000642 polymer Polymers 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000006243 chemical reaction Methods 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
- 239000003623 enhancer Substances 0.000 description 6
- 230000001965 increasing effect Effects 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000002287 radioligand Substances 0.000 description 6
- 230000000638 stimulation Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 229920001710 Polyorthoester Polymers 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 102000030621 adenylate cyclase Human genes 0.000 description 5
- 108060000200 adenylate cyclase Proteins 0.000 description 5
- 239000000443 aerosol Substances 0.000 description 5
- 125000000539 amino acid group Chemical group 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000036772 blood pressure Effects 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 210000000170 cell membrane Anatomy 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 229940011871 estrogen Drugs 0.000 description 5
- 239000000262 estrogen Substances 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 235000021050 feed intake Nutrition 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 238000010253 intravenous injection Methods 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000013268 sustained release Methods 0.000 description 5
- 239000012730 sustained-release form Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- 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 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 4
- 108091006027 G proteins Proteins 0.000 description 4
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 4
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 4
- 102000030782 GTP binding Human genes 0.000 description 4
- 108091000058 GTP-Binding Proteins 0.000 description 4
- 239000007995 HEPES buffer Substances 0.000 description 4
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 230000035515 penetration Effects 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 238000011552 rat model Methods 0.000 description 4
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical group CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 230000032258 transport Effects 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 3
- 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 3
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 3
- 230000021736 acetylation Effects 0.000 description 3
- 238000006640 acetylation reaction Methods 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 230000037007 arousal Effects 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 229940098773 bovine serum albumin Drugs 0.000 description 3
- FFHBJDQSGDNCIV-MFVUMRCOSA-N bremelanotide Chemical compound C([C@@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCNC(=O)C[C@@H](C(N[C@@H](CC=2NC=NC=2)C(=O)N1)=O)NC(=O)[C@@H](NC(C)=O)CCCC)C(O)=O)C1=CC=CC=C1 FFHBJDQSGDNCIV-MFVUMRCOSA-N 0.000 description 3
- 108010072543 bremelanotide Proteins 0.000 description 3
- 229950000740 bremelanotide Drugs 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000009137 competitive binding Effects 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 238000010494 dissociation reaction Methods 0.000 description 3
- 230000005593 dissociations Effects 0.000 description 3
- 230000009429 distress Effects 0.000 description 3
- 229960004756 ethanol Drugs 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000004310 lactic acid Substances 0.000 description 3
- 235000014655 lactic acid Nutrition 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002865 melanocortin Substances 0.000 description 3
- 201000001441 melanoma Diseases 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 239000004031 partial agonist Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 230000011664 signaling Effects 0.000 description 3
- 239000007790 solid phase Substances 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 3
- 230000004584 weight gain Effects 0.000 description 3
- 235000019786 weight gain Nutrition 0.000 description 3
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- 229920003178 (lactide-co-glycolide) polymer Polymers 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- 102100022455 Adrenocorticotropic hormone receptor Human genes 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 102400000739 Corticotropin Human genes 0.000 description 2
- 101800000414 Corticotropin Proteins 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 238000011891 EIA kit Methods 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- QGWNDRXFNXRZMB-UUOKFMHZSA-N GDP Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O QGWNDRXFNXRZMB-UUOKFMHZSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- XKMLYUALXHKNFT-UUOKFMHZSA-N Guanosine-5'-triphosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XKMLYUALXHKNFT-UUOKFMHZSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000979190 Homo sapiens Transcription factor MafB Proteins 0.000 description 2
- 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 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 108010008364 Melanocortins Proteins 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 208000008238 Muscle Spasticity Diseases 0.000 description 2
- 229940122905 Neuropeptide Y receptor agonist Drugs 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 229940083324 Selective androgen receptor modulator Drugs 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 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 2
- 102100023234 Transcription factor MafB Human genes 0.000 description 2
- 108010021430 Type 2 Melanocortin Receptor Proteins 0.000 description 2
- 108010003205 Vasoactive Intestinal Peptide Proteins 0.000 description 2
- 102400000015 Vasoactive intestinal peptide Human genes 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 239000000674 adrenergic antagonist Substances 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000003542 behavioural effect Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 239000003833 bile salt Substances 0.000 description 2
- 229940093761 bile salts Drugs 0.000 description 2
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- 210000001217 buttock Anatomy 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- ZNEWHQLOPFWXOF-UHFFFAOYSA-N coenzyme M Chemical compound OS(=O)(=O)CCS ZNEWHQLOPFWXOF-UHFFFAOYSA-N 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 2
- 229960000258 corticotropin Drugs 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- ZOOGRGPOEVQQDX-UHFFFAOYSA-N cyclic GMP Natural products O1C2COP(O)(=O)OC2C(O)C1N1C=NC2=C1NC(N)=NC2=O ZOOGRGPOEVQQDX-UHFFFAOYSA-N 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 210000000852 deltoid muscle Anatomy 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- MGHPNCMVUAKAIE-UHFFFAOYSA-N diphenylmethanamine Chemical compound C=1C=CC=CC=1C(N)C1=CC=CC=C1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000002792 enkephalinase inhibitor Substances 0.000 description 2
