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Work on this series of non-peptide oxytocin antagonists was then terminated at Merck, in favour of a promising new template. Binding affinity data for key compounds in this new series are summarised in Table 7.3. Some years ago, dihydroquinolinones such as OPC-21268, (28), had been disclosed as vasopressin V1 antagonists. This compound underwent clinical evaluation by Otsuka for hypertension and cardiac failure [76], but was h2n

Table 7.3 BINDING AFFINITIES OF BENZOXAZINONE OXYTOCIN ANTAGONISTS

Compound Rat OT Rat V1A Rat V2 Human OT Human V1A Human V2 Reference

(28) 230a 32b >30000c 170d 52000e >81000f [77]

"Binding affinity inhibition constant Ki (nM) versus [3H]oxytocin in rat uterine tissue. ^Binding affinity inhibition constant Ki (nM) versus [3H]arginine vasopressin in rat liver tissue. cBinding affinity inhibition constant Ki (nM) versus [3H] arginine vasopressin in rat kidney tissue.

^Binding affinity inhibition constant Ki (nM) versus [3H]oxytocin in human uterine tissue. eBinding affinity inhibition constant Ki (nM) versus [3H]arginine vasopressin in human platelet tissue.

fBinding affinity inhibition constant Ki (nM) versus [3H] arginine vasopressin in human kidney tissue.

^Binding affinity inhibition constant Ki (nM) versus [3H]oxytocin in human CHO cells.

found to have poor affinity for the human V1a receptor compared to rat [77]. However, this compound was shown by the Merck researchers to have modest but significant affinity for both the rat and human oxytocin receptors [78]. This series evidently offered potential for a selective human ox-ytocin antagonist, though the non-selective vasopressin pharmacology in rat presented some challenges.

Replacement of the dihydroquinolinone moiety with quinazolinone led to a loss of potency, but the benzoxazinone was found to retain the activity shown by (28). A breakthrough came when the acetamidopropyl substituent was constrained into a piperidine ring, leading to an oxytocin antagonist L-371,257, (29), with much improved potency. This compound was highly active as an oxytocin antagonist in human uterine tissue and showed around a 1,000-fold selectivity compared to a human V1a preparation. However, it retained the poor selectivity in rat, where it was a potent V1a antagonist. It was active in vivo, blocking oxytocin-induced uterine contractions in the rat after intravenous or intraduodenal administration. Further optimisation of the pharmacokinetic properties of this series has been achieved through the incorporation of a pyridine N-oxide group. A preferred compound is

L-372,662, (30), which retained excellent in vitro and in vivo potency, with an AD50 0.7mg/kg following intravenous administration in rat [79]. It also showed very high (>90%) oral bioavailability in both rat and dog and has excellent aqueous solubility suitable for intravenous administration. Enhancement of in vitro potency in this series was achieved through substitution with a fluorine atom on the phenyl ring of the benzoxazinone moiety and through incorporation of additional lipophilic substituents on the terminal pyridine ring. However, these modifications were generally associated with inferior pharmacokinetic or metabolic properties, although the introduction of a 4-trifluoromethyl group on the pyridine ring offered some protection from P450-mediated metabolism.

NHAc
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