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.

01 May 1997·General Pharmacology: The Vascular System

Inhibition of voltage-dependent Ca2+ channels of porcine tracheal smooth muscle by the novel Ca2+ channel antagonist RWJ-22108

Article

Author: Yamakage, Michiaki ; Hirshman, Carol A. ; Croxton, Thomas L. ; Namiki, Akiyoshi

1. We compared electrophysiological effects of the bronchoselective Ca2+ channel antagonist RWJ-22108 on voltage-dependent Ca2+ channels (VDCs) of porcine tracheal smooth muscle cells to the effects of nicardipine and verapamil. 2. Each of the three Ca2+ channel antagonists tested inhibited inward Ca2+ currents (ICa) measured by whole-cell patch clamp techniques. Inhibition was dose-dependent with approximately 50% inhibition of peak ICa at +20 mV obtained with 3 x 10(-6) M RWJ-22108, 3 x 10(-7) M nicardipine, or 10(-5) M verapamil. 3. Both RWJ-22108 (3 x 10(-6) M) and nicardipine (3 x 10(-7) M) shifted the voltage dependence of steady-state inactivation to more negative potentials; however, the change in the potential of half-maximal inactivation induced by RWJ-22108 (-18 mV) was significantly greater than that induced by nicardipine (-12 mV). Verapamil did not alter the voltage dependence of inactivation. 4. We conclude that inhibition of VDCs by RWJ-22108 is qualitatively similar to that by nicardipine but with a greater stabilizing effect on the inactivated channel state.

01 Sep 1993·Agents and Actions

RWJ-22108 — a novel airway tissue — selective calcium channel blocker

Article

Author: John B. Moore ; William C. Miller ; Sandra Mockoviak

RWJ-22108 is a novel calcium entry blocker that has potential therapeutic use as an antiasthmatic agent. Although displaying typical potent inhibition of 45Ca uptake into aortic rings (IC50 = 7.1 nM) and displacement of [3H]nitrendipine from cardiac membranes (IC50 = 137 nM), RWJ-22108 demonstrates tissue selectivity in the inhibition of KCl-induced contractions. RWJ-22108 inhibits the calcium-dependent contraction of canine bronchiolar smooth muscle with an IC50 of 5.7 nM. The IC50 femoral artery/IC50 bronchiolar ratios are 2.85, 8.02, 1.47 and 1.96 for nifedipine, RWJ-22108, verapamil, and gallopamil, respectively. Furthermore, this selectivity ratio (range 2.8-5.5) of RWJ-22108 is also observed when inhibition of other pulmonary and cardiovascular smooth muscles are compared. Using canine tracheal muscle and rabbit aortae, the IC50 aorta/IC50 trachea ratio is 1.75 for RWJ-22108 compared to approximately 0.5 for several calcium blocker standards. These results indicate that in vitro RWJ-22108 is a bronchoselective calcium channel blocker.

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Discovery	US	R.W. Johnson Pharmaceutical Research Institute	-

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