CA2386893A1

CA2386893A1 - N-alkylated peptides having antiangiogenic activity

N-alkylated peptides having antiangiogenic activity Download PDF

Info

Publication number: CA2386893A1
Authority: CA; Canada
Prior art keywords: ile; alanyl; sar; gly; arg
Prior art date: 1999-11-22
Legal status : Abandoned

Application number

CA002386893A

Other languages

English (en)

French (fr)

Inventor

Fortuna Haviv

Jack Henkin

Michael F. Bradley

Douglas M. Kalvin

Current Assignee

Abbott Laboratories

Original Assignee

Individual

Priority date

1999-11-22

Filing date

2000-11-22

Publication date

2001-05-31

2000-11-22 Application filed by Individual filed Critical Individual

2001-05-31 Publication of CA2386893A1 publication Critical patent/CA2386893A1/en

Status Abandoned legal-status Critical Current

Links

108090000765 processed proteins & peptides Proteins 0.000 title abstract description 201
102000004196 processed proteins & peptides Human genes 0.000 title abstract description 21
230000001772 anti-angiogenic effect Effects 0.000 title description 7
238000000034 method Methods 0.000 claims abstract description 27
239000000203 mixture Substances 0.000 claims abstract description 22
230000033115 angiogenesis Effects 0.000 claims abstract description 17
-1 N-methylprolyl Chemical group 0.000 claims description 651
150000001875 compounds Chemical class 0.000 claims description 102
150000001413 amino acids Chemical class 0.000 claims description 86
125000001288 lysyl group Chemical group 0.000 claims description 37
125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 32
125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 30
125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 claims description 29
125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 claims description 29
125000000217 alkyl group Chemical group 0.000 claims description 25
125000002072 seryl group Chemical group 0.000 claims description 24
125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 23
125000000741 isoleucyl group Chemical group [H]N([H])C(C(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(=O)O* 0.000 claims description 23
125000000613 asparagine group Chemical group N[C@@H](CC(N)=O)C(=O)* 0.000 claims description 22
125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 claims description 22
229950003188 isovaleryl diethylamide Drugs 0.000 claims description 21
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
125000002058 D-lysyl group Chemical group N[C@@H](C(=O)*)CCCCN 0.000 claims description 19
AHLPHDHHMVZTML-BYPYZUCNSA-N ornithyl group Chemical group N[C@@H](CCCN)C(=O)O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 19
238000011282 treatment Methods 0.000 claims description 19
125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 claims description 18
125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 18
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
239000001257 hydrogen Substances 0.000 claims description 17
229910052739 hydrogen Inorganic materials 0.000 claims description 17
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 17
125000000405 phenylalanyl group Chemical group 0.000 claims description 17
125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 claims description 17
125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 16
125000000249 D-isoleucyl group Chemical group N[C@@H](C(=O)*)[C@@H](CC)C 0.000 claims description 15
125000003301 D-leucyl group Chemical group N[C@@H](C(=O)*)CC(C)C 0.000 claims description 15
206010028980 Neoplasm Diseases 0.000 claims description 15
201000010099 disease Diseases 0.000 claims description 15
150000003839 salts Chemical class 0.000 claims description 15
125000003545 alkoxy group Chemical group 0.000 claims description 14
229910052614 beryl Inorganic materials 0.000 claims description 14
102000005962 receptors Human genes 0.000 claims description 14
108020003175 receptors Proteins 0.000 claims description 14
125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 claims description 13
125000000722 D-seryl group Chemical group N[C@@H](C(=O)*)CO 0.000 claims description 12
125000000197 D-threonyl group Chemical group N[C@@H](C(=O)*)[C@H](C)O 0.000 claims description 12
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
125000000753 cycloalkyl group Chemical group 0.000 claims description 12
125000000623 heterocyclic group Chemical group 0.000 claims description 12
125000003182 D-alloisoleucine group Chemical group [H]N([H])[C@@]([H])(C(=O)[*])[C@](C([H])([H])[H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 11
125000000180 D-prolyl group Chemical group N1[C@@H](C(=O)*)CCC1 0.000 claims description 11
125000001203 alloisoleucine group Chemical group 0.000 claims description 11
125000003625 D-valyl group Chemical group N[C@@H](C(=O)*)C(C)C 0.000 claims description 10
125000002252 acyl group Chemical group 0.000 claims description 10
125000003118 aryl group Chemical group 0.000 claims description 10
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 9
125000000392 cycloalkenyl group Chemical group 0.000 claims description 9
125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
