Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs.
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.
Hale
J J
JJ
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
Mills
S G
SG
MacCoss
M
M
Dorn
C P
CP
Finke
P E
PE
Budhu
R J
RJ
Reamer
R A
RA
Huskey
S E
SE
Luffer-Atlas
D
D
Dean
B J
BJ
McGowan
E M
EM
Feeney
W P
WP
Chiu
S H
SH
Cascieri
M A
MA
Chicchi
G G
GG
Kurtz
M M
MM
Sadowski
S
S
Ber
E
E
Tattersall
F D
FD
Rupniak
N M
NM
Williams
A R
AR
Rycroft
W
W
Hargreaves
R
R
Metzger
J M
JM
MacIntyre
D E
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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
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