title: 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.
authors.affiliation: 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. jeffrey_hale@merck.com
authors.forename: J J
authors.initials: JJ
authors.lastname: Hale
authors.forename: S G
authors.initials: SG
authors.lastname: Mills
authors.forename: M
authors.initials: M
authors.lastname: MacCoss
authors.forename: C P
authors.initials: CP
authors.lastname: Dorn
authors.forename: P E
authors.initials: PE
authors.lastname: Finke
authors.forename: R J
authors.initials: RJ
authors.lastname: Budhu
authors.forename: R A
authors.initials: RA
authors.lastname: Reamer
authors.forename: S E
authors.initials: SE
authors.lastname: Huskey
authors.forename: D
authors.initials: D
authors.lastname: Luffer-Atlas
authors.forename: B J
authors.initials: BJ
authors.lastname: Dean
authors.forename: E M
authors.initials: EM
authors.lastname: McGowan
authors.forename: W P
authors.initials: WP
authors.lastname: Feeney
authors.forename: S H
authors.initials: SH
authors.lastname: Chiu
authors.forename: M A
authors.initials: MA
authors.lastname: Cascieri
authors.forename: G G
authors.initials: GG
authors.lastname: Chicchi
authors.forename: M M
authors.initials: MM
authors.lastname: Kurtz
authors.forename: S
authors.initials: S
authors.lastname: Sadowski
authors.forename: E
authors.initials: E
authors.lastname: Ber
authors.forename: F D
authors.initials: FD
authors.lastname: Tattersall
authors.forename: N M
authors.initials: NM
authors.lastname: Rupniak
authors.forename: A R
authors.initials: AR
authors.lastname: Williams
authors.forename: W
authors.initials: W
authors.lastname: Rycroft
authors.forename: R
authors.initials: R
authors.lastname: Hargreaves
authors.forename: J M
authors.initials: JM
authors.lastname: Metzger
authors.forename: D E
authors.initials: DE
authors.lastname: MacIntyre
mesh_terms: D000080:Acetals / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000932:Antiemetics / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents; D000077608:Aprepitant; D002945:Cisplatin; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005289:Ferrets; D006168:Guinea Pigs; D006801:Humans; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014839:Vomiting / Q000139:chemically induced / Q000188:drug therapy; D014867:Water
chemical_list: C406348:2-(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; D000080:Acetals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000932:Antiemetics; D000970:Antineoplastic Agents; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D011355:Prodrugs; D014867:Water; D000077608:Aprepitant; D002945:Cisplatin