438:. By intravenous and oral administration it produces a dose-dependent decrease in oxytocin-induced uterine contractions in non-pregnant female rats. In late-term pregnant rats it significantly reduces spontaneous uterine contractions in a dose-dependent manner by intravenous administration. In humans retosiban prolongs pregnancy and reduces preterm birth. Intravenous administration of retosiban in women with spontaneous preterm labour was associated with a greater than 1-week increase in time to delivery compared with placebo, a significant reduction in preterm deliveries, a non-significant increase in uterine quiescence, and a favourable safety profile. The results demonstrate proof-of-concept in the treatment of threatened spontaneous preterm labour
600:(SAR) is supported by the crystal structure of the human oxytocin receptor in complex with retosiban, where the lipophilic indanyl substituent penetrates into a deep, mainly hydrophobic crevice at the bottom of the binding pocket, while the oxazol-morpholine amide moiety is closest to the extracellular surface. The oxazole ring is the most solvent-exposed substituent, and the morpholine ring has no direct interactions with the receptor. The 2,5-diketopiperazine core specifically interacts with the receptor through a polar interaction interface.
712:
249:
474:
29:
421:
Retosiban is a competitive oxytocin receptor antagonist which blocks the oxytocin-mediated contraction of the uterine smooth muscle in the female uterus that occurs during the initiation of preterm labour. This has been used to prevent preterm labour and
907:
McCafferty GP, Pullen MA, Wu C, Edwards RM, Allen MJ, Woollard PM, Borthwick AD, Liddle J, Hickey DM, Brooks DP, Westfall TD (2007). "Use of a novel and highly selective oxytocin receptor antagonist to characterize uterine contractions in the rat".
587:
group at position 3 is the best choice in terms of oxytocin receptor antagonist potency, its replacement by phenethyl and benzyl groups led to a progressive weakening of activity. At C-3, a 4-carbon branched alkyl was shown to be preferred with
322:
596:-secButyl) being the best; smaller alkyl groups result in reduced antagonist activity. The 2-methyl oxazole ring at the 7 position gives good aqueous solubility, low protein binding and minimal Cyp450 interaction. This
1068:
364:
InChI=1S/C27H34N4O5/c1-4-16(2)23-25(32)29-22(20-13-18-7-5-6-8-19(18)14-20)26(33)31(23)24(21-15-36-17(3)28-21)27(34)30-9-11-35-12-10-30/h5-8,15-16,20,22-24H,4,9-14H2,1-3H3,(H,29,32)/t16-,22+,23+,24+/m0/s1
1061:
559:)-isomer where the stereochemistry in the amide side-chain at C-7 is inverted, is 10-fold less potent. Typically in this series of 2,5 diketopiperazine oxytocin antagonists the (3
1054:
49:
583:)-isomer. In addition to the 2,5 diketopiperazine essential core, retosiban also contains several structural characteristics that improve its effectiveness and safety. An
861:
Borthwick AD, Liddle J (July 2011). "The Design of Orally
Bioavailable 2,5-Diketopiperazine Oxytocin Antagonists: From Concept to Clinical Candidate for Premature Labour".
764:
Liddle J, Allen MJ, Borthwick AD, Brooks DP, Davies DE, Edwards RM, et al. (January 2008). "The discovery of GSK221149A: a potent and selective oxytocin antagonist".
711:
336:
446:
The oral bioavailability of retosiban is in the order of 100% in the rat with a half life of 1.4 hours. It has low to moderate intrinsic clearance in
1809:
799:
Borthwick AD, Liddle J (January 2013). "Retosiban and
Epelsiban: Potent and Selective Orally available Oxytocin Antagonists". In Domling A (ed.).
1834:
816:
597:
454:(Cyp450) profile with no significant inhibition, with IC50 > 100ÎŒM, low protein binding (<80%) and low predicted CNS penetration.
356:
1819:
1479:
1335:
1583:
1288:
94:
70:
450:
from three pre-clinical species (rat, dog, cynomolgus monkey) and low intrinsic clearance in human microsomes. It has a good
1839:
188:
228:
1829:
943:
Thornton S, Miller H, Valenzuela G, Snidow J, Stier B, Fossler MJ, Montague TH, Powell M, Beach KJ (October 2015).
