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.
MeSH terms
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Acetals / chemical synthesis*
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Acetals / chemistry
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Acetals / metabolism*
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Acetals / pharmacology
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / metabolism
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Antiemetics / chemical synthesis*
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Antiemetics / chemistry
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Antiemetics / metabolism
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Antiemetics / pharmacology
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Antineoplastic Agents
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Aprepitant
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Cisplatin
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Dogs
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Drug Evaluation, Preclinical
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Ferrets
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Guinea Pigs
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Humans
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Morpholines / chemical synthesis*
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Morpholines / chemistry
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Morpholines / metabolism*
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Morpholines / pharmacology
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Neurokinin-1 Receptor Antagonists*
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Prodrugs / chemical synthesis*
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Prodrugs / chemistry
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Prodrugs / metabolism
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Prodrugs / pharmacology
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Rats
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Solubility
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Stereoisomerism
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Structure-Activity Relationship
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Vomiting / chemically induced
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Vomiting / drug therapy
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Water
Substances
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2-(1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluoro)phenyl-4-(5-(2-phosphoryl-3-oxo-4H,-1,2,4-triazolo))methylmorpholine, bis(N-methylglucamine) salt
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Acetals
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Anti-Inflammatory Agents, Non-Steroidal
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Antiemetics
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Antineoplastic Agents
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Morpholines
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Neurokinin-1 Receptor Antagonists
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Prodrugs
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Water
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Aprepitant
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Cisplatin