Article

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

Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, and Merck, Sharp & Dohme, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K.
Journal of Medicinal Chemistry (impact factor: 5.25). 04/2000; 43(6):1234-41. DOI:10.1021/jm990617v pp.1234-41
Source: PubMed

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.

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    Article: Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT₃ receptor antagonists.
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Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

10-fold lower affinity
 
32 mg/kg doses iv
 
8 mg/kg doses iv
 
catalytic reduction
 
clinical candidate 2 suitable
 
guinea pig
 
hepatic circulation
 
human NK-1 receptor
 
human plasma
 
NK-1-mediated inflammation
 
preclinical models
 
prodrug
 
regioselective dibenzylphosphorylation
 
vivo
 
water-soluble prodrug
 

J J Hale