Retosiban

Last updated
Retosiban
Retosiban structure.svg
Clinical data
Other namesGSK-221149-A
ATC code
  • None
Legal status
Legal status
  • In general: non-regulated
Identifiers
  • (3R,6R)-6-[(2S)-butan-2-yl]-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2-methyl-1,3-oxazol-4-yl)-2-(morpholin-4-yl)-2-oxoethyl]piperazine-2,5-dione
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
Formula C27H34N4O5
Molar mass 494.592 g·mol−1
3D model (JSmol)
  • CC[C@H](C)[C@@H]1C(=O)N[C@@H](C(=O)N1[C@H](C2=COC(=N2)C)C(=O)N3CCOCC3)C4CC5=CC=CC=C5C4
  • 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
  • Key:PLVGDGRBPMVYPB-FDUHJNRSSA-N

Retosiban also known as GSK-221,149-A [1] [2] is an oral drug which acts as an oxytocin receptor antagonist. It is being developed by GlaxoSmithKline for the treatment of preterm 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 related vasopressin receptors

Contents

Mechanism of action

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 premature birth.

Pharmacology

Retosiban has been shown to be an effective tocolytic. 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]

Pharmacokinetics

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 microsomes from three pre-clinical species (rat, dog, cynomolgus monkey) and low intrinsic clearance in human microsomes. It has a good cytochrome P450 (Cyp450) profile with no significant inhibition, with IC50 > 100μM, low protein binding (<80%) and low predicted CNS penetration. [4]

Physical and chemical properties

At physiological pH, retosiban exists in an uncharged state. It has good solubility (> 0.22 mg/ml), with a logd of 2.2. [4]

Numbered structure of retosiban, showing the 2,5-diketopiperazine pharmacophore required for good activity (in red) and the required (3R, 6R, 7R)-stereochemistry for optimal potency Phamacophore of Retosiban.svg
Numbered structure of retosiban, showing the 2,5-diketopiperazine pharmacophore required for good activity (in red) and the required (3R, 6R, 7R)-stereochemistry for optimal potency

Retosiban consists of a central 2,5 diketopiperazine ring with an R-indanyl group at the 3 position and an R (S-secButyl) at the 6 position, both cis to each other, and with a R-2-methyl oxazole 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 receptor antagonist, 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. An indanyl 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 R (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. This structure–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.

Synthesis

Retosiban is a cyclic dipeptide or 2,5-diketopiperazine and these are formed by cyclising the corresponding linear dipeptide. In the short lab-scale and highly stereoselective synthesis of Retosiban 8 the linear peptide 5 is formed by the four-component Ugi reaction of the carboxybenzyl (Cbz) protected R-indanylglycine 1, D-alloisoleucine methyl ester hydrochloride 2, 2-methyloxazole-4-carboxaldehyde 3 and 2-benzyloxyphenylisonitrile 4. Hydrogenation to remove the Cbz and benzyl protecting groups, enabled cyclization of the linear peptide 5 to occur to give the phenolic cyclic dipeptide 6. Hydrolysis of the phenolic amide, by reaction with carbonyl diimidazole (CDI), followed addition of aqueous hydrochloric acid gave the acid 7 which was converted to the amide Retosiban 8 by activating the acid with the peptide coupling reagent PyBOP (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate) followed by the addition of morpholine. [4] Although the linear peptide 5 and the cyclic dipeptide 6 are a mixture of diastereoisomers (7RS) at the exocyclic amide, the hydrochloric acid hydrolysis of the activated phenolic amide caused epimerisation at the exocyclic position and yielded the acid 7 with the required (7R)-stereochemistry as the major product.

A synthetic scheme for the production of Retosiban via the Ugi reaction. Synthesis of Retosiban.svg
A synthetic scheme for the production of Retosiban via the Ugi reaction.