- 230000009986 erectile function Effects 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000010419 fine particle Substances 0.000 description 2
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 235000012631 food intake Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 238000011990 functional testing Methods 0.000 description 2
- 239000000499 gel Substances 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
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- QGWNDRXFNXRZMB-UHFFFAOYSA-N guanidine diphosphate Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O QGWNDRXFNXRZMB-UHFFFAOYSA-N 0.000 description 2
- 210000003128 head Anatomy 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 210000003405 ileum Anatomy 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- VBUWHHLIZKOSMS-RIWXPGAOSA-N invicorp Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)C)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 VBUWHHLIZKOSMS-RIWXPGAOSA-N 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 229910052747 lanthanoid Inorganic materials 0.000 description 2
- 150000002602 lanthanoids Chemical class 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 229940071648 metered dose inhaler Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000011859 microparticle Substances 0.000 description 2
- 238000003801 milling Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 239000002658 neuropeptide Y receptor agonist Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000014593 oils and fats Nutrition 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 2
- 238000010979 pH adjustment Methods 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 238000010647 peptide synthesis reaction Methods 0.000 description 2
- 230000000737 periodic effect Effects 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 2
- 239000002745 poly(ortho ester) Substances 0.000 description 2
- 229940050929 polyethylene glycol 3350 Drugs 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000000849 selective androgen receptor modulator Substances 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 208000018198 spasticity Diseases 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 238000013222 sprague-dawley male rat Methods 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 230000035488 systolic blood pressure Effects 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 229960003604 testosterone Drugs 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- ABDKAPXRBAPSQN-UHFFFAOYSA-N veratrole Chemical compound COC1=CC=CC=C1OC ABDKAPXRBAPSQN-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- MPVGCCAXXFLGIU-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-(prop-2-enoxycarbonylamino)propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CNC(=O)OCC=C)C(=O)O)C3=CC=CC=C3C2=C1 MPVGCCAXXFLGIU-IBGZPJMESA-N 0.000 description 1
- YIVBOSPUFNDYMF-FQEVSTJZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-(prop-2-enoxycarbonylamino)butanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCNC(=O)OCC=C)C(=O)O)C3=CC=CC=C3C2=C1 YIVBOSPUFNDYMF-FQEVSTJZSA-N 0.000 description 1
- FBNFRRNBFASDKS-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-prop-2-enoxybutanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CC(=O)OCC=C)C(=O)O)C3=CC=CC=C3C2=C1 FBNFRRNBFASDKS-IBGZPJMESA-N 0.000 description 1
- RXLIOYNXBHZZBI-NRFANRHFSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-5-(prop-2-enoxycarbonylamino)pentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCNC(=O)OCC=C)C(=O)O)C3=CC=CC=C3C2=C1 RXLIOYNXBHZZBI-NRFANRHFSA-N 0.000 description 1
- OJBNDXHENJDCBA-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-6-(prop-2-enoxycarbonylamino)hexanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCCNC(=O)OCC=C)C(=O)O)C3=CC=CC=C3C2=C1 OJBNDXHENJDCBA-QFIPXVFZSA-N 0.000 description 1
- ZZDRDGKSMGGBDI-KRWDZBQOSA-N (2s)-4-azaniumyl-2-(9h-fluoren-9-ylmethoxycarbonylamino)butanoate Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCN)C(O)=O)C3=CC=CC=C3C2=C1 ZZDRDGKSMGGBDI-KRWDZBQOSA-N 0.000 description 1
- HNICLNKVURBTKV-NDEPHWFRSA-N (2s)-5-[[amino-[(2,2,4,6,7-pentamethyl-3h-1-benzofuran-5-yl)sulfonylamino]methylidene]amino]-2-(9h-fluoren-9-ylmethoxycarbonylamino)pentanoic acid Chemical group C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)N[C@H](C(O)=O)CCCN=C(N)NS(=O)(=O)C1=C(C)C(C)=C2OC(C)(C)CC2=C1C HNICLNKVURBTKV-NDEPHWFRSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- LNOLJFCCYQZFBQ-BUHFOSPRSA-N (ne)-n-[(4-nitrophenyl)-phenylmethylidene]hydroxylamine Chemical compound C=1C=C([N+]([O-])=O)C=CC=1C(=N/O)/C1=CC=CC=C1 LNOLJFCCYQZFBQ-BUHFOSPRSA-N 0.000 description 1
- VYMPLPIFKRHAAC-UHFFFAOYSA-N 1,2-ethanedithiol Chemical compound SCCS VYMPLPIFKRHAAC-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- JFLSOKIMYBSASW-UHFFFAOYSA-N 1-chloro-2-[chloro(diphenyl)methyl]benzene Chemical compound ClC1=CC=CC=C1C(Cl)(C=1C=CC=CC=1)C1=CC=CC=C1 JFLSOKIMYBSASW-UHFFFAOYSA-N 0.000 description 1
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 1
- XCMULUAPJXCOHI-UHFFFAOYSA-N 2-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylphenyl]-5-methyl-7-propyl-1h-imidazo[5,1-f][1,2,4]triazin-4-one;hydrochloride Chemical compound Cl.CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 XCMULUAPJXCOHI-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 1
- APIXJSLKIYYUKG-UHFFFAOYSA-N 3 Isobutyl 1 methylxanthine Chemical compound O=C1N(C)C(=O)N(CC(C)C)C2=C1N=CN2 APIXJSLKIYYUKG-UHFFFAOYSA-N 0.000 description 1
- 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 1
- OEBIVOHKFYSBPE-UHFFFAOYSA-N 4-Benzyloxybenzyl alcohol Chemical compound C1=CC(CO)=CC=C1OCC1=CC=CC=C1 OEBIVOHKFYSBPE-UHFFFAOYSA-N 0.000 description 1
- DODQJNMQWMSYGS-QPLCGJKRSA-N 4-[(z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1-phenylbut-1-en-2-yl]phenol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 DODQJNMQWMSYGS-QPLCGJKRSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- JLLYLQLDYORLBB-UHFFFAOYSA-N 5-bromo-n-methylthiophene-2-sulfonamide Chemical compound CNS(=O)(=O)C1=CC=C(Br)S1 JLLYLQLDYORLBB-UHFFFAOYSA-N 0.000 description 1
- SSQLMQBZAPRIRS-UHFFFAOYSA-N 6-(4-hydroxyphenyl)-5-[[4-(2-piperidin-1-ylethoxy)phenyl]methyl]naphthalen-2-ol Chemical compound C1=CC(O)=CC=C1C1=CC=C(C=C(O)C=C2)C2=C1CC(C=C1)=CC=C1OCCN1CCCCC1 SSQLMQBZAPRIRS-UHFFFAOYSA-N 0.000 description 1
- JBYXPOFIGCOSSB-GOJKSUSPSA-N 9-cis,11-trans-octadecadienoic acid Chemical compound CCCCCC\C=C\C=C/CCCCCCCC(O)=O JBYXPOFIGCOSSB-GOJKSUSPSA-N 0.000 description 1
