Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs.

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Hale JJ, Mills SG, MacCoss M, Dorn CP, Finke PE, Budhu RJ, Reamer RA, Huskey SE, Luffer-Atlas D, Dean BJ, McGowan EM, Feeney WP, Chiu SH, Cascieri MA, Chicchi GG, Kurtz MM, Sadowski S, Ber E, Tattersall FD, Rupniak NM, Williams AR, Rycroft W, Hargreaves R, Metzger JM, MacIntyre DE

Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs.

J Med Chem. 2000 Mar 23;43(6):1234-41.

PubMed ID

10737756 [ View in PubMed

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Abstract

The regioselective dibenzylphosphorylation of 2 followed by catalytic reduction in the presence of N-methyl-D-glucamine afforded 2-(S)-(1-(R)-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-(2- phosphoryl-3-oxo-4H,-1,2,4-triazolo)methylmorpholine, bis(N-methyl-D-glucamine) salt, 11. Incubation of 11 in rat, dog, and human plasma and in human hepatic subcellular fractions in vitro indicated that conversion to 2 would be expected to occur in vivo most readily in humans during hepatic circulation. Conversion of 11 to 2 occurred rapidly in vivo in the rat and dog with the levels of 11 being undetectable within 5 min after 1 and 8 mg/kg doses iv in the rat and within 15 min after 0.5, 2, and 32 mg/kg doses iv in the dog. Compound 11 has a 10-fold lower affinity for the human NK-1 receptor as compared to 2, but it is functionally equivalent to 2 in preclinical models of NK-1-mediated inflammation in the guinea pig and cisplatin-induced emesis in the ferret, indicating that 11 acts as a prodrug of 2. Based in part on these data, 11 was identified as a novel, water-soluble prodrug of the clinical candidate 2 suitable for intravenous administration in humans.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Aprepitant	Neurokinin 1 receptor	IC 50 (nM)	0.09	N/A	N/A	Details