A novel class of calcium-entry blockers: the 1[[4-(aminoalkoxy)phenyl]sulfonyl]indolizines.

The synthesis and initial biological evaluation of a series of 1-sulfonylindolizines is described. These compounds have been shown to be representatives of a novel class of potent, slow-channel calcium antagonists. All compounds were found to be at least as active as the reference calcium antagonists verapamil and cis-(+)-diltiazem. Structure-activity relationship studies have shown that all compounds possessing an aralkyl group in the amine moiety and an isopropyl or cyclopropyl group at the 2 position of the indolizine are among the most potent calcium antagonists known outside the 1,4-dihydropyridine series. The IC50 values for the inhibition of [3H]nitrendipine binding vary between 0.19 and 4.5 nM whereas the IC50 value for nifedipine is 2.5 nM. One of the compounds in this group (9ab) has now been selected for clinical development.

Novel heterocyclic analogues of the new potent class of calcium entry blockers: 1-[[4-(aminoalkoxy)phenyl]sulfonyl]indolizines.

Several heterocyclic analogues of the potent 1-[[4-(aminoalkoxy)phenyl]sulfonyl]indolizines were synthesized and evaluated for their antagonistic calcium activities in comparison with the 1-sulfonylindolizine SR 33557 and the usual calcium antagonist references verapamil, cis-(+)-diltiazem, and nifedipine. The bicyclic nine-membered rings were, in general, more potent than the bicyclic 10-membered or five-membered rings. Among the bicyclic nine-membered rings, the indole nucleus appeared to be extremely favorable to support the calcium antagonistic activity. In particular, compound 36, with an IC50 value for the inhibition of [3H]nitrendipine equal to 0.072 nM, is among the most potent calcium antagonist known. This compound has been selected for clinical development.

O6-methylguanine-DNA methyltransferase activity in tissues and cells of the rat respiratory tract.

A product of alkylating agents and DNA, O6-methylguanine (O6-MG), can mispair with thymine, resulting in initiation of a carcinogenic tissue response. O6-alkylguanine-DNA alkyltransferase (AGT) is an acceptor protein responsible for repairing O6-MG. The purpose of our experiments was to characterize in vitro AGT activity in tissues and cells in the respiratory tract, a target tissue for inhaled alkylating agents. Anatomically defined regions throughout the respiratory tract of male F344 rats were obtained. These included two regions of the lateral wall of the left and right nasal airway (maxilloturbinates and ethmoturbinates), trachea, extrapulmonary bronchi and peripheral lung. Alveolar type II cells were also used in these studies. Radioactive 3H-methylated DNA was synthesized for use in all experiments. Removal of [3H]methyl from O6-MG was measured by high-pressure liquid chromatography after incubation for up to 30 min of tissue and cell extracts with the [3H]DNA. With the exception of tracheal and bronchial extracts, all tissues and cells analyzed contained AGT activity, which was found to increase proportionally to the amount of protein added to reaction flasks. AGT activity in tracheal and bronchial extracts was only detected at the highest protein concentration used (1.5 mg protein/ml) and ranged from 10-15 fmol/mg protein. AGT activity was highest in the lung (integral of 75 fmol/mg protein) and a region of the nasal tissue, the ethmoturbinates (integral of 45 fmol/mg protein). AGT activity in the maxilloturbinates was about 50% less than the AGT activity measured in the ethmoturbinates. These data suggest that methylated DNA in specific regions of the rat respiratory tract should be readily repaired, albeit to different extents.