- 239000000275 Adrenocorticotropic Hormone Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 208000031648 Body Weight Changes Diseases 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- BSGGUWQNNPVZQJ-VLVSKCHCSA-N CC(N[C@@H](CCCNC(N)=N)C(N[C@@H](CCC(NCCC[C@@H](C(N)=O)NC([C@H](Cc1c[nH]c2ccccc12)NC([C@H](CCCNC(N)=N)NC([C@@H](Cc1ccccc1)NC([C@H](CCN)N1)=O)=O)O)=O)=O)C1=O)=O)=O Chemical compound CC(N[C@@H](CCCNC(N)=N)C(N[C@@H](CCC(NCCC[C@@H](C(N)=O)NC([C@H](Cc1c[nH]c2ccccc12)NC([C@H](CCCNC(N)=N)NC([C@@H](Cc1ccccc1)NC([C@H](CCN)N1)=O)=O)O)=O)=O)C1=O)=O)=O BSGGUWQNNPVZQJ-VLVSKCHCSA-N 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 229930182832 D-phenylalanine Natural products 0.000 description 1
- 125000001711 D-phenylalanine group Chemical group [H]N([H])[C@@]([H])(C(=O)[*])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 description 1
- 206010012374 Depressed mood Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 1
- 239000012594 Earle’s Balanced Salt Solution Substances 0.000 description 1
- 208000021473 Ejaculation disease Diseases 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 102000034353 G alpha subunit Human genes 0.000 description 1
- 108091006099 G alpha subunit Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 208000032456 Hemorrhagic Shock Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- JJKOTMDDZAJTGQ-DQSJHHFOSA-N Idoxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN2CCCC2)=CC=1)/C1=CC=C(I)C=C1 JJKOTMDDZAJTGQ-DQSJHHFOSA-N 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229940126661 MC4 antagonist Drugs 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102000017351 Melanocortin 3 receptors Human genes 0.000 description 1
- 108050005365 Melanocortin 3 receptors Proteins 0.000 description 1
- 102000001796 Melanocortin 4 receptors Human genes 0.000 description 1
- 108050009019 Melanocortin 4 receptors Proteins 0.000 description 1
- 101800001751 Melanocyte-stimulating hormone alpha Proteins 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 102000003729 Neprilysin Human genes 0.000 description 1
- 108090000028 Neprilysin Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 102400000050 Oxytocin Human genes 0.000 description 1
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 description 1
- 101800000989 Oxytocin Proteins 0.000 description 1
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 102000007079 Peptide Fragments Human genes 0.000 description 1
- 108010033276 Peptide Fragments Proteins 0.000 description 1
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102100027467 Pro-opiomelanocortin Human genes 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 206010049771 Shock haemorrhagic Diseases 0.000 description 1
- 208000027520 Somatoform disease Diseases 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 description 1
- 208000010399 Wasting Syndrome Diseases 0.000 description 1
- 241000289690 Xenarthra Species 0.000 description 1
- 206010048232 Yawning Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- MMWCIQZXVOZEGG-HOZKJCLWSA-N [(1S,2R,3S,4S,5R,6S)-2,3,5-trihydroxy-4,6-diphosphonooxycyclohexyl] dihydrogen phosphate Chemical compound O[C@H]1[C@@H](O)[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H](O)[C@H]1OP(O)(O)=O MMWCIQZXVOZEGG-HOZKJCLWSA-N 0.000 description 1
- OEKMGABCSLYWOP-DHUJRADRSA-N [4-[(2s)-7-(2,2-dimethylpropanoyloxy)-4-methyl-2-[4-(2-piperidin-1-ylethoxy)phenyl]-2h-chromen-3-yl]phenyl] 2,2-dimethylpropanoate Chemical compound C1=CC([C@H]2C(=C(C3=CC=C(OC(=O)C(C)(C)C)C=C3O2)C)C=2C=CC(OC(=O)C(C)(C)C)=CC=2)=CC=C1OCCN1CCCCC1 OEKMGABCSLYWOP-DHUJRADRSA-N 0.000 description 1
- IUPVFHXEIGLEFF-UHFFFAOYSA-N [4-[2-(3-azabicyclo[2.2.1]heptan-3-yl)ethoxy]phenyl]-[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]methanone Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3C4CCC(C4)C3)=CC=2)C2=CC=C(O)C=C2S1 IUPVFHXEIGLEFF-UHFFFAOYSA-N 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- OMZAMQFQZMUNTP-UHFFFAOYSA-N acetic acid;1-[[4-[2-(azepan-1-yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methylindol-5-ol Chemical compound CC(O)=O.C=1C=C(OCCN2CCCCCC2)C=CC=1CN1C2=CC=C(O)C=C2C(C)=C1C1=CC=C(O)C=C1 OMZAMQFQZMUNTP-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- DUYNJNWVGIWJRI-LJAQVGFWSA-N acolbifene Chemical compound C1=CC([C@H]2C(=C(C3=CC=C(O)C=C3O2)C)C=2C=CC(O)=CC=2)=CC=C1OCCN1CCCCC1 DUYNJNWVGIWJRI-LJAQVGFWSA-N 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000005076 adamantyloxycarbonyl group Chemical group C12(CC3CC(CC(C1)C3)C2)OC(=O)* 0.000 description 1
- 239000002998 adhesive polymer Substances 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 102000004305 alpha Adrenergic Receptors Human genes 0.000 description 1
- 108090000861 alpha Adrenergic Receptors Proteins 0.000 description 1
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 1
- 235000008206 alpha-amino acids Nutrition 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 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
- 150000001408 amides Chemical class 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 229940043379 ammonium hydroxide Drugs 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N anhydrous trimethylamine Natural products CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 1
- 229960004046 apomorphine Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229960000817 bazedoxifene Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 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
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 230000004579 body weight change Effects 0.000 description 1
- 239000012888 bovine serum Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 description 1
- 229960001058 bupropion Drugs 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 230000001593 cAMP accumulation Effects 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000001311 chemical methods and process Methods 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
- 229940117229 cialis Drugs 0.000 description 1
- 230000005796 circulatory shock Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 238000007398 colorimetric assay Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229940108924 conjugated linoleic acid Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000020176 deacylation Effects 0.000 description 1
- 238000005947 deacylation reaction Methods 0.000 description 1
- 230000020335 dealkylation Effects 0.000 description 1
- 238000006900 dealkylation reaction Methods 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000001982 diacylglycerols Chemical class 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 230000019439 energy homeostasis Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 230000001856 erectile effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 229940031098 ethanolamine Drugs 0.000 description 1
