Phosphorylated Morpholine Acetal Human Neurokinin-1 Receptor Antagonists as Water-Soluble Prodrugs

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.

The Metabolic Disposition of Aprepitant, a Substance P Receptor Antagonist, in Rats and Dogs

“…Aprepitant 3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl) phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one; Fig. 1), a potent and selective human NK 1 receptor antagonist with a mean IC 50 value of 0.12 nM, has been approved recently in the United States for clinical evaluation for the treatment of chemotherapy-induced nausea and vomiting (Navari et al, 1999;Diemunsch and Grelot, 2000;Hale et al, 2000;Campos et al, 2001;Cocquyt et al, 2001). This article describes the absorption, metabolism, was added to the triacetyl methyl ester glucuronide of aprepitant (2.0 mg in 450 l of 50% aqueous MeOH) at room temperature.…”

Phase II study of fosaprepitant + 5HT3 receptor antagonist + dexamethasone in patients with germ cell tumors undergoing 5-day cisplatin-based chemotherapy: a Hoosier Cancer Research Network study

“…Fosaprepitant is a water-soluble phosphoryl prodrug of aprepitant which when administered intravenously, rapidly converts to aprepitant within 30 minutes of administration [19]. A phase III trial compared single dose fosaprepitant 150mg IV in combination with granisetron 40 µg/kg IV and dexamethasone to a control regimen of placebo, granisetron, and dexamethasone [20].…”

Synthesis of new 1,2,4-triazole compounds containing Schiff and Mannich bases (morpholine) with antioxidant and antimicrobial activities

“…They have been reported to have antimicrobial, antiemetic, platelet aggregation inhibitory, antihyperlipo, proteinemic, and bronchodilator activity. In addition, they are also used in the treatment of pain, migraine, and asthma [19][20][21][22] . In recent years, the thiophene chemistry have attracted more interest because of the biological significance.…”