125000003442 D-glutaminyl group Chemical group N[C@@H](C(=O)*)CCC(=O)N 0.000 claims description 8
125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 claims description 8
HQMLIDZJXVVKCW-UWTATZPHSA-N (2r)-2-aminopropanamide Chemical compound C[C@@H](N)C(N)=O HQMLIDZJXVVKCW-UWTATZPHSA-N 0.000 claims description 7
125000000240 D-tyrosyl group Chemical group N[C@@H](C(=O)*)CC1=CC=C(C=C1)O 0.000 claims description 7
125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 claims description 6
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical compound NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 claims description 6
JIZNFRPSBHXXMD-BYPYZUCNSA-N (4s)-1,4-diaminopentan-3-one Chemical compound C[C@H](N)C(=O)CCN JIZNFRPSBHXXMD-BYPYZUCNSA-N 0.000 claims description 5
ODANWMOQWMHGCY-UHFFFAOYSA-N 1,4-diaminobutan-2-one Chemical compound NCCC(=O)CN ODANWMOQWMHGCY-UHFFFAOYSA-N 0.000 claims description 5
HQMLIDZJXVVKCW-REOHCLBHSA-N L-alaninamide Chemical compound C[C@H](N)C(N)=O HQMLIDZJXVVKCW-REOHCLBHSA-N 0.000 claims description 5
125000000539 amino acid group Chemical group 0.000 claims description 5
239000003937 drug carrier Substances 0.000 claims description 5
210000002889 endothelial cell Anatomy 0.000 claims description 5
125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 claims description 5
150000003457 sulfones Chemical class 0.000 claims description 5
QKNFFJHHPCWXTH-GSVOUGTGSA-N (2r)-2-(methylamino)propanamide Chemical compound CN[C@H](C)C(N)=O QKNFFJHHPCWXTH-GSVOUGTGSA-N 0.000 claims description 4
MGOGKPMIZGEGOZ-UWTATZPHSA-N (2r)-2-amino-3-hydroxypropanamide Chemical compound OC[C@@H](N)C(N)=O MGOGKPMIZGEGOZ-UWTATZPHSA-N 0.000 claims description 4
RKGFWMYLTBPZGL-YUMQZZPRSA-N (2s)-2-amino-1-[(2s)-2-amino-4-methylsulfanylbutanoyl]sulfinyl-4-methylsulfanylbutan-1-one Chemical compound CSCC[C@H](N)C(=O)S(=O)C(=O)[C@@H](N)CCSC RKGFWMYLTBPZGL-YUMQZZPRSA-N 0.000 claims description 4
RZTMKPNHKUTQSB-YUMQZZPRSA-N (2s)-2-amino-1-[(2s)-2-amino-4-methylsulfanylbutanoyl]sulfonyl-4-methylsulfanylbutan-1-one Chemical compound CSCC[C@H](N)C(=O)S(=O)(=O)C(=O)[C@@H](N)CCSC RZTMKPNHKUTQSB-YUMQZZPRSA-N 0.000 claims description 4
WAMWSIDTKSNDCU-ZETCQYMHSA-N (2s)-2-azaniumyl-2-cyclohexylacetate Chemical group OC(=O)[C@@H](N)C1CCCCC1 WAMWSIDTKSNDCU-ZETCQYMHSA-N 0.000 claims description 4
JIZNFRPSBHXXMD-SCSAIBSYSA-N (4R)-1,4-diaminopentan-3-one Chemical compound C[C@@H](N)C(=O)CCN JIZNFRPSBHXXMD-SCSAIBSYSA-N 0.000 claims description 4
125000000170 D-asparaginyl group Chemical group N[C@@H](C(=O)*)CC(=O)N 0.000 claims description 4
125000002436 D-phenylalanyl group Chemical group N[C@@H](C(=O)*)CC1=CC=CC=C1 0.000 claims description 4
102000014187 peptide receptors Human genes 0.000 claims description 4
108010011903 peptide receptors Proteins 0.000 claims description 4
239000008194 pharmaceutical composition Substances 0.000 claims description 4
238000002560 therapeutic procedure Methods 0.000 claims description 4
206010012689 Diabetic retinopathy Diseases 0.000 claims description 3
201000004681 Psoriasis Diseases 0.000 claims description 3
230000003527 anti-angiogenesis Effects 0.000 claims description 3
206010003246 arthritis Diseases 0.000 claims description 3
208000015181 infectious disease Diseases 0.000 claims description 3
208000002780 macular degeneration Diseases 0.000 claims description 3
238000011477 surgical intervention Methods 0.000 claims description 3
125000002038 D-arginyl group Chemical group N[C@@H](C(=O)*)CCCNC(=N)N 0.000 claims description 2
201000011510 cancer Diseases 0.000 claims description 2
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
125000001980 alanyl group Chemical group 0.000 claims 25
125000002114 valyl group Chemical group 0.000 claims 9
125000000030 D-alanine group Chemical group [H]N([H])[C@](C([H])([H])[H])(C(=O)[*])[H] 0.000 claims 5
125000000028 D-cysteine group Chemical group [H]N([H])[C@@]([H])(C(=O)[*])C(S[H])([H])[H] 0.000 claims 4
125000000296 D-methionine group Chemical group [H]N([H])[C@@]([H])(C(=O)[*])C([H])([H])C([H])([H])SC([H])([H])[H] 0.000 claims 2
125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 1
125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims 1
125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims 1
RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 1
230000002401 inhibitory effect Effects 0.000 abstract description 7
241000124008 Mammalia Species 0.000 abstract description 2
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238000002953 preparative HPLC Methods 0.000 description 79
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 79
VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 78
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NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 10
125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 9
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 8
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MIDZLCFIAINOQN-WPRPVWTQSA-N Phe-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=CC=C1 MIDZLCFIAINOQN-WPRPVWTQSA-N 0.000 description 6
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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 5
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