- 235000010944 ethyl methyl cellulose Nutrition 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
- 239000010685 fatty oil Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000012921 fluorescence analysis Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 230000003370 grooming effect Effects 0.000 description 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 102000034345 heterotrimeric G proteins Human genes 0.000 description 1
- 108091006093 heterotrimeric G proteins Proteins 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 229950002248 idoxifene Drugs 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007915 intraurethral administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- GXESHMAMLJKROZ-IAPPQJPRSA-N lasofoxifene Chemical compound C1([C@@H]2[C@@H](C3=CC=C(C=C3CC2)O)C=2C=CC(OCCN3CCCC3)=CC=2)=CC=CC=C1 GXESHMAMLJKROZ-IAPPQJPRSA-N 0.000 description 1
- 229960002367 lasofoxifene Drugs 0.000 description 1
- 229940097443 levitra Drugs 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- LBSANEJBGMCTBH-UHFFFAOYSA-N manganate Chemical compound [O-][Mn]([O-])(=O)=O LBSANEJBGMCTBH-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000002752 melanocyte Anatomy 0.000 description 1
- 210000001259 mesencephalon Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 description 1
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
- 229920003087 methylethyl cellulose Polymers 0.000 description 1
- 229940102838 methylmethacrylate Drugs 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 239000002077 nanosphere Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 150000007523 nucleic acids Chemical group 0.000 description 1
- URPYMXQQVHTUDU-OFGSCBOVSA-N nucleopeptide y Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 URPYMXQQVHTUDU-OFGSCBOVSA-N 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- XZEUAXYWNKYKPL-URLMMPGGSA-N ormeloxifene Chemical compound C1([C@@H]2[C@H](C3=CC=C(C=C3OC2(C)C)OC)C=2C=CC(OCCN3CCCC3)=CC=2)=CC=CC=C1 XZEUAXYWNKYKPL-URLMMPGGSA-N 0.000 description 1
- 229960003327 ormeloxifene Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 1
- 229960001723 oxytocin Drugs 0.000 description 1
- 208000027753 pain disease Diseases 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000004466 pelleted feed Substances 0.000 description 1
- 210000003899 penis Anatomy 0.000 description 1
- 108010011903 peptide receptors Proteins 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008014 pharmaceutical binder Substances 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 208000024335 physical disease Diseases 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 206010036596 premature ejaculation Diseases 0.000 description 1
- 239000000955 prescription drug Substances 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
- 229960004919 procaine Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000033300 receptor internalization Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000003571 reporter gene assay Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 208000001076 sarcopenia Diseases 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000035946 sexual desire Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229960003310 sildenafil Drugs 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
- FIWQZURFGYXCEO-UHFFFAOYSA-M sodium;decanoate Chemical compound [Na+].CCCCCCCCCC([O-])=O FIWQZURFGYXCEO-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 210000003670 sublingual gland Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229960000835 tadalafil Drugs 0.000 description 1
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 description 1
- WOXKDUGGOYFFRN-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 WOXKDUGGOYFFRN-IIBYNOLFSA-N 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 238000011191 terminal modification Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical group OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 210000001578 tight junction Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229940094720 viagra Drugs 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
- C07K14/68—Melanocyte-stimulating hormone [MSH]
- C07K14/685—Alpha-melanotropin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/02—Peptides of undefined number of amino acids; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/50—Cyclic peptides containing at least one abnormal peptide link
- C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
- C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
Description
本出願は、2008年6月9日に提出された米国仮特許出願第61/059,910号、タイトル「性的不能の治療用のメラノコルチンレセプタ特異的ペプチド」を提出したことによる優先権及び利益を主張する。その明細書及びクレームはここで言及することによって組み込まれている。
以下の記載は、多数の刊行物を著者及び公表年よって引用しており、公表日が最近であるため、特定の刊行物は、本発明に対する先行技術と考えられない。本書におけるそのような刊行物の検討は、より完全な背景を示すためのものであり、そのような刊行物が特許性判断の目的における先行技術と認めるものとして解釈されてはならない。
(ここで、前記Rが−C(=O)−OH又は−C(=O)−NH2であり、前記xが1又は2であり、前記yが3又は4である)環状ペプチド又はその薬学的に許容可能な塩に関する。
Ac−Arg−シクロ(Asp−Dab−D−Phe−Arg−Trp−Lys)−NH2(配列番号:4)
Ac−Arg−シクロ(Asp−Dab−D−Phe−Arg−Trp−Lys)−OH(配列番号:5)
Ac−Arg−シクロ(Glu−Dab−D−Phe−Arg−Trp−Orn)−NH2(配列番号:6)、又は、
Ac−Arg−シクロ(Glu−Dab−D−Phe−Arg−Trp−Orn)−OH(配列番号:7)であってもよい。
1.0 定義
本発明の説明に移る前に本明細書に記載されている用語を定義する。
「リガンド」は、放射性リガンドの濃度であり、KDは、放射性リガンドによる50%のレセプタ占有を生じさせる放射性リガンドに対するレセプタ親和性の逆の指標である。別段の定めがない限り、Ki決定に関係する濃度は、nMである。Kiを、特異的レセプタ(例えば、MC1−R、MC3−R、MC4−R又はMC5−R)及び特異的リガンド(例えば、α−MSH又はNDP−α−MSH)に換算して表してもよい。
本明細書に開示されている組成物及び方法は、医療用途及び畜産又は獣医学的用途の両方に用いることができる。通常、この方法は、ヒトに用いられるが、その他の哺乳動物に用いられてもよい。「患者」という用語は、哺乳類の個体を意味するように意図されており、明細書及び請求項の全体にわたってそのように用いられている。本発明の主たる用途はヒト患者を含むが、本発明は、研究所、農場、動物園、野生生物、ペット、競技用又はその他の動物にも適用可能である。
本発明のペプチド、組成物及び方法は、1つ以上の他の薬学活性化合物と組み合わせた投与によって、前述の疾病、兆候、病状若しくは症候群のいずれか、又は、メラノコルチンレセプタによって媒介される任意の疾病、兆候、病状若しくは症候群の治療に用いることができる。そのような組合せ投与は、本発明のペプチド及び1つ以上の他の薬学活性化合物の両方を含む単一投薬形態によるものであってもよい。そのような単一投薬形態には、錠剤、カプセル、スプレイ、吸入粉末、注射可能液体などが含まれる。代替的に、組合せ投与は、1つの投薬形態が本発明のペプチドを含み、他方の投薬形態が別の薬学活性化合物を含む、2つの異なる投薬形態の投与によるものであってもよい。この例において、投薬形態は、同一であってもよいし、異なっていてもよい。併用療法を限定する意味ではなく、以下に使用可能な併用療法を例示する。
本発明の環状ペプチドを性的不能の治療用の他の医薬品又は薬剤と組み合わせて用いることは、可能であり、意図されている。これらの他の医薬品及び薬剤には、ホスホジエステラーゼ−5(PDE−5)阻害剤、テストステロン、及び、プロスタグランジンなどを含む勃起活動を促進する薬剤が含まれ得る。本発明の好ましい実施形態において、本発明の環状ペプチドは、サイクリックGMP特異的ホスホジエステラーゼ阻害薬又はα−アドレナリン作動性受容体アンタゴニストの治療的有効量と組み合わせて用いられる。米国特許第7,235,625号、タイトル「Multiple Agent Therapy for Sexual Dysfunction」の教示及び開示は、ここで言及することによってその全体が組み込まれている。
投与及び使用の方法は、本発明の特定のペプチドの特性、治療する疾病、兆候、病状又は症候群、及び、当業者に公知のその他の要因に応じて変わる。通常、当業界で公知の、又は、将来的に開発される投与及び使用のあらゆる方法を、本発明のペプチドと共に使用することができる。上述のものを限定するものではないが、下記の投与及び使用の方法は、示されている適応症への特定の用途を有している。
一般に、本発明のペプチドを、固相合成によって合成し、当業界で公知の方法によって精製することができる。様々な樹脂及び試薬を用いた数多くの周知のあらゆる工程を用いて、本発明のペプチドを調製することができる。
本発明の環状ペプチドの1つ以上を含む組成物の製剤形態は、所望の投与経路に応じて変わってもよい。したがって、製剤形態は、皮下注射、静脈注射、局所適用、眼内適用、鼻内噴霧用途、吸入適用、及び、他の経皮的適用に適したものであってもよい。
