Development of Orally Active Oxytocin Antagonists:  Studies on 1-(1-{4-[1-(2-Methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxy]-2- methoxybenzoyl}piperidin-4-yl)-1,4-dihydrobenz[d][1,3]oxazin-2-one (L-372,662) and Related Pyridines

Abstract

The previously reported oxytocin antagonist L-371,257 (2) has been modified at its acetylpiperidine terminus to incorporate various pyridine N-oxide groups. This modification has led to the identification of compounds with improved pharmacokinetics and excellent oral bioavailability. The pyridine N-oxide series is exemplified by L-372,662 (30), which possessed good potency in vitro (Ki = 4.1 nM, cloned human oxytocin receptor) and in vivo (intravenous AD50 = 0.71 mg/kg in the rat), excellent oral bioavailability (90% in the rat, 96% in the dog), good aqueous solubility (>8.5 mg/mL at pH 5.2) which should facilitate formulation for iv administration, and excellent selectivity against the human arginine vasopressin receptors. Incorporation of a 5-fluoro substituent on the central benzoyl ring of this class of oxytocin antagonists enhanced in vitro and in vivo potency but was detrimental to the pharmacokinetic profiles of these compounds. Although lipophilic substitution around the pyridine ring of compound 30 gave higher affinity in vitro, such substituents were a metabolic liability and caused shortfalls in vivo. Two approaches to prevent this metabolism, addition of a cyclic constraint and incorporation of trifluoromethyl groups, were examined. The former approach was ineffective because of metabolic hydroxylation on the constrained ring system, whereas the latter showed improvement in plasma pharmacokinetics in some cases.

SSR126768A (4-Chloro-3-[(3R)-(+)-5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2- oxo-2,3-dihydro-1H-indol-3-yl]-N-ethyl-N-(3-pyridylmethyl)-benzamide, Hydrochloride): A New Selective and Orally Active Oxytocin Receptor Antagonist for the Prevention of Preterm Labor

“…Moreover, synthetic OT is commonly used to induce labor and peptide oxytocin antagonists have been shown to inhibit preterm uterine contractions (Mitchell and Schmid, 2001). To overcome the problem of poor oral bioavailability associated with peptide compounds such as Atosiban, small molecules (mainly piperidine and benzazepine derivatives), selective for OT receptors, have been synthesized by Merck as orally active OT receptor antagonists but have been discontinued for pharmacokinetics reasons (Bell et al, 1998). More recently, a pyrrolidine derivative has been reported to possess oral efficacy in anesthetized pregnant rats (Cirillo et al, 2003).…”

Recent pharmacological advances in the treatment of preterm membrane rupture, labour and delivery

“…These include L-372,662 [78], Compound 1 [79] and SSR126786A (Figure 2) [80]. Both Compound 1 [78] and SSR126786A [80] have been shown to inhibit uterine contractions of pregnant rats near term.…”

Preterm Labour: An Overview of Current and Emerging Therapeutics

“…Striving, as usual, for superior quality, Merck continued the compound optimisation program, with the aim of further improving pharmacokinetic half-life, solubility, potency, and bioavailability. Several new compounds have emanated from these efforts, the most prominent being 32 [275] and 33 [276], as well as others, such as 34 [277]. Especially compound 32, or L-372,662, shows an impressive overall profile, in combining the positive features of L-371,257 with improved physicochemical and pharmacokinetic properties [278].…”