613:
648:. Hydrogenation to remove the Cbz and benzyl protecting groups, enabled cyclization of the linear peptide
1156:
612:
and these are formed by cyclising the corresponding linear dipeptide. In the short lab-scale and highly
1326:
1081:
1005:
657:
609:
478:
244:
1206:
394:
123:
1652:
1563:
1558:
1414:
1409:
696:) at the exocyclic amide, the hydrochloric acid hydrolysis of the activated phenolic amide caused
1151:
1146:
1084:
886:
466:, retosiban exists in an uncharged state. It has good solubility (> 0.22 mg/ml), with a
1716:
1711:
1667:
1268:
1263:
1218:
1168:
1136:
1116:
1106:
676:(benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate) followed by the addition of
1736:
1553:
1424:
1404:
1253:
1248:
1228:
1046:
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1033:
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781:
661:
541:
391:
1538:
801:
Methods and
Principles in Medicinal Chemistry: Protein-Protein Interactions in Drug Discovery
528:
ring at the 7 position in the acyclic amide attached to the N1-position. Retosiban is the (3
177:
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1459:
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689:
463:
265:
132:
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833:
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197:
1126:
945:"Treatment of spontaneous preterm labour with retosiban: a phase 2 proofâofâconcept study"
451:
423:
398:
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1746:
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993:
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28:
910:
American
Journal of Physiology. Regulatory, Integrative and Comparative Physiology
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1111:
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992:
WaltenspĂŒhl Y, Schöppe J, Ehrenmann J, Kummer L, PlĂŒckthun A (July 2020).
20:
1622:
1449:
1389:
1283:
1201:
1178:
1141:
725:
715:
A synthetic scheme for the production of
Retosiban via the Ugi reaction.
1751:
1607:
1533:
1419:
1173:
584:
525:
505:
409:= 0.65 nM) and has greater than 1400-fold selectivity over the related
143:
960:
874:
1439:
217:
673:
500:
Retosiban consists of a central 2,5 diketopiperazine ring with an
472:
321:
312:
834:"Statement on a Nonproprietary Name Adopted by the USAN Council"
467:
344:
CC(C)1C(=O)N(C(=O)N1(C2=COC(=N2)C)C(=O)N3CCOCC3)C4CC5=CC=CC=C5C4
208:
1050:
710:
233:
405:. Retosiban has high affinity for the oxytocin receptor (K
672:
by activating the acid with the peptide coupling reagent
484:
required for good activity (in red) and the required (3
656:. Hydrolysis of the phenolic amide, by reaction with
1769:
1696:
1582:
1478:
1334:
1325:
1091:
310:
297:
264:
259:
227:
207:
187:
167:
142:
122:
85:
69:
64:
48:
40:
35:
994:"Crystal structure of the human oxytocin receptor"
156:
700:at the exocyclic position and yielded the acid
652:to occur to give the phenolic cyclic dipeptide
540:)-isomer and is a sub-nanomolar (Ki = 0.65 nM)
131:
902:
900:
856:
854:
852:
850:
848:
846:
636:, D-alloisoleucine methyl ester hydrochloride
1062:
477:Numbered structure of retosiban, showing the
8:
766:Bioorganic & Medicinal Chemistry Letters
434:Retosiban has been shown to be an effective
19:
668:which was converted to the amide Retosiban
571:) isomer is >500 less active than the (3
1331:
1069:
1055:
1047:
247:
176:
1027:
1017:
968:
803:. Weinheim: Wiley-VCH. pp. 225â256.
196:
949:British Journal of Clinical Pharmacology
708:)-stereochemistry as the major product.