本発明の環状ペプチドは、薬学的に許容可能な任意の塩の形態であってもよい。「薬学的に許容可能な塩」という用語は、無機若しくは有機の塩基及び無機若しくは有機の酸を含む、薬学的に許容可能な非毒性の塩基又は酸から調製された塩を表す。無機塩基に由来する塩には、アルミニウム、アンモニウム、カルシウム、銅、第二鉄、第一鉄、リチウム、マグネシウム、マンガン酸塩、亜マンガン酸、カリウム、ナトリウム、亜鉛などが含まれる。特に、アンモニウム塩、カルシウム塩、リチウム塩、マグネシウム塩、カリウム塩及びナトリウム塩が好ましい。薬学的に許容可能な非毒性の有機塩基に由来する塩には、アルギニン、ベタイン、カフェイン、コリン、N,N’−ジベンジルエチレンジアミン、ジエチルアミン、2−ジエチルアミノエタノール、2−ジメチルアミノエタノール、エタノールアミン、エチレンジアミン、N−エチル−モルホリン、N−エチルピペリジン、グルカミン、グルコサミン、ヒスチジン、ヒドラバミン、イソプロピルアミン、リジン、メチルグルカミン、モルホリン、ピペラジン、ピペリジン、ポリアミン樹脂、プロカイン、プリン、テオブロミン、トリエチルアミン、トリメチルアミン、トリプロピルアミン、及び、トロメタミンなどの、第一級アミン、第二級アミン及び第三級アミン、自然発生の置換されたアミンを含む置換されたアミン、環状アミン、並びに、塩基性イオン交換樹脂が含まれる。
本発明は、本発明の環状ペプチド及び薬学的に許容可能な担体を含む医薬品組成物を提供する。この担体は、液体製剤であってもよく、好ましくは、緩衝された等張水性溶液である。以下に説明するように、薬学的に許容可能な担体は、希釈剤及び担体などの賦形剤、並びに、安定化剤、保存剤、可溶化剤、及び、バッファなどの添加剤も含む。
一態様においては、本発明の環状ペプチドが経口送達用に調剤される。ペプチドは、好ましくは、腸溶性保護剤に覆われるように、より好ましくは、錠剤又はカプセルが胃を通過するまで、選択的にはさらに小腸の一部を通過するまで、放出されないように調剤及び作成される。本出願の文脈において、腸溶性のコーティング又は成分という用語は、実質的に損傷を受けずに胃を通過するが、小腸で急速に分解して活性な薬剤物質を放出するコーティング又は材料を意味することは理解されるであろう。使用可能な腸溶性コーティング溶液の1つは、酢酸フタル酸セルロースと、選択的に、水酸化アンモニウム、トリアセチン、エチルアルコール、メチレンブルー及び精製水などの他の成分とを含む。酢酸フタル酸セルロースは、錠剤及びカプセル剤などの個々の投薬形態を腸溶的にコーティングするための医薬品工業において用いられており、約5.8未満のpHにおいて水に溶解しないポリマーである。酢酸フタル酸セルロースを含む腸溶性コーティングは、胃の酸性環境から保護するが、十二指腸の環境(pH約6乃至6.5)において溶解し始め、投薬形態が回腸(pH約7乃至8)に達する時までに完全に溶解する。酢酸フタル酸セルロースに加えて、限定されるものではないが、ヒドロキシプロピルメチルエチルセルローススクシナート、ヒドロキシプロピルメチルセルロースフタレート、ポリ酢酸ビニルフタレート及びメタクリル酸メタクリル酸メチル共重合体を含む他の腸溶性コーティング材料が、公知であり、本発明のペプチドと共に使用可能である。使用される腸溶性コーティングは、主として胃の外側の部位で投薬形態の溶解を促進し、少なくとも6.0のpHにおいて、より好ましくは約6.0乃至約8.0のpHにおいて腸溶性コーティングが溶解するように選択されてもよい。好ましい一態様においては、腸溶性コーティングが回腸の付近において溶解及び分解する。
本発明の環状ペプチドの1つ以上を含む組成物が注射によって投与される場合、注射は、静脈内、皮下、筋肉内、腹腔内、又は、当業界で公知のその他の手段であってもよい。本発明のペプチドは、限定されるものではないが、錠剤、カプセル剤、カプレット、懸濁液、粉末、凍結乾燥された調製、坐薬、視覚の滴剤、皮膚貼付剤、経口可溶性製剤、スプレイ、及び、エアゾール剤などの製剤を含む、当業界において公知のあらゆる手段によって調剤されてもよく、また、バッファ、バインダ、賦形剤、安定化剤、酸化防止剤、及び、当業界において公知の他の薬剤と混ぜて製剤されてもよい。一般に、本発明のペプチドが細胞の表皮層を超えて取り入まれる任意の投与経路を使用することもできる。したがって、投与は、粘膜、口腔投与、経口投与、経皮投与、吸入投与、鼻腔投与、尿道内投与、膣内投与、直腸内投与などの投与を意味し、これらを含んでいてもよい。
一般に、患者に投与される本発明の環状ペプチドの実際の量は、投与の態様、使用する製剤、及び、所望の反応に応じてかなり広範囲で変わるだろう。治療のための投薬量は、所望の治療効果を生じさせるのに充分な量の、前述の手段又は当業界において公知のその他の任意の手段による投与である。したがって、治療的有効量は、患者において性的不能を治療的に緩和するか、又は、性的不能の発病若しくは再発を防止若しくは遅延させるのに充分な本発明のペプチド又は医薬品組成物の量を含む。一般に、本発明の環状ペプチドは、高度に活性である。例えば、環状ペプチドは、選択した特定のペプチド、所望の治療効果、投与経路、製剤形態、及び、当業者に公知のその他の要因に応じて、体重1kg当たりおよそ、0.1、0.5、1、5、50、100、500又は5000μg/kgで投与することができる。
結合、機能的状態及び有効性を決定するための様々な分析系及び動物モデルによって、本発明のメラノコルチンレセプタ特異的環状ペプチドを試験することができる。
組換えのhMC4−R、hMC3−R又はhMC5−Rを発現するHEK−293細胞から、及び、B−16マウスメラノーマ細胞(内因性のMC1−Rを含む)から調製された細胞膜破砕物を用いて競合的阻害結合アッセイを行う。いくつかの事例においては、組換えhMC1−Rを発現するHEK−293細胞を用いた。その後の実施例において、すべてのMC3−R、MC4−R及びMC5−R値は、ヒト組換え型レセプタに対するものである。値がヒト組み換えMC1−Rに対するものである先頭が「hMC1−R」でなければ、MC1−R値は、B−16マウスメラノーマ細胞に対するものである。分析は、0.5%のウシ血清アルブミン(画分V)であらかじめコーティングした96ウェルのGF/B Milliporeマルチスクリーンフィルタプレート(MAFB NOB10)中で実行された。膜破砕物を、0.2nM(hMC4−Rに対して)、0.4nM(MC3−R及びMC5−Rに対して)、又は、0.1nM(マウスB16のMC1−R又はhMC1−Rに対して)の[I125]NDP−α−MSH(Perkin Elmer)と、100mMのNaCl、2mMのCaCl2、2mMのMgCl2、0.3mMの1,10−フェナントロリン及び0.2%のウシ血清アルブミンと共に25mMのHEPESバッファ(pH7.5)を含むバッファ中の漸増する濃度の本発明の環状ペプチドと共に培養した。37℃での60分間のインキューベーションの後に、分析混合物をろ過し、氷冷したバッファで膜を3回洗浄した。フィルタを乾燥し、γ計数器で結合した放射能についてカウントした。非特異的結合は、1μMのNDP−α−MSHの存在下において、[I125]−NDP−α−MSHの結合の阻害によって測定した。最大の特異的結合(100%)を、1μMのNDP−α−MSHの非存在下及び存在下で細胞膜に結合した放射能(cpm)における差異として定義した。[I125]−NDP−α−MSH結合のパーセント阻害を決定するために、試験化合物の存在下で得られた放射能(サイクル毎分)を、100%の特異的結合に対して標準化した。各分析を3回反復して実施し、0%未満の結果を0%として報告するように、実際の平均値が記載されている。本発明の環状ペプチドに対するKi値は、グラフパッドプリズム(登録商標)曲線適合ソフトウェアを用いて決定した。hMC3−Rで行ったのと同様に、[I125]−NDP−α−MSHを用いてhMC1−R及びhMC4−Rに対する結合についてのデータをここにおいて報告する。
代替的に、競合的阻害結合分析は、ランタニドキレート化合物の時間分解蛍光測定(TRF)による決定によって、Eu−NDP−α−MSH(PerkinElmer Life SciencesカタログNo.AD0225)を使用して実行された。[I125]−NDP−α−MSHを用いた比較研究において、パーセント阻害及びKiについては、実験誤差範囲内の同じ値が得られた。一般に、Ki値を決定するための競合試験は、組換え型のhMC4−Rを発現するHEK−293細胞から調製した細胞膜破砕物を、9つの異なる濃度の本発明の環状ペプチドと、並びに、100mMのNaCl、2mMのCaCl2、2mMのMgCl2、0.1%のBSA、及び、0.3mMの1,10−フェナントロリンと共に25mMのHEPESバッファを含む溶液中の1nMのEu−NDP−α−MSHと共にインキュベートすることによって実行した。37℃での90分間のインキューベーションの後に、この反応を、AcroWell96ウェルフィルタプレート(Pall Life Sciences)による濾過によって停止させた。このフィルタプレートを、氷冷した200μlのリン酸塩緩衝食塩水で4回洗浄した。DELFIA Enhancement溶液(PerkinElmer Life Sciences)を各ウェルに加えた。このプレートを撹拌器において15分間培養し、340nmの励起及び615nmの放射波長において読み取った。各分析を2回反復して実施して平均値を用いた。Ki値は、一部位固定の勾配競合結合モデルを用いて、グラフパッドプリズム(登録商標)ソフトウェアを用いた曲線適合によって決定した。hMC5−Rに対する結合についてのデータ及びEu−NDP−α−MSHを用いたhMC3−R及びhMC4−Rでのデータをここに報告する。
hMC4−Rを発現する細胞から分離した細胞膜破砕物を用いて、[I125]−AgRP(83−132)を用いた競合的結合試験を実行する。この分析は、0.5%のウシ血清アルブミン(画分V)で予めコーティングされた、96ウェルのGF/B Milliporeマルチスクリーンフィルタプレート(MAFB NOB10)中で実行した。分析用混合物は、全容積200μL中に、100mMのNaCl、2mMのCaCl2、2mMのMgCl2、0.3mMの1,10−フェナントロリン、0.5%のウシ血清アルブミン、膜破砕物、25mMのHEPESバッファ(pH7.5)、放射性リガンド[I125]−AgRP(83−132)(Perkin Elmer)と共に、漸増する濃度の本発明のペプチドを含んでいた。0.2nMの放射性リガンド濃度において結合を測定した。37℃で1時間インキュベートした後に、その反応混合物をろ過し、500mMのNaClを含む分析バッファで洗浄した。乾燥したティスクをそのプレートから打ち抜いて、γ計数器でカウントした。放射性リガンドの全結合は、反応混合物に加えた数の10%を超えなかった。本発明の環状ペプチドに対するKi値は、グラフパッドプリズム(登録商標)曲線適合ソフトウェアを用いて決定した。
MC4−Rを発現するHEK−293細胞内において本発明の環状ペプチドが機能的反応を誘導する能力を指標として、細胞内のcAMPの蓄積を調べた。組換え型のhMC4−Rを発現するコンフルエントのHEK−293細胞を、酵素を含まない細胞解離バッファ中のインキューベーションによって培養皿から分離した。分散した細胞を、10mMのHEPES(pH7.5)、1mMのMgCl2、1mMのグルタミン、0.5%のアルブミン、及び、0.3mMの3−イソブチル−1−メチルキサンチン(IBMX)(ホスホジエステラーゼ阻害薬)を含むEarle’s Balanced Salt Solutionに懸濁させた。この細胞を1ウェル当たり0.5×105個の細胞密度で96ウェルプレートに被覆し、30分間予備培養した。細胞を37℃で1時間供することによって、200μLの全分析容積でDMSO(最終濃度1%のDMSO)中に0.05〜5000nMの濃度範囲で溶解させた本発明の試験環状ペプチドを試験した。NDP−α−MSHを対照アゴニストとして用いた。インキュベーションの終了時に、細胞を、50μLの溶解バッファ(cAMP EIAキット、Amersham)の添加、及び、その後の激しいピペット操作によって分断した。cAMP EIAキット(Amersham)を用いて溶解産物中のcAMPのレベルを決定した。グラフパッドプリズム(登録商標)ソフトウェアを用いた非線形回帰分析によってデータ解析を実行した。本発明の環状ペプチドの最大の効力を、対照メラノコルチンアゴニストNDP−αMSHによって達成された有効性と比較した。
静脈内(IV)又は皮下の注射経路によって投与した選択されたペプチドについて、飼料摂取量及び体重における変化を評価する。Hilltop Lab Animals社(スコッツデール、ペンシルベニア)又は他の供給業者からオスのスプラーグドーリーラットを入手する。動物を、慣用ポリスチレンハンギングケージにそれぞれ収容し、管理された12時間のオン/オフ光サイクル中で保持する。水及びペレット化した飼料を無制限に与える。ラットに、溶媒若しくは選択したペプチド(0.3〜1.0mg/kg)を静脈投薬し、又は、溶媒若しくは選択したペプチド(最大30mg/kg)を皮下投与する。投薬後の24時間の期間の体重及び飼料摂取量における変化を測定する。投薬後の48時間及び72時間の期間の体重及び飼料摂取量における変化を測定することによって、体重及び飼料摂取量効果の変化がベースラインレベルまで戻るのを測定する。
選択したペプチドを用いて、本発明のペプチドがオスラットにおいてペニス勃起(PE)を誘導する能力を評価する。体重250g〜300gのオスのスプラーグドーリーラットを、飼料及び水を無制限に与えながら12時間のオン/オフ光サイクル中で保持する。すべての行動研究を午前9時から午後4時の間に行い、6乃至8頭のラットのグループに、静脈経路から様々な量のペプチドを投与する。治療直後に、ラットを、通常は遠隔ビデオモニタリングによる行動観察用のポリスチレンケージ(長さ27cm、幅16cm及び高さ25cm)にそれぞれ収容する。ラットを1時間観察し、あくびの回数、毛づくろい、及び、PEを10分範囲で記録する。
式(I)に包含される環状ペプチドは、立体中心及び立体軸などの1つ以上の不斉元素を含んでおり、その結果、式(I)に包含されるペプチドは、様々な体アイソマーで存在することができる。式(I)に包含されるペプチドを含む具体的に及び一般的に記載されたペプチドについて、エナンチオマー及びジアステレオマーを含むすべてのキラル又は他のアイソマー中心におけるすべてのアイソマーが本発明に包含されるように意図されている。本発明のペプチドは、それぞれ複数の不斉中心を含んでおり、ラセミ混合物として使用されてもよいし、又は、エナンチオピュアな調製における本発明のペプチドの使用に加えて、鏡像異性的に濃縮された混合物として使用されてもよい。一般に、本発明のペプチドは、鏡像異的純度が維持される一方で、ラセミ混合物を作ることが可能になり、また、意図されるような試剤、条件及び方法を用いて、特定のL型又はD型アミノ酸などのキラル的に純粋な試剤を用いて合成される。そのようなラセミ混合物を、選択的に周知技術を用いて分離することができ、個々のエナンチオマーを単独で使用することもできる。ペプチドが互変アイソマーとして存在し得る、温度、溶媒及びpHの特定条件の下及び場合において、各互変異体は、平衡状態又は一形態が優勢な状態で存在していても、本発明に包含されるものとして意図されている。したがって、式(I)のペプチドの単一のエナンチオマーであって、光学活性体であるものは、不斉合成、光学的に純粋な前駆物質からの合成、又は、ラセミ化合物の分解によって得ることができる。
