Metabolic stabilization of benzylidene ketal M(2) muscarinic receptor antagonists via halonaphthoic acid substitution.
The potential toxicological liabilities of the M(2) muscarinic antagonist 1 were addressed by replacing the methylenedioxyphenyl moiety with a p-methoxyphenyl group, resulting in M(2) selective compounds such as 3. Several halogenated naphthamide derivatives of 3 were studied in order to improve the pharmacokinetic profile via blockage of oxidative metabolism. Compound 4 demonstrated excellent M(2) affinity and selectivity, human microsomal stability, and oral bioavailability in rodents and primates.
Boyle
C D
CD
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. craig.boyle@spcorp.com
Chackalamannil
S
S
Clader
J W
JW
Greenlee
W J
WJ
Josien
H B
HB
Kaminski
J J
JJ
Kozlowski
J A
JA
McCombie
S W
SW
Nazareno
D V
DV
Tagat
J R
JR
Wang
Y
Y
Zhou
G
G
Billard
W
W
Binch
H
H
Crosby
G
G
Cohen-Williams
M
M
Coffin
V L
VL
Cox
K A
KA
Grotz
D E
DE
Duffy
R A
RA
Ruperto
V
V
Lachowicz
J E
JE
D000109:Acetylcholine / Q000032:analysis / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001597:Benzylidene Compounds / Q000737:chemistry* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004149:Dioxoles / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D006801:Humans; D008252:Macaca fascicularis; D017551:Microdialysis; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D018727:Muscarinic Antagonists / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry* / Q000494:pharmacology*
C442374:1-((3,4-methylenedioxyphenyl)sulfonylphenyl)-1-(1-(1-(n-propylsulfonyl)morpholin-4-yl)morpholin-4-yl)dioxole; C442375:1-((4-methoxyphenyl)sulfonylphenyl)-1(1-(1-(1-naphthylcarbonyl)morpholin-4-yl)morpholin-4-yl)dioxole; C442376:1-((4-methoxyphenyl)sulfonylphenyl)-1-(1-(1-(4-fluoro-1-naphthylcarbonyl)morpholin-4-yl)morpholin-4-yl)dioxole; D001597:Benzylidene Compounds; D004149:Dioxoles; D018727:Muscarinic Antagonists; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D013450:Sulfones; D003577:Cytochrome P-450 Enzyme System; D000109:Acetylcholine