Design and discovery of RWJ 22108--a novel bronchoselective calcium channel blocker.
A series of cyclic sulfone dihydropyridines ranging in sulfone ring size from five to nine membered have been evaluated for calcium antagonist activity. Increasing the sulfone ring size from 5 to 8 membered resulted in a two orders of magnitude in vitro potency increase. Aromatic substitution which favored tracheal effects over aortic effects was found to be 2-NO2 and 2-Cl, 6-F. The ester side chain which was found to maximize in vivo activity was the N-benzyl-N-methyl aminoethyl moiety. Combination of all these structural features resulted in RWJ 22108, a bronchoselective calcium channel blocker which preclinically exhibits an antiasthmatic profile.
R. W. Johnson Pharmaceutical Research Institute, Raritan, N.J. 08869, USA.
J H
JH
Dodd
C F
CF
Schwender
J B
JB
Moore
D M
DM
Ritchie
Y
Y
Gray-Nunez
D
D
Loughney
T
T
Kirchner
W C
WC
Miller
S
S
Mockoviak
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000737:chemistry / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001980:Bronchi / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004285:Dogs; D015195:Drug Design; D005260:Female; D066298:In Vitro Techniques; D008958:Models, Molecular; D009568:Nitrendipine / Q000493:pharmacokinetics; D009928:Organ Specificity; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects / Q000378:metabolism
D018927:Anti-Asthmatic Agents; D002121:Calcium Channel Blockers; D011725:Pyridines; C080337:RWJ 22108; D009568:Nitrendipine