このペプチドは、アミノ酸配列Ac−Arg−シクロ(Asp−Dab−D−Phe−Arg−Trp−Lys)−NH2を有している。実施例8.1の環状ペプチドは、酢酸(AcOH)及びトリフルオロ酢酸(TFA)塩形態として調製された。実施例8.1の環状ペプチドは、分子式C48H71N17O9を有しており、計算上1030.19の分子量を有する。実施例8.1の環状ペプチドの分子量は、酢酸塩形態としては1210.34であり、TFA塩形態としては1372.25であった。
このペプチドは、アミノ酸配列Ac−Arg−シクロ(Asp−Dab−D−Phe−Arg−Trp−Lys)−OHを有していた。実施例8.2の環状ペプチドは、TFA塩形態として調製された。実施例8.2の環状ペプチドは、分子式C48H70N16O10を有しており、計算上1031.17の分子量を有する。TFA塩形態の実施例8.2の環状ペプチドの分子量は、1373.23であった。
このペプチドは、アミノ酸配列Ac−Arg−シクロ(Glu−Dab−D−Phe−Arg−Trp−Orn)−NH2を有する。実施例8.3の環状ペプチドは、TFA塩形態として調製された。実施例8.3の環状ペプチドは、分子式C48H71N17O9を有しており、計算上1030.19の分子量を有する。TFA塩形態の実施例8.3の環状ペプチドの分子量は、1372.25であった。
このペプチドは、アミノ酸配列Ac−Arg−シクロ(Glu−Dab−D−Phe−Arg−Trp−Orn)−OHを有する。実施例8.4の環状ペプチドは、酢酸及びTFAの塩形態として調製された。実施例8.4の環状ペプチドは、分子式C48H70N16O10を有しており、計算上1031.17の分子量を有する。酢酸塩形態の実施例8.4の環状ペプチドの分子量は1211.32であり、TFA塩形態は1373.23であった。
Claims (18)
- Ac−Arg−シクロ(Asp−Dab−D−Phe−Arg−Trp−Lys)−NH2(配列番号:4)で表されることを特徴とする請求項1に記載の環状ペプチド。
- Ac−Arg−シクロ(Asp−Dab−D−Phe−Arg−Trp−Lys)−OH(配列番号:5)で表されることを特徴とする請求項1に記載の環状ペプチド。
- Ac−Arg−シクロ(Glu−Dab−D−Phe−Arg−Trp−Orn)−NH2(配列番号:6)で表されることを特徴とする請求項1に記載の環状ペプチド。
- Ac−Arg−シクロ(Glu−Dab−D−Phe−Arg−Trp−Orn)−OH(配列番号:7)で表されることを特徴とする請求項1に記載の環状ペプチド。
- 請求項1に記載の環状ペプチド又はその薬学的に許容可能な塩と、薬学的に許容可能な担体とを具えることを特徴とする医薬品組成物。
- ヒト又は非ヒトの哺乳動物においてメラノコルチンレセプタによって媒介される疾病、兆候、病状、又は、症候群を治療する方法において、請求項7に記載の医薬品組成物を投与するステップを具えることを特徴とする方法。
- ヒト又は非ヒト哺乳動物においてメラノコルチンレセプタ機能の変化に対して反応する病状を治療する方法において、請求項7に記載の医薬品組成物を投与するステップを具えることを特徴とする方法。
- 前記病状が性的不能であることを特徴とする請求項9に記載の方法。
- 前記性的不能がオスの勃起不全であることを特徴とする請求項10に記載の方法。
- 前記性的不能がメスの性的不全であることを特徴とする請求項10に記載の方法。
- 前記投与するステップが、経口、非経口、尿道、膣、直腸、鼻、口腔、又は、舌下において投与するステップを具えることを特徴とする請求項9に記載の方法。
- 第2の性的不能用医薬品を投与するステップをさらに具えることを特徴とする請求項9に記載の方法。
- 請求項1に記載の環状ペプチド又はその薬学的に許容可能な塩と、第2の性的不能用医薬品とを具えることを特徴とする医薬品組成物。
- 医薬品として使用するのためのものであることを特徴とする請求項1乃至6のいずれか1項に記載のペプチド。
- MC4レセプタの活性化に反応する疾病、疾患及び/又は病状の治療に使用するためのものであることを特徴とする請求項1乃至6のいずれか1項に記載のペプチド。
- オスの勃起不全及びメスの性的不全を含む性的不能に使用するためのものであることを特徴とする請求項1乃至6のいずれか1項に記載のペプチド。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US5991008P | 2008-06-09 | 2008-06-09 | |
US61/059,910 | 2008-06-09 | ||
PCT/US2009/046571 WO2009152079A1 (en) | 2008-06-09 | 2009-06-08 | Melanocortin receptor-specific peptides for treatment of sexual dysfunction |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2011522839A true JP2011522839A (ja) | 2011-08-04 |
JP2011522839A5 JP2011522839A5 (ja) | 2012-06-07 |
JP5628796B2 JP5628796B2 (ja) | 2014-11-19 |
Family
ID=41417081
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2011512730A Expired - Fee Related JP5628796B2 (ja) | 2008-06-09 | 2009-06-08 | 性的不能の治療用のメラノコルチンレセプタ特異的ペプチド |
Country Status (14)
Country | Link |
---|---|
US (2) | US8487073B2 (ja) |
EP (1) | EP2300036B1 (ja) |
JP (1) | JP5628796B2 (ja) |
KR (1) | KR101687037B1 (ja) |
CN (1) | CN102131514B (ja) |
AU (1) | AU2009257631B2 (ja) |
BR (1) | BRPI0909947A2 (ja) |
CA (1) | CA2727317C (ja) |
EA (1) | EA018630B1 (ja) |
IL (1) | IL209867A (ja) |
MX (1) | MX2010013436A (ja) |
NZ (1) | NZ590254A (ja) |
WO (1) | WO2009152079A1 (ja) |
ZA (1) | ZA201009165B (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2019531329A (ja) * | 2016-10-24 | 2019-10-31 | アイビックス・リミテッドIvixltd. | 女性の性機能障害を治療する医薬組成物および方法 |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ590254A (en) | 2008-06-09 | 2012-07-27 | Palatin Technologies Inc | Melanocortin receptor-specific cyclic peptides for treatment of sexual dysfunction |
EP2440572B1 (en) * | 2009-06-08 | 2017-04-05 | Palatin Technologies, Inc. | Lactam-bridged melanocortin receptor-specific peptides |
WO2010144344A2 (en) | 2009-06-08 | 2010-12-16 | Palatin Technologies, Inc. | Melanocortin receptor-specific peptides |
UY32690A (es) * | 2009-06-08 | 2011-01-31 | Astrazeneca Ab | Péptidos específicos para receptores de melanocortina |
JP2013511554A (ja) | 2009-11-23 | 2013-04-04 | パラティン テクノロジーズ,インコーポレイテッド | メラノコルチン−1受容体特異的線状ペプチド |
WO2011063366A1 (en) | 2009-11-23 | 2011-05-26 | Palatin Technologies, Inc. | Melanocortin-1 receptor-specific cyclic peptides |
DK3539551T3 (da) | 2011-12-29 | 2021-11-01 | Rhythm Pharmaceuticals Inc | Fremgangsmåde til behandling af melanocortin-4 receptor-associerede forstyrrelser i heterozygotiske bærere |
CN102702330B (zh) * | 2012-03-01 | 2015-04-01 | 张嘎 | 环状核心序列与生物素或穿膜肽相连而成的促黑激素类似物 |
WO2013138340A1 (en) * | 2012-03-13 | 2013-09-19 | Tensive Controls Inc. | Melanocortin analogs having enhanced activity and transport |
WO2014071339A2 (en) | 2012-11-05 | 2014-05-08 | Palatin Technologies, Inc. | Uses of bremelanotide in therapy for female sexual dysfunction |
WO2016168388A2 (en) | 2015-04-14 | 2016-10-20 | Palatin Technologies, Inc. | Therapies for obesity, diabetes and related indications |
AU2016330772A1 (en) | 2015-09-30 | 2018-04-19 | Rhythm Pharmaceuticals, Inc. | Method of treating melanocortin-4 receptor pathway-associated disorders |
AU2019249255A1 (en) | 2018-04-06 | 2020-11-05 | Alastair GARFIELD | Compositions for treating kidney disease |
CN115279390A (zh) * | 2020-02-03 | 2022-11-01 | 帕拉丁科技公司 | 反向酰胺连接的促黑素受体特异性环状肽 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006527773A (ja) * | 2003-06-19 | 2006-12-07 | イーライ リリー アンド カンパニー | メラノコルチン受容体4(mc4)作用薬とその用途 |
JP2007532471A (ja) * | 2003-09-30 | 2007-11-15 | ノボ ノルディスク アクティーゼルスカブ | 新規メラノコルチンレセプターアゴニスト |
Family Cites Families (85)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5674839A (en) * | 1987-05-22 | 1997-10-07 | Competitive Technologies, Inc. | Cyclic analogs of alpha-MSH fragments |
DE3851002T2 (de) | 1987-05-22 | 1995-02-02 | University Patents Inc | Lineare und zyklische Analoge von alpha-MSH-Fragmenten mit ausserordentlicher Wirkung. |
US5192746A (en) | 1990-07-09 | 1993-03-09 | Tanabe Seiyaku Co., Ltd. | Cyclic cell adhesion modulation compounds |
US6100048A (en) * | 1992-04-10 | 2000-08-08 | Oregon Health Sciences University | Methods and reagents for discovering and using mammalian melanocortin receptor agonists and antagonists to modulate feeding behavior in animals |
DE69429768T2 (de) | 1993-04-05 | 2002-09-19 | Competitive Tech Inc | Diagnose und behandlung von erektilen funktionsstörungen |
US5731408A (en) * | 1995-04-10 | 1998-03-24 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Peptides having potent antagonist and agonist bioactivities at melanocortin receptors |
US6054556A (en) * | 1995-04-10 | 2000-04-25 | The Arizona Board Of Regents On Behalf Of The University Of Arizona | Melanocortin receptor antagonists and agonists |
US7396814B2 (en) * | 1995-06-07 | 2008-07-08 | Palatin Technologies, Inc. | Metallopeptide compositions for treatment of sexual dysfunction |
CA2158425C (en) | 1995-09-15 | 2003-01-28 | Mac E. Hadley | Diagnostic and treatment of erectile dysfunction |
IL118003A0 (en) | 1996-04-23 | 1996-08-04 | Yeda Res & Dev | Novel vip fragments and pharmaceutical compositions comprising them |