See also

Related Research Articles

<span class="mw-page-title-main">Oxytocin</span> Peptide hormone and neuropeptide

Oxytocin is a peptide hormone and neuropeptide normally produced in the hypothalamus and released by the posterior pituitary. Present in animals since early stages of evolution, in humans it plays roles in behavior that include social bonding, reproduction, childbirth, and the period after childbirth. Oxytocin is released into the bloodstream as a hormone in response to sexual activity and during labour. It is also available in pharmaceutical form. In either form, oxytocin stimulates uterine contractions to speed up the process of childbirth. In its natural form, it also plays a role in maternal bonding and milk production. Production and secretion of oxytocin is controlled by a positive feedback mechanism, where its initial release stimulates production and release of further oxytocin. For example, when oxytocin is released during a contraction of the uterus at the start of childbirth, this stimulates production and release of more oxytocin and an increase in the intensity and frequency of contractions. This process compounds in intensity and frequency and continues until the triggering activity ceases. A similar process takes place during lactation and during sexual activity.

<span class="mw-page-title-main">Dipeptide</span> Shortest peptide molecule, containing two amino acids joined by a single peptide bond

A dipeptide is an organic compound derived from two amino acids. The constituent amino acids can be the same or different. When different, two isomers of the dipeptide are possible, depending on the sequence. Several dipeptides are physiologically important, and some are both physiologically and commercially significant. A well known dipeptide is aspartame, an artificial sweetener.

Uterine contractions are muscle contractions of the uterine smooth muscle that occur during the menstrual cycle and labour. Uterine contractions occur throughout the menstrual cycle in the non-pregnant state and throughout gestation.

<span class="mw-page-title-main">Atosiban</span> Chemical compound

Atosiban, sold under the brand name Tractocile among others, is an inhibitor of the hormones oxytocin and vasopressin. It is used as an intravenous medication as a labour repressant (tocolytic) to halt premature labor. It was developed by Ferring Pharmaceuticals in Sweden and first reported in the literature in 1985. Originally marketed by Ferring Pharmaceuticals, it is licensed in proprietary and generic forms for the delay of imminent preterm birth in pregnant adult women.

Tocolytics are medications used to suppress premature labor. Preterm birth accounts for 70% of neonatal deaths. Therefore, tocolytic therapy is provided when delivery would result in premature birth, postponing delivery long enough for the administration of glucocorticoids, which accelerate fetal lung maturity but may require one to two days to take effect.

<span class="mw-page-title-main">Cyclic peptide</span> Peptide chains which contain a circular sequence of bonds

Cyclic peptides are polypeptide chains which contain a circular sequence of bonds. This can be through a connection between the amino and carboxyl ends of the peptide, for example in cyclosporin; a connection between the amino end and a side chain, for example in bacitracin; the carboxyl end and a side chain, for example in colistin; or two side chains or more complicated arrangements, for example in alpha-amanitin. Many cyclic peptides have been discovered in nature and many others have been synthesized in the laboratory. Their length ranges from just two amino acid residues to hundreds. In nature they are frequently antimicrobial or toxic; in medicine they have various applications, for example as antibiotics and immunosuppressive agents. Thin-Layer Chromatography (TLC) is a convenient method to detect cyclic peptides in crude extract from bio-mass.

<span class="mw-page-title-main">Oxytocin receptor</span> Genes on human chromosome 3

The oxytocin receptor, also known as OXTR, is a protein which functions as receptor for the hormone and neurotransmitter oxytocin. In humans, the oxytocin receptor is encoded by the OXTR gene which has been localized to human chromosome 3p25.

<span class="mw-page-title-main">Carbetocin</span> Pabal contains carbetocin used for preventing postpartum bleeding. Potent than oxytocin.

Carbetocin, sold under the brand names Pabal among others, is a medication used to prevent excessive bleeding after childbirth, particularly following Cesarean section. It appears to work as well as oxytocin. Due to it being less economical than other options, use is not recommended by NHS Scotland. It is given by injection into a vein or muscle.

<span class="mw-page-title-main">Prostaglandin F2alpha</span> Chemical compound

Prostaglandin F, pharmaceutically termed carboprost is a naturally occurring prostaglandin used in medicine to induce labor and as an abortifacient. Prostaglandins are lipids throughout the entire body that have a hormone-like function. In pregnancy, PGF2 is medically used to sustain contracture and provoke myometrial ischemia to accelerate labor and prevent significant blood loss in labor. Additionally, PGF2 has been linked to being naturally involved in the process of labor. It has been seen that there are higher levels of PGF2 in maternal fluid during labor when compared to at term. This signifies that there is likely a biological use and significance to the production and secretion of PGF2 in labor. Prostaglandin is also used to treat uterine infections in domestic animals.

