GB2262886A - Calcium channel blocking drugs - Google Patents

Abstract

N-channel calcium antagonists are useful in the treatment of diseases which cause bronchoconstriction e.g. asthma, bronchitis, Farmers or Pigeon fanciers lung. Preferred antagonists are conotoxin peptides.

Description

PHARMACEUTICAL USES OF ORGANIC COMPOUNDS This invention relates to the use of pharmaceutical compounds in the treatment of disease.

The calcium channel blocking drugs, or calcium antagonists, are a group of drugs that inhibit the movement of calcium ions into cardiac tissue or smooth muscle. They have been widely used in the treatment of cardiovascular diseases such as angina. More recently calcium channels have been distinguished into different types, and they can be designated T-, Land N-type based on distinct electrophysiological characteristics. Drugs which are known to block calcium L-channels have been found to have little activity in inhibiting bronchospasm in diseases such as asthma, see for example the review by R. Towart and H. P. Rounding in Asthma Clinical Pharmacology and Therapeutic Progress edited by A. B. Kay, Blackwell Scientific Publications.

We have now found that N-channel calcium antagonists are surprisingly effective in controlling bronchoconstriction as indicated in animal models devised to show the potential of compounds for treatment of diseases such as asthma.

Accordingly, this invention comprises the use of an N-channel calcium antagonist for the manufacture of a medicament for the treatment of diseases which cause bronchoconstriction.

N-channel calcium antagonists can be identified by inhibition of neurotransmitter release from the cholinergic and non-adrenergic-noncholinergic (NANC) nerves in guinea pig airways. They include peptide neurotoxin omega-conotoxins, and particular examples of o-conotoxin N-channel calcium antagonists are 0)-conotoxin GVIA and Co-conotoxin MVIIA and the Co-conotoxins described in, for example, International Publication Number WO 91/07980. Calcium antagonists GLI;A and MVIIA are the most preferred for use in the present invention. Their structure and isolation from Conus venom is described in WO 91/07980 and in, for instance, B. M.Olivera et al, Biochemistry 1987, 26, 2086-2090, and in Marine Toxins, Amer. Chem. Soc. Washington DC, 1990.

Other compounds having similar properties disclosed in WO 91/07980 are MVIIA (195), MVIIA (194), MVIIA (190), MVIIA (200), MVIIA (201), SVIB (202), MVIIA (193), MVIIB, MVIIA (198), MVIIA (191), TVIA, MVIIA (196), RVIA, SVIB, GVIIA, MVIIA (197).

Particular groups of CO-conotoxin peptides are of the form: (1) CKGKGAX1CX2RX3X4YDCCTGSCX5RX6GKC-t, where X1=K or S; X2=S or H; X3=L or T; X4=M or S; Xs=N or a deletion; X6=S or deletion; and t is a carboxy or amidated carboxy terminal group; (2) CX1SXGSSCSXTSYNCCRSCNxYX2X3X4CX5-t, where X1=K or L; X2=T or S; X3=K or R; X4=R or K; Xs=Y or R; and t= a carboxy or amidated carboxy terminal group; (3) CKGKGAX1CX2RX3X4YDCCTCSCX5RX6GKC-t, where X1=K or S; X2=S or H; X3=L or T;X4=M or S; Xs=N or a deletion; X6=S or deletion; and t= a carboxy or amidated carboxy terminal group, excluding the peptides in which X1=K, X2=S, X3=L, X4=M, Xs=deletion, and X6=S; and X1=S, X2=H, X3=T, X4=S, Xs=N, and X6=deletion; and (4) CX1SXGSSCSXTSYNCCRSCNXYX2X3X4CX5-t, where X-1=K or L; X2=T or S; X3=K or R; X4=R or K; Xs=Y or R; and t= a carboxy or amidated carboxy terminal group, excluding the peptides in which X1=K, X2=T, X3=K, X4=R, and Xs=Y; and X1=L, X2=S, X3=R, X4=K, and Xs=R.

It has been found that N-channel calcium antagonists are active in tests which indicate that they have potential in diseases which cause bronchoconstriction, for example, allergic lung disorders such as extrinsic asthma and industrial asthmas such as Farmer's lung and Pigeon Fancier's lung, and in other inflammatory disorders such as chronic obstructive pulmonary disease and bronchitis, or when there is evidence of airway hyperreactivity resulting from, for example, viral infection.

The N-channel calcium antagonists have been demonstrated to inhibit vagallyinduced bronchospasm in the guinea-pig. In tests anaesthetised guinea-pigs were artificially ventilated and total pulmonary resistance, a measure of bronchomotor tone, was recorded with a pressure transducer attached to the side arm of the tracheal cannula. Vagal Stimulation (12.5 v, 10 Hz, 1 msec for 5 sec) produced a consistent rise in total pulmonary resistance. This rise in total pulmonary resistance is reduced or blocked by N-channel antagonists, and there is evidence that they block both the cholinergic and nonadrenergic, noncholinergic components of vagally-induced bronchospasm.

For example, o-conotoxin GVIA, at 20 pg/kg i.v., reduced total pulmonary resistance in this test by 87%. C9-conotoxin MVA at this concentration resulted in 100% reduction in pulmonary resistance.

For the purpose of treating diseases which cause bronchoconstriction, the N-channel antagonists may be administered by various routes, for example by the oral or rectal route, topically, by inhalation, and especially parenterally, for example by intravenous injection or infusion. It is preferred to administer them by inhalation using, for example, an aerosol.

They are usually employed in the form of a pharmaceutical composition. Such compositions are prepared in a manner well known in the pharmaceutical art and normally comprise at least one active compound. In making the compositions, the active ingredient will usually be in salt form mixed with a carrier, or diluted by a carrier, which may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the composition may be in the form of aerosols (as a solid or in a liquid medium), injection solutions, suspensions, ointments, tablets, lozenges, sachets, cachets, elixirs, soft and hard gelatin capsules, suppositories, and sterile packaged powders.

A preferred pharmaceutical composition of the invention is an aerosol comprising the N-channel calcium antagonist. An aerosol is any formulation that can be inhaled, including, for example, dry powder inhalants and nebulised inhalants.

When compositions for use in the invention are formulated in unit dosage form, it is preferred that each unit dosage form contains from 1 mg to 500 mg, for example from 5 mg to 100 mg.

The active compounds are effective over a wide dosage range and, for example, dosages per day will normally fall within the range of from 0.01 to 50 mg/kg, more usually in the range of from 0.05 to 10 mg/kg. However, it will be understood that the amount administered will be determined by the physician in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.

Claims (2)

1. The use of an N-channel calcium antagonist for the manufacture of a medicament for the treatment for diseases which cause bronchoconstriction.

2. The use of an N-channel antagonist which is o-conotoxin G2IA or o-conotoxin MVIIA, according to claim 1.