CA2275442A1 (en) | 1996-12-17 | 1998-06-25 | Quadrant Holdings Cambridge Limited | Melanocortin derivatives for specific binding of melanocortin receptor 3, 4 or 5 |
US6350430B1 (en) * | 1997-10-27 | 2002-02-26 | Lion Bioscience Science Ag | Melanocortin receptor ligands and methods of using same |
US20020099003A1 (en) * | 1997-10-28 | 2002-07-25 | Wilson Leland F. | Treatment of female sexual dysfunction with vasoactive agents, particularly vasoactive intestinal polypeptide and agonists thereof |
GB9808229D0 (en) | 1998-04-17 | 1998-06-17 | Quadrant Holdings Cambridge | Melanocortin receptor ligands |
SE9801571D0 (sv) * | 1998-05-05 | 1998-05-05 | Wapharm Ab | Melanokortin-1-receptorselektiva föreningar |
SE9804614A0 (en) | 1998-07-06 | 2000-01-07 | A+ Science Invest Ab | New peptides and use thereof |
GB9816234D0 (en) | 1998-07-24 | 1998-09-23 | William Harvey Research Limite | Compounds for use in the treatment of inflammation |
GB9827500D0 (en) | 1998-12-14 | 1999-02-10 | Wapharm Ab | Compounds for control of eating, growth and body weight |
US6887846B2 (en) * | 1999-03-24 | 2005-05-03 | Zengen, Inc. | Antimicrobial amino acid sequences derived from alpha-melanocyte-stimulating hormone |
KR100558131B1 (ko) * | 1999-03-29 | 2006-03-10 | 더 프록터 앤드 갬블 캄파니 | 멜라노코르틴 수용체 리간드를 함유하는 약제학적 조성물및 멜라노코르틴 수용체 리간드를 함유하는 약제의제조방법 |
US7176279B2 (en) | 2000-06-28 | 2007-02-13 | Palatin Technologies, Inc. | Cyclic peptide compositions and methods for treatment of sexual dysfunction |
US6579968B1 (en) * | 1999-06-29 | 2003-06-17 | Palatin Technologies, Inc. | Compositions and methods for treatment of sexual dysfunction |
US7235625B2 (en) * | 1999-06-29 | 2007-06-26 | Palatin Technologies, Inc. | Multiple agent therapy for sexual dysfunction |
US6699873B1 (en) * | 1999-08-04 | 2004-03-02 | Millennium Pharmaceuticals, Inc. | Melanocortin-4 receptor binding compounds and methods of use thereof |
WO2001030808A1 (en) | 1999-10-27 | 2001-05-03 | The Regents Of The University Of California | Methods and compounds for modulating melanocortin receptor-ligand binding |
US20030064921A1 (en) * | 1999-10-27 | 2003-04-03 | The Regents Of The University Of California | Methods and compounds for modulating melanocortin receptor ligand binding and activity |
WO2001052880A1 (en) | 2000-01-18 | 2001-07-26 | Merck & Co., Inc. | Cyclic peptides as potent and selective melanocortin-4 receptor antagonists |
US6600015B2 (en) | 2000-04-04 | 2003-07-29 | Hoffmann-La Roche Inc. | Selective linear peptides with melanocortin-4 receptor (MC4-R) agonist activity |
WO2001085930A2 (en) | 2000-05-09 | 2001-11-15 | The Regents Of The University Of California | Methods and compounds for modulating melanocortin receptor ligand binding and activity |
GB0012370D0 (en) | 2000-05-22 | 2000-07-12 | Quadrant Holdings Cambridge | Peptoids |
EP1315750B1 (en) | 2000-08-30 | 2007-02-14 | F. Hoffmann-La Roche Ag | Cyclic peptides having melanocortin-4 receptor agonist activity |
NZ524190A (en) | 2000-09-27 | 2004-09-24 | Procter & Gamble | Melanocortin receptor ligands |
US20030113263A1 (en) * | 2001-02-13 | 2003-06-19 | Oregon Health And Sciences University, A Non-Profit Organization | Methods and reagents for using mammalian melanocortin receptor antagonists to treat cachexia |
ITMI20011057A1 (it) | 2001-05-22 | 2002-11-22 | Bracco Imaging Spa | Preparazione ed uso di peptidi ciclici e ramificati e loro deriati marcati come agenti terapeutici agonisti o antagonisti della colecistochi |
US7342089B2 (en) | 2001-07-11 | 2008-03-11 | Palatin Technologies, Inc. | Cyclic peptides for treatment for cachexia |
JP2004534851A (ja) * | 2001-07-11 | 2004-11-18 | パラチン テクノロジーズ インク. | メラノコルチン受容体に特異的な線状および環状ペプチド |
US7345144B2 (en) * | 2001-07-11 | 2008-03-18 | Palatin Technologies, Inc. | Cyclic peptides for treatment of cachexia |
US6960646B2 (en) | 2001-07-12 | 2005-11-01 | Merck & Co., Inc. | Cyclic peptides as potent and selective melanocortin-4 receptors agonists |
ES2274201T3 (es) * | 2002-01-23 | 2007-05-16 | Eli Lilly And Company | Agonistas del receptor de melanocortina. |
FR2835528B1 (fr) * | 2002-02-01 | 2004-03-12 | Inst Europ Biolog Cellulaire | Nouveaux derives peptidiques, leur preparation et leur application therapeutique et cosmetique |
US7034004B2 (en) | 2002-05-07 | 2006-04-25 | University Of Florida | Peptides and methods for the control of obesity |
AU2003248888A1 (en) | 2002-07-09 | 2004-01-23 | Palatin Technologies, Inc. | Peptide composition for treatment of sexual dysfunction |
US7135548B2 (en) * | 2002-11-14 | 2006-11-14 | Zengen, Inc. | Modified α-MSH peptides and derivatives thereof |
AU2003290886A1 (en) | 2002-11-14 | 2004-06-15 | Zengen, Inc. | Modified alpha-msh peptides and derivatives thereof |
US20050101535A1 (en) * | 2003-05-06 | 2005-05-12 | Rosenstein David H. | Use of a synthetic alpha-melanocyte stimulating hormone agonist to decrease steroid induced weight gain |
WO2004099246A2 (en) | 2003-05-09 | 2004-11-18 | Novo Nordisk A/S | Peptides for use in treating obesity |
KR20060026011A (ko) * | 2003-05-09 | 2006-03-22 | 노보 노르디스크 에이/에스 | 비만 치료용 펩티드 |
WO2005000338A1 (en) | 2003-06-19 | 2005-01-06 | Eli Lilly And Company | Uses of melanocortin-3 receptor (mc3r) agonist peptides |
US7084111B2 (en) | 2003-06-23 | 2006-08-01 | University Of Florida Research Foundation, Inc. | Melanocortin receptor templates, peptides, and use thereof |
US20070293423A1 (en) * | 2003-08-20 | 2007-12-20 | Eli Lilly And Company | Compounds, Methods and Formulations for the Oral Delivery of a Glucagon-Like Peptide (Glp)-1 Compound or a Melanocortin-4 Receptor (Mc4) Agonist Peptide |
DK1689349T3 (da) | 2003-11-24 | 2013-12-02 | Clinuvel Pharmaceuticals Ltd | Fremgangsmåde til induktion af melanogenese i mennesker med variante MC1R-alleler |
WO2005060985A1 (en) | 2003-12-10 | 2005-07-07 | Merck & Co., Inc. | Inhibition of voluntary ethanol consumption with selective melanocortin 4-receptor agonists |
CA2557739A1 (en) * | 2004-03-29 | 2005-11-03 | Eli Lilly And Company | Uses of melanocortin-4 receptor (mc4r) agonist peptides administered by continuous infusion |
CN1563076A (zh) | 2004-04-02 | 2005-01-12 | 西南生物工程产业化中试基地有限公司 | 一种用于治疗性功能障碍的α-MSH类似物及制备方法 |
WO2006012667A1 (en) | 2004-08-04 | 2006-02-09 | Clinuvel Pharmaceuticals Limited | Methods of inducing melanogenesis in a subject. |
TW200626611A (en) | 2004-09-20 | 2006-08-01 | Lonza Ag | Peptide cyclisation |
AU2005291862B2 (en) | 2004-10-08 | 2010-07-08 | Clinuvel Pharmaceuticals Limited | Compositions and methods for inducing melanogenesis in a subject |
CA2585287A1 (en) * | 2004-10-25 | 2006-05-04 | Centocor, Inc. | Melanocortin receptor binding mimetibodies, compositions, methods and uses |
WO2006048452A2 (en) | 2004-11-04 | 2006-05-11 | Novo Nordisk A/S | Peptides for use in treating of obesity |