<span class="mw-page-title-main">Demoxytocin</span> Chemical compound

Demoxytocin (INN), also known as desaminooxytocin or deaminooxytocin, as well as 1-(3-mercaptopropanoic acid)oxytocin ([Mpa1]OT), is an oxytocic peptide drug that is used to induce labor, promote lactation, and to prevent and treat puerperal (postpartum) mastitis. Demoxytocin is a synthetic analogue of oxytocin and has similar activities, but is more potent and has a longer half-life in comparison. Unlike oxytocin, which is given via intravenous injection, demoxytocin is administered as a buccal tablet formulation.

<span class="mw-page-title-main">L-371,257</span> Chemical compound

L-371,257 is a compound used in scientific research which acts as a selective antagonist of the oxytocin receptor with over 800x selectivity over the related vasopressin receptors. It was one of the first non-peptide oxytocin antagonists developed, and has good oral bioavailability, but poor penetration of the blood–brain barrier, which gives it good peripheral selectivity with few central side effects. Potential applications are likely to be in the treatment of premature labour.

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<span class="mw-page-title-main">L-368,899</span> Chemical compound

L-368,899 is a drug used in scientific research which acts as a selective antagonist of the oxytocin receptor, with good selectivity over the related vasopressin receptors. Unlike related drugs such as the peripherally selective L-371,257, the oral bioavailabity is high and the brain penetration of L-368,899 is rapid, with selective accumulation in areas of the limbic system. This makes it a useful tool for investigating the centrally mediated roles of oxytocin, such as in social behaviour and pair bonding, and studies in primates have shown L-368,899 to reduce a number of behaviours such as food sharing, sexual activity and caring for infants, demonstrating the importance of oxytocinergic signalling in mediating these important social behaviours.

<span class="mw-page-title-main">Epelsiban</span> Chemical compound

Epelsiban is an orally bioavailable drug which acts as a selective and potent oxytocin receptor antagonist. It was initially developed by GlaxoSmithKline (GSK) for the treatment of premature ejaculation in men and then as an agent to enhance embryo or blastocyst implantation in women undergoing embryo or blastocyst transfer associated with in vitro fertilization (IVF)., and was also investigated for use in the treatment of adenomyosis.

2,5-Diketopiperazine is an organic compound with the formula (NHCH2C(O))2. The compound features a six-membered ring containing two amide groups at opposite positions in the ring. It was first compound containing a peptide bond to be characterized by X-ray crystallography in 1938. It is the parent of a large class of 2,5-Diketopiperazines (2,5-DKPs) with the formula (NHCH2(R)C(O))2 (R = H, CH3, etc.). They are ubiquitous peptide in nature. They are often found in fermentation broths and yeast cultures as well as embedded in larger more complex architectures in a variety of natural products as well as several drugs. In addition, they are often produced as degradation products of polypeptides, especially in processed foods and beverages. They have also been identified in the contents of comets.

<span class="mw-page-title-main">Diketopiperazine</span> Class of chemical compounds

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Synthetic oxytocin, sold under the brand name Pitocin among others, is a medication made from the peptide oxytocin. As a medication, it is used to cause contraction of the uterus to start labor, increase the speed of labor, and to stop bleeding following delivery. For this purpose, it is given by injection either into a muscle or into a vein.

Peripherally acting μ-opioid receptor antagonists (PAMORAs) are a class of chemical compounds that are used to reverse adverse effects caused by opioids interacting with receptors outside the central nervous system (CNS), mainly those located in the gastrointestinal tract. PAMORAs are designed to specifically inhibit certain opioid receptors in the gastrointestinal tract and with limited ability to cross the blood–brain barrier. Therefore, PAMORAs do not affect the analgesic effects of opioids within the central nervous system.

References

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