1-(((7,7-Dimethyl-2(S)-(2(S)-amino-4-(methylsulfonyl)butyramido)bicyclo[2.2.1]heptan-1(S)-yl)methyl)sulfonyl)-4-(2-methylphenyl)piperazine (L-368,899): An Orally Bioavailable, Non-Peptide Oxytocin Antagonist with Potential Utility for Managing Preterm Labor

Abstract

Modifications to the previously reported spiroindenylpiperidine camphor-sulfonamide oxytocin (OT) antagonist L-366,509 have produced a new series of o-tolylpiperazine (TP) camphor-sulfonamides. A number of analogues in the TP series that incorporate a modified or unmodified L-methionine sulfone amide at the C2 endo position on the camphor ring exhibit high affinity for OT receptors (IC50 = 1.3-15 nM) and good selectivity for binding to OT versus arginine vasopressin V1a and V2 receptors. Several of these analogues were additionally characterized as potent antagonists of OT-stimulated contractions of the isolated and/or in situ rat uterus. Compound 7 (L-368,899) exhibited the best overall profile of OT receptor affinity (IC50 = 8.9 nM, rat uterus; 26 nM, human uterus), potency for inhibition of OT-stimulated contractions of the isolated rat uterus (pA2 = 8.9) and in situ rat uterus (AD50 = 0.35 mg/kg after intravenous (i.v.) administration and 7.0 mg/kg after intraduodenal administration), aqueous solubility (3.7 mg/mL at pH 5.0), and oral bioavailability in several species (35% (rat), 25% (dog), and 21% (chimpanzee) as estimated from radioreceptor determination of drug levels in plasma after oral and i.v. dosing). On the basis of these favorable properties, 7 has begun clinical testing for use as an oral and i.v. tocolytic agent. Molecular modeling alignment studies have provided support for the hypothesis that the TP camphor-sulfonamide portion of the non-peptide structures may serve as a mimetic of the important D-AA2-Ile3 dipeptide (AA = aromatic amino acid) found in many potent OT antagonists from the cyclic hexapeptide and OT analogue structural classes.

Oxytocin Mediates Entrainment of Sensory Stimuli to Social Cues of Opposing Valence

“…We blocked Oxtr signaling by administering L-368,899, a non-peptidergic Oxtr antagonist that penetrates the blood-brain barrier (OTA, 5 mg/kg, intraperitoneally) (Boccia et al, 2007; 4), before training and/or testing. Males injected with saline (Figure 1D and E) (S-S: CS+ chamber = 184.07 ± 13.79 s; Center = 36.73 ± 8.79 s; CS− chamber = 79.10 ± 9.11 s, n = 7) or the antagonist before testing only (S-OTA: CS+ chamber = 163.61 ± 11.96 s; Center = 52.58 ± 12.48 s; CS− chamber = 82.37 ± 4.99 s, n = 6) maintained a preference for the CS+ chamber.…”

Inequity aversion strategies between marmosets are influenced by partner familiarity and sex but not by oxytocin

“…Intranasal administration of OXT in macaques and humans leads to increases in OXT concentrations in both plasma and CSF (Dal Monte, Noble, Turchi, Cummins, & Averbeck, 2014; Striepens et al, 2013), but see, (Leng & Ludwig, 2015), about important considerations of intranasal OXT administration. The OXTa (L-368,899; provided by Dr. Peter Williams, Merck) is a non-peptide antagonist with high affinity for OXT receptors (it also has a high affinity for AVPRla and AVPRlb) (Manning et al, 2012; Williams et al, 1994). The OXTa (L-368,899) has been shown to localize in both CSF and brain areas known to contain neurons with OXT receptors in rodents after oral administration (Boccia, Goursaud, Bachevalier, Anderson, & Pedersen, 2007).…”

Autism-Like Behavior in BTBR Mice Is Improved by Electroconvulsive Therapy

“…While L-368,899 shows a reasonably high preference towards oxytocin receptors versus vasopressin receptors (approximately 40-fold), it also binds to V 1a and V 2 vasopressin receptors [27]. It is difficult, if impossible, to choose a dose that would not affect vasopressin receptors upon in vivo drug delivery.…”