Inhibition of smooth muscle cell migration by (R)-amlodipine

Details Inhibition of smooth muscle cell migration by (R)-amlodipine Inhibition of smooth muscle cell migration by (R)-amlodipine

1996-02-21

2000-06-27

Criares, Theodore J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

H01N 4340

Patent

active

06080761&

DESCRIPTION:

BRIEF SUMMARY
This invention relates to treatment of medical conditions involving smooth muscle cell migration using the R(+) isomer of 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(2-chlorophenyl)-1,4-dihydro-6 -methylpyridine-3,5-dicarboxylate, a compound having the approved non-proprietary name "amlodipine".
Amlodipine is a known calcium channel-blocking agent having vasodilatory activity and is currently used, generally in the form of a pharmaceutically acceptable salt such as its maleate or besylate, in treatment of hypertension and angina. The compound and its preparation are described in European patent 0089167 B1. Amlodipine is a racemic compound due to its symmetry at position 4 of the dihydropyridine ring and the R- and S-enantiomers may be prepared by methods described in J. Med. Chem. 1986 29 1696 (Arrowsmith et al.) and European Patent Application 0331315 A. It was formerly believed that the two resolved enantiomers consisted of the R-(-) and S-(+) isomers but it has subsequently been found that these are in fact the S(-) and the R(+) isomer, respectively (see J. Med. Chem., 35, 3341-3344 (1992), Goldmann et al.). It is known that the calcium channel blocking activity of amlodipine is substantially confined to the S(-) form and the racemic mixture of R(+) and S(-) forms; the R(+) isomer has little or no calcium channel blocking activity and so is not likely to have significant cardiovascular effects when administered to a patient.
It is known that calcium channel blockers in general tend to inhibit smooth muscle cell migration. Thus they have been found to impede lesion development in various animal models of atherosclerosis (see Arteriosclerosis 5; 250 (1985), Willis et al., Arteriosclerosis 6; 237 (1986), Sugano et al.); also smooth muscle cell proliferative lesions following endothelial cell damage by balloon angioplasty are reduced by Isradipine, a calcium channel blocker (see Am. J. Pathol 124, 88-93 (1986) Handley et al.). During restenosis following balloon angioplasty and atherogenesis, vascular smooth muscle cells migrate from the media to the intima where they proliferate. It is believed that the efficacy of calcium channel blockers in animal models of re-stenosis post-balloon angioplasty and atherosclerosis is due to inhibition of vascular smooth muscle cell migration and subsequent reduction in smooth muscle cell proliferation and neointimal formation.
Thus, calcium channel blockers would be expected to be useful in the treatment of conditions of smooth muscle cell migration, including atherosclerosis, re-stenosis after angioplasty and endometriosis.
It has now been discovered, surprisingly and contrary to all existing theory, that the R(+) isomer of amlodipine, despite its lack of calcium channel-blocking activity, is a potent inhibitor of smooth muscle cell migration and its potency in this respect is greater that of the S(-) isomer of amlodipine and some other known calcium channel-blockers. The R(+) isomer thus provides a means of treating conditions involving smooth muscle cell migration without any concomitant cardiovascular effects.
It is therefore applicable to patients for whom reduction of blood pressure would be undesirable.
Thus, one aspect of the invention comprises the R(+) isomer of amlodipine or a pharmaceutically acceptable salt thereof for use in the treatment of conditions requiring inhibition of vascular smooth muscle cell migration.
The invention also provides use of the R(+) isomer of amlodipine or a pharmaceutically acceptable salt thereof for making a medicament for treatment of conditions requiring inhibition of smooth muscle cell migration.
A further aspect of the invention provides a pharmaceutical composition comprising the R(+) isomer of amlodipine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said composition being substantially free of calcium channel-blocking activity.
The invention also provides a method of treating conditions requiring inhibition of smooth muscle cell migration which comprises administering to

REFERENCES:
patent: 5750707 (1998-05-01), Spargo
Nayler, W. et al., J. Cardiovasc. Pharmacol., 17, 4, pp. 587-592 (1991).
Lakitsch, M. et al., Mol. Pharmacol., 43, 2, pp. 293-301 (1993).

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