756:
361:
341:
243:
99:
18:
496:)-stereochemistry for optimal potency
7:
660:(CDI), followed addition of aqueous
640:, 2-methyloxazole-4-carboxaldehyde
608:Retosiban is a cyclic dipeptide or
516:-secButyl) at the 6 position, both
216:
147:
114:-inden-2-yl)-1-piperazine-2,5-dione
14:
632:(Cbz) protected R-indanylglycine
644:and 2-benzyloxyphenylisonitrile
624:is formed by the four-component
458:Physical and chemical properties
282:
276:
27:
598:structureâactivity relationship
508:group at the 3 position and an
369:Key:PLVGDGRBPMVYPB-FDUHJNRSSA-N
1810:Drugs not assigned an ATC code
680:. Although the linear peptide
288:
270:
78:In general: non-regulated
1:
1835:Oxytocin receptor antagonists
397:. It is being developed by
1856:
922:10.1152/ajpregu.00057.2007
863:Medicinal Research Reviews
809:10.1002/9783527648207.ch10
778:10.1016/j.bmcl.2007.11.008
520:to each other, and with a
260:Chemical and physical data
1638:Vasotocin (argiprestocin)
1633:Vasopressin (argipressin)
1524:Vasotocin (argiprestocin)
1519:Vasopressin (argipressin)
1380:Vasotocin (argiprestocin)
1375:Vasopressin (argipressin)
1162:Vasotocin (argiprestocin)
684:and the cyclic dipeptide
614:stereoselective synthesis
352:
332:
90:
26:
1820:4-Morpholinyl compounds
1554:ORG-52186 (SCH-740935)
1276:Catabolism inhibitors:
1019:10.1126/sciadv.abb5419
716:
497:
832:USAN Council (2007).
714:
476:
401:for the treatment of
110:)-6--3-(2,3-dihydro-1
1082:vasopressin receptor
704:with the required (7
658:carbonyl diimidazole
610:2,5-diketopiperazine
479:2,5-diketopiperazine
1840:Sec-Butyl compounds
1284:Bestatin (ubenimex)
1010:2020SciA....6.5419W
620:the linear peptide
417:Mechanism of action
23:
717:
498:
1830:Diketopiperazines
1797:
1796:
1777:Carrier proteins:
1765:
1764:
1756:lithium carbonate
1744:Other inhibitors:
1296:
1152:PF-06655075 (PF1)
961:10.1111/bcp.12646
875:10.1002/med.20193
818:978-3-527-33107-9
688:are a mixture of
662:hydrochloric acid
542:oxytocin receptor
392:oxytocin receptor
390:which acts as an
377:
376:
323:Interactive image
229:CompTox Dashboard
16:Chemical compound
1847:
1332:
1307:o-Phenanthroline
1294:
1071:
1064:
1057:
1048:
1042:
1041:
1031:
1021:
1004:(29): eabb5419.
998:Science Advances
989:
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796:
790:
789:
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690:diastereoisomers
464:physiological pH
442:Pharmacokinetics
325:
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22:
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1321:
1127:Lipo-oxytocin-1
1087:
1075:
1045:
991:
990:
986:
942:
941:
937:
916:(1): R299â305.
906:
905:
898:
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836:
831:
830:
826:
819:
798:
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722:
606:
460:
452:cytochrome P450
444:
432:
424:premature birth
419:
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399:GlaxoSmithKline
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1747:Demeclocycline
1740:
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1312:Phosphoramidon
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984:
955:(4): 740â749.
935:
896:
869:(4): 576â604.
842:
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791:
755:
753:
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749:
748:
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721:
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664:gave the acid
605:
602:
547:, while the (3
459:
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403:preterm labour
382:also known as
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1207:Tocinoic acid
1205:
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723:
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699:
698:epimerisation
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679:
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663:
659:
655:
651:
647:
643:
639:
635:
631:
630:carboxybenzyl
627:
623:
619:
616:of Retosiban
615:
611:
603:
601:
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582:
578:
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36:Clinical data
34:
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1776:
1743:
1704:Antagonists:
1703:
1653:JNJ-17079166
1645:Antagonists:
1644:
1628:Terlipressin
1598:Desmopressin
1594:
1570:
1564:TASP-0390325
1559:TASP-0233278
1531:Antagonists:
1530:
1514:Terlipressin
1494:Desmopressin
1490:
1415:JNJ-17308616
1410:JNJ-17079166
1387:Antagonists:
1386:
1370:Terlipressin
1346:
1275:
1258:
1211:Non-peptide:
1210:
1198:
1196:Antagonists:
1195:
1166:Non-peptide:
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430:Pharmacology
420:
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71:Legal status
65:Legal status
44:GSK-221149-A
1780:Neurophysin
1618:Ornipressin
1603:Felypressin
1544:Brezivaptan
1509:Ornipressin
1499:Felypressin
1435:Relcovaptan
1365:Selepressin
1360:Ornipressin
1350:Felypressin
1327:Vasopressin
1297:-Methionine
1147:PF-06478939
1122:Demoxytocin
772:(1): 90â4.
