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| Other names | GSK-221149-A |
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| Formula | C27H34N4O5 |
| Molar mass | 494.592 g·mol−1 |
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Retosiban also known asGSK-221,149-A[1][2] is anoral drug which acts as anoxytocin receptorantagonist. It is being developed byGlaxoSmithKline for the treatment ofpreterm labour.[3][4] Retosiban has high affinity for the oxytocin receptor (Ki = 0.65 nM) and has greater than 1400-fold selectivity[5] over the relatedvasopressin receptors
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 andpremature birth.
Retosiban has been shown to be an effectivetocolytic. 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.[5]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[6]
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 inmicrosomes from three pre-clinical species (rat, dog, cynomolgus monkey) and low intrinsic clearance in human microsomes. It has a goodcytochrome P450 (Cyp450) profile with no significant inhibition, with IC50 > 100μM, low protein binding (<80%) and low predicted CNS penetration.[4]
Atphysiological pH, retosiban exists in an uncharged state. It has good solubility (> 0.22 mg/ml), with alogd of 2.2.[4]
Retosiban consists of a central 2,5 diketopiperazine ring with anR-indanyl group at the 3 position and anR (S-secButyl) at the 6 position, bothcis to each other, and with aR-2-methyloxazole ring at the 7 position in the acyclic amide attached to the N1-position. Retosiban is the (3R, 6R, 7R)-isomer and is a sub-nanomolar (Ki = 0.65 nM)oxytocin receptorantagonist, while the (3R, 6R, 7S)-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 (3S, 6S, 7S) isomer is >500 less active than the (3R, 6R, 7R)-isomer. In addition to the 2,5 diketopiperazine essential core, retosiban also contains several structural characteristics that improve its effectiveness and safety. Anindanyl 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 withR (S-secButyl) being the best; smaller alkyl groups result in reduced antagonist activity.[4] The 2-methyl oxazole ring at the 7 position gives good aqueous solubility, low protein binding and minimal Cyp450 interaction. Thisstructure–activity relationship (SAR) is supported by the crystal structure of the human oxytocin receptor in complex with retosiban,[7] 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.
Retosiban is a cyclic dipeptide or2,5-diketopiperazine and these are formed by cyclising the corresponding linear dipeptide. In the short lab-scale and highlystereoselective synthesis of Retosiban8 the linear peptide5 is formed by the four-componentUgi reaction of thecarboxybenzyl (Cbz) protected R-indanylglycine1, D-alloisoleucine methyl ester hydrochloride2, 2-methyloxazole-4-carboxaldehyde3 and 2-benzyloxyphenylisonitrile4. Hydrogenation to remove the Cbz and benzyl protecting groups, enabled cyclization of the linear peptide5 to occur to give the phenolic cyclic dipeptide6. Hydrolysis of the phenolic amide, by reaction withcarbonyl diimidazole (CDI), followed addition of aqueoushydrochloric acid gave the acid7 which was converted to the amide Retosiban8 by activating the acid with the peptide coupling reagentPyBOP (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate) followed by the addition ofmorpholine.[4]Although the linear peptide5 and the cyclic dipeptide6 are a mixture ofdiastereoisomers (7RS) at the exocyclic amide, the hydrochloric acid hydrolysis of the activated phenolic amide causedepimerisation at the exocyclic position and yielded the acid7 with the required (7R)-stereochemistry as the major product.
![A synthetic scheme for the production of Retosiban via the Ugi reaction.[4]](/mt/?noimg=&dark=on&url=http%3a%2f%2fen.wikipedia.org%2fwiki%2fFile%3aSynthesis_of_Retosiban.svg)