JP2008519006A (ja) * | 2004-11-04 | 2008-06-05 | ノボ ノルディスク アクティーゼルスカブ | 肥満症の治療に使用するためのペプチド |
EP1809666A2 (en) | 2004-11-04 | 2007-07-25 | Novo Nordisk A/S | Peptides for use in the treating obesity |
US20080306008A1 (en) | 2004-11-04 | 2008-12-11 | Nova Nordisk A/S | Peptides for Use in the Treatment of Obesity |
WO2006060873A1 (en) | 2004-12-09 | 2006-06-15 | Prince Henry's Institute Of Medical Research | Method for restoring reproductive function |
WO2006073771A2 (en) | 2005-01-05 | 2006-07-13 | Eli Lilly And Company | Polyethylene glycol linked mc4r or mc3r agonist peptides |
WO2006076442A2 (en) | 2005-01-14 | 2006-07-20 | Janssen Pharmaceutica N.V. | Triazolopyrimidine derivatives |
US20080207493A1 (en) | 2005-03-17 | 2008-08-28 | Novo Nordisk A/S | Compounds for Use in the Treatment of Obesity |
KR20080027246A (ko) | 2005-05-31 | 2008-03-26 | 이섬 리서치 디벨러프먼트 컴파니 오브 더 히브루 유니버시티 오브 예루살렘 | 기본구조에 고리가 형성된 멜라노코르틴 자극 호르몬유사체 |
KR20080041639A (ko) | 2005-07-08 | 2008-05-13 | 소시에떼 더 콘세이유 더 레세르세 에 다플리까띠옹 시엔띠피끄, 에스.아.에스. | 멜라노코르틴 수용체의 리간드 |
CA3228910A1 (en) | 2005-07-08 | 2007-01-18 | Ipsen Pharma S.A.S | Melanocortin receptor ligands |
CN1709906A (zh) | 2005-07-15 | 2005-12-21 | 中国科学技术大学 | α-促黑激素的环状类似肽及其应用 |
MX2007016024A (es) | 2005-07-18 | 2008-03-10 | Novo Nordisk As | Peptidos novedosos para el uso en el tratamiento contra la obesidad. |
US20080227693A1 (en) | 2005-08-29 | 2008-09-18 | Palatin Technologies, Inc. | Cyclic Peptide Isolation by Spray Drying |
WO2007035474A2 (en) | 2005-09-15 | 2007-03-29 | Novomed Technologies, Inc. (Shanghai) | Transdermal delivery peptides and method of use thereof |
EP2091914A4 (en) | 2006-11-08 | 2010-12-29 | Chongxi Yu | TRANSDERMAL ADMINISTRATION SYSTEMS FOR PEPTIDES AND RELATED CONNECTIONS |
EP2104684A1 (en) | 2007-01-18 | 2009-09-30 | Novo Nordisk A/S | Peptides for use in the treatment of obesity |
JP2010516652A (ja) | 2007-01-18 | 2010-05-20 | ノボ・ノルデイスク・エー/エス | 肥満の治療に使用される新規ペプチド |
EP2106407A2 (en) | 2007-01-18 | 2009-10-07 | Novo Nordisk A/S | Novel peptides for use in the treatment of obesity |
US20100022446A1 (en) | 2007-01-18 | 2010-01-28 | Novo Nordisk A/S | Use of Peptides in Combination with Surgical Intervention for the Treatment of Obesity |
US20100056433A1 (en) | 2007-01-18 | 2010-03-04 | Novo Nordisk A/S | Novel Peptides for Use in the Treatment of Obesity |
FR2914646A1 (fr) | 2007-04-04 | 2008-10-10 | Neorphys Soc Par Actions Simpl | Analogues peptidiques des recepteurs des melanocortines |
EP2167112A4 (en) | 2007-06-15 | 2012-01-25 | Ipsen Pharma Sas | CYCLIC PEPTIDE MELANOCORTIN RECEPTOR LIGANDS |
US20090305960A1 (en) * | 2008-06-09 | 2009-12-10 | Palatin Technologies, Inc | Melanocortin Receptor-Specific Peptides for Treatment of Obesity / 669 |
NZ590254A (en) | 2008-06-09 | 2012-07-27 | Palatin Technologies Inc | Melanocortin receptor-specific cyclic peptides for treatment of sexual dysfunction |
UY32690A (es) * | 2009-06-08 | 2011-01-31 | Astrazeneca Ab | Péptidos específicos para receptores de melanocortina |
EP2440572B1 (en) | 2009-06-08 | 2017-04-05 | Palatin Technologies, Inc. | Lactam-bridged melanocortin receptor-specific peptides |
-
2009
- 2009-06-08 NZ NZ590254A patent/NZ590254A/en not_active IP Right Cessation
- 2009-06-08 CN CN200980129114.3A patent/CN102131514B/zh not_active Expired - Fee Related
- 2009-06-08 CA CA2727317A patent/CA2727317C/en not_active Expired - Fee Related
- 2009-06-08 MX MX2010013436A patent/MX2010013436A/es active IP Right Grant
- 2009-06-08 EP EP09763370.5A patent/EP2300036B1/en not_active Not-in-force
- 2009-06-08 BR BRPI0909947A patent/BRPI0909947A2/pt not_active Application Discontinuation
- 2009-06-08 EA EA201001722A patent/EA018630B1/ru not_active IP Right Cessation
- 2009-06-08 WO PCT/US2009/046571 patent/WO2009152079A1/en active Application Filing
- 2009-06-08 JP JP2011512730A patent/JP5628796B2/ja not_active Expired - Fee Related
- 2009-06-08 KR KR1020117000494A patent/KR101687037B1/ko active IP Right Grant
- 2009-06-08 AU AU2009257631A patent/AU2009257631B2/en not_active Ceased
-
2010
- 2010-11-23 US US12/952,238 patent/US8487073B2/en active Active
- 2010-12-09 IL IL209867A patent/IL209867A/en not_active IP Right Cessation
- 2010-12-21 ZA ZA2010/09165A patent/ZA201009165B/en unknown
-
2013
- 2013-06-05 US US13/910,506 patent/US8729224B2/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006527773A (ja) * | 2003-06-19 | 2006-12-07 | イーライ リリー アンド カンパニー | メラノコルチン受容体4(mc4)作用薬とその用途 |
JP2007532471A (ja) * | 2003-09-30 | 2007-11-15 | ノボ ノルディスク アクティーゼルスカブ | 新規メラノコルチンレセプターアゴニスト |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2019531329A (ja) * | 2016-10-24 | 2019-10-31 | アイビックス・リミテッドIvixltd. | 女性の性機能障害を治療する医薬組成物および方法 |
JP7155116B2 (ja) | 2016-10-24 | 2022-10-18 | オゥ・ブイ・ビィ・(アイルランド)・リミテッド | 女性の性機能障害を治療する医薬組成物および方法 |
Also Published As
Publication number | Publication date |
---|---|
EP2300036A1 (en) | 2011-03-30 |
IL209867A0 (en) | 2011-02-28 |
IL209867A (en) | 2015-08-31 |
ZA201009165B (en) | 2012-03-28 |
JP5628796B2 (ja) | 2014-11-19 |
EA018630B1 (ru) | 2013-09-30 |
CA2727317A1 (en) | 2009-12-17 |
MX2010013436A (es) | 2011-06-21 |
KR101687037B1 (ko) | 2016-12-15 |
NZ590254A (en) | 2012-07-27 |
CA2727317C (en) | 2015-02-17 |
BRPI0909947A2 (pt) | 2017-06-27 |
US8729224B2 (en) | 2014-05-20 |
EA201001722A1 (ru) | 2011-08-30 |
US8487073B2 (en) | 2013-07-16 |
KR20110040819A (ko) | 2011-04-20 |
EP2300036A4 (en) | 2012-01-18 |
AU2009257631B2 (en) | 2014-07-24 |
CN102131514B (zh) | 2014-08-20 |
WO2009152079A1 (en) | 2009-12-17 |
US20130288987A1 (en) | 2013-10-31 |
AU2009257631A1 (en) | 2009-12-17 |
US20110065652A1 (en) | 2011-03-17 |
EP2300036B1 (en) | 2017-04-05 |
CN102131514A (zh) | 2011-07-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5628796B2 (ja) | 性的不能の治療用のメラノコルチンレセプタ特異的ペプチド | |
US10632171B2 (en) | Melanocortin receptor-specific peptides | |
US8455618B2 (en) | Melanocortin receptor-specific peptides | |
JP5999702B2 (ja) | メラノコルチン−1受容体特異的環状ペプチド | |
US9273098B2 (en) | Lactam-bridged melanocortin receptor-specific peptides | |
US20090305960A1 (en) | Melanocortin Receptor-Specific Peptides for Treatment of Obesity / 669 | |
US8247530B2 (en) | N-alkylated cyclic peptide melanocortin agonists |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20120420 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20120420 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20131203 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20140228 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20140307 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20140902 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20141002 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5628796 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
LAPS | Cancellation because of no payment of annual fees |