411:vasopressin
306: g·mol
133:820957-38-8
86:Identifiers
41:Other names
1804:Categories
1717:RWJ-339489
1712:Ribuvaptan
1707:Balovaptan
1673:Satavaptan
1668:RWJ-351647
1663:Mozavaptan
1658:Lixivaptan
1648:Conivaptan
1549:Nelivaptan
1455:WAY-267464
1400:Conivaptan
1395:Balovaptan
1269:WAY-162720
1264:SSR-126768
1219:Cligosiban
1184:WAY-267464
1137:Nacartocin
1117:Cargutocin
1112:Carbetocin
1107:Aspartocin
1085:modulators
752:References
678:morpholine
545:antagonist
524:-2-methyl
448:microsomes
413:receptors
395:antagonist
311:3D model (
299:Molar mass
198:GIE06H28OX
169:ChemSpider
124:CAS Number
95:IUPAC name
1737:YM-222546
1678:Tolvaptan
1613:Lypressin
1595:Agonists:
1504:Lypressin
1491:Agonists:
1430:PF-184563
1425:LY-307174
1405:FR-218944
1355:Lypressin
1347:Agonists:
1317:Puromycin
1302:Leupeptin
1279:Amastatin
1259:Retosiban
1254:Nolasiban
1249:L-372,662
1244:L-371,257
1239:L-368,899
1229:Erlosiban
1224:Epelsiban
1214:Barusiban
1132:Merotocin
1101:Agonists:
746:L-371,257
741:L-368,899
736:Epelsiban
731:Barusiban
604:Synthesis
470:of 2.2.
436:tocolytic
388:oral drug
380:Retosiban
21:Retosiban
1825:Oxazoles
1732:VMAX-382
1727:VMAX-372
1722:VMAX-367
1697:Unsorted
1688:YM-35471
1623:TC OT 39
1574:TASP-699
1571:Ligands:
1470:YM-35471
1450:TC OT 39
1390:Atosiban
1202:Atosiban
1199:Peptide:
1179:TC OT 39
1142:Oxytocin
1104:Peptide:
1093:Oxytocin
1078:Oxytocin
1038:32832646
979:25819462
930:17395790
891:22514154
883:20027670
786:18032036
726:Atosiban
720:See also
158:11340891
50:ATC code
1815:Indanes
1752:Lithium
1608:LIT-001
1539:ABT-558
1534:ABT-436
1420:LIT-001
1174:LIT-001
1029:7439316
1006:Bibcode
970:4594710
628:of the
585:indanyl
526:oxazole
506:indanyl
304:494.592
266:Formula
178:9515833
144:PubChem
1770:Others
1683:YM-471
1465:YM-471
1460:YM-218
1445:SRX251
1440:SRX246
1189:WJ0679
1036:
1026:
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386:is an
337:SMILES
218:D08986
1234:IX-01
887:S2CID
837:(PDF)
674:PyBOP
357:InChI
313:JSmol
1289:EDTA
1157:TGOT
1080:and
1034:PMID
975:PMID
926:PMID
879:PMID
813:ISBN
782:PMID
468:logd
209:KEGG
189:UNII
57:None
1169:CA7
1024:PMC
1014:doi
965:PMC
957:doi
918:doi
914:293
871:doi
805:doi
774:doi
579:, 7
575:, 6
567:, 7
563:, 6
555:, 7
551:, 6
536:, 7
532:, 6
518:cis
492:, 7
488:, 6
462:At
234:EPA
148:CID
1806::
1788:II
1786:,
1482:1B
1338:1A
1209:;
1164:;
1032:.
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951:.
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770:18
768:.
694:RS
692:(7
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280:34
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106:,6
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1758:)
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1586:2
1584:V
1480:V
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1295:L
1070:e
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618:8
594:S
592:(
590:R
581:R
577:R
573:R
569:S
565:S
561:S
557:S
553:R
549:R
538:R
534:R
530:R
522:R
514:S
512:(
510:R
504:-
502:R
494:R
490:R
486:R
407:i
315:)
292:5
289:O
286:4
283:N
277:H
271:C
236:)
232:(
112:H
108:R
104:R
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