1. Field of Invention
The present invention relates to a method for selecting organic compounds having useful pharmacological activity in a mammal. More specifically, the present invention provides a method for selection of pharmacologically active compounds which are 4-substituted and hydroxyl substituted derivatives of 2,6-diiodophenol according to specific spatial atom arrangements. These compounds which may themselves be novel, are designed to produce pharmacological activity. In alternative, the evaluation of known compounds according to a novel method of this invention may discover new pharmacological activity and utility.
2. Related Disclosures
Many pharmacologically active drugs act on the cellular receptor level by either mimicking the action of a natural signal molecule (agonist) or by blocking the action of the natural signal molecule (antagonist).
Natural signalling molecules are endogenous compounds which chemically effect receptors located either on the outside of the cell membrane or on the membrane of the interior subcellular structure. For example, under the normal physiological conditions there is a certain level of a neurotransmitter or signal molecule released and/or present in the vicinity of the receptors. When, for any reason, such level is disturbed, that is when there is either the excess, deficiency or lack of neurotransmitter or signalling molecule, pathological conditions such as depression, schizophrenia, Parkinson's disease, Huntington's chorea, Grave's disease or Cushing's disease and many other debilitating conditions may develop.
Consequently, most cell receptors have a developed pharmacology of agents that act as agonists or antagonists. For example, suitable antagonists are known which can block the actions of transmitters dopamine, adrenalin, noradrenalin and acetylcholine or dopaminergic, alpha and beta adrenergic, and cholinergic agonists. Antagonists have been described in Pharmacological Basis of Therapeutics, 7th Ed., MacMillan, N.Y. (1985) acting on the endocrine molecules interacting with mineralocorticoid, glucocorticoid, estrogen and progesterone receptors. It is surprising, however, that despite extensive pharmacological research and development of many new methodologies and laboratory techniques, certain receptors, and/or their action still remain elusive and no antagonists have been yet discovered to inhibit or modulate their activity. Thyroid hormone receptors are one of them and despite numerous structure activity studies conducted over the past 20 years, no antagonist for thyroid hormone receptor action has been identified.
Thus, it would be advantageous to have available method which would, based on certain chemical spatial arrangements, provide and allow the design of new chemical materials which would match, complement, partially block, completely inhibit, modify, accentuate or otherwise alter or effect the function of known receptors.
Numerous structure-activity studies of various endogenous chemicals and pharmaceutical drugs have suggested the necessity of bulky iodine or propyl substituents on the outer ring 3' position and the presence of a carboxylic acid group for effective receptor thyroid hormone binding and/or agonist function. Hormonal Proteins and Peptides, VI, 107-204 (1978), Academic Press, N.Y.; Endocrine Rev., 1: 140-166 (1980).
Thyroid hormones thyronine (T4) and triiodothyronine (T3) affect the growth, development and metabolism of virtually all tissues of higher organisms. Since these hormones are endogenous, they act as agonists on the thyroid gland cell receptors known as iodothyronine receptors.
Recent studies summarized in Proc. Nat. Acad. Sci., 70:3488 (1973) have demonstrated that T4 is converted to T3 by deiodination in vivo which suggest that T4 functions as a prohormone, and all T4 biological activity, in fact, results from its conversion to T3 in vivo. High-affinity limited capacity thyroid hormone receptors have been identified in the nuclei of most tissues and the specific association between thyroid hormone and thyronine binding globulin and prealbumin, two proteins responsible for transport of the thyroid hormones to tissue sites, have also been described in Biochemistry, 21-163 (1982).
T3 and T4 induce a maximal 4-fold increase in the rates of growth and glucose utilization of GH.sub.1 cells, a pituitary tumor cell line in cell culture. Binding studies of T3 and T4 to cellular fraction showed high-affinity, low capacity binding sites for the hormones in nuclear but not mitochondrial or cytosol fractions of the cell.
In view of the above studies, any compound which would act on iodothyronine receptors should meet the structural requirements, i.e., bulky iodine or propyl substituent on the outer 3-ring position and the presence of a carboxylic acid group together with the ability to bind to a nuclear fraction of thyroid hormone receptors.
It has, however, been recently reported that certain chemical compounds which possess neither of the required moieties nor the obvious structural similarities with T3, or T4 when their two-dimensional chemical structures are compared with these compounds, do show hyper- and hypothyroid-like activity. The drug which has been shown to have such activity but is not structurally similar to T3 or T4 is amiodarone.
Amiodarone is a benzofuran having a chemical formula (2-butyl-3-[3,5-diiodo-4-(.beta.-diethylaminoethoxy)-benzoyl]benzofuran). Amiodarone is widely used for the treatment of angina pectoris, ventricular and supraventricular arrhythmias, which has a number of effects on parameters of thyroid function. For example, chronic administration of amiodarone has been associated with both hyper- and hypothyroid-like side effects. Clin. Endocr., 22:257 (1985). The drug has also been reported to cause changes in the concentrations of serum thyroxine (T4) and triiodothyronine (T3) levels, which have been attributed to an inhibition of peripheral T4 monodeiodination, and to iodine-induced changes in glandular hormonogenesis. J. Clin. Invest., 58:255 (1976). However, cases of clinical hypothyroidism have occurred, often with mildly elevated thyroid-stimulating hormone (TSH) and normal or slightly decreased T4 and T3 serum levels, which produce decreased pituitary thyroid receptor hormone binding. Clin. Endocr., 22:257 (1985).
Despite the chemical and structural dissimilarities, these observations suggest that amiodarone could act as a thyroid hormone antagonist at the receptor level. If that is true, then other structurally dissimilar compounds and drugs could also possess such ability but because of their obvious chemical dissimilarity, such pharmacological ability would seldom or never be discovered.
Thus it would be very advantageous to have available method which would quickly and effectively determine whether the compound does/does not possess a pharmacological activity and whether it would act as either the agonist or the antagonist on the receptor level.
Despite the research in this area, a predictive method to select novel pharmacologically active compounds, e.g. 4-substituted and hydroxyl substituted derivatives of 2,6-diiodophenol, having useful pharmacological action in a mammal, or discovering new utilities for known compounds has not been presented. In addition, the compounds potentially predicted as having useful pharmaceutical activity may not have been disclosed or prepared.
The present invention provides such a predictive method and the compounds having a useful pharmaceutical activity in a mammal.
All references and documents cited herein are incorporated in their entirety by reference.