Selective thyromimetics. Cardiac-sparing thyroid hormone analogues containing 3'-arylmethyl substituents.

Introduction of specific arylmethyl groups at the 3'-position of the thyroid hormone 3,3',5-triiodo-L-thyronine (T3), and its known hormonally active derivatives, gives liver-selective, cardiac-sparing thyromimetics, with potential utility as plasma cholesterol lowering agents. Selectivity-conferring 3'-substituents include substituted benzyl, e.g. p-hydroxybenzyl, and heterocyclic methyl, e.g. 2-oxo-1,2-dihydropyrid-5-ylmethyl and 6-oxo-1,6-dihydropyridazin-3-ylmethyl. Correlations between in vivo and in vitro receptor binding affinities show that liver/heart selectivity does not depend on receptor recognition but on penetration or access to receptors in vivo. QSAR studies of the binding data of a series of 20 3'-arylmethyl T3 analogues show that electronegative groups at the para position increase both receptor binding and selectivity in vivo. However, increasing 3'-arylmethyl hydrophobicity increases receptor binding but reduces selectivity. Substitution at ortho and meta positions reduces both binding and selectivity. Replacement of the 3,5-iodo groups by halogen or methyl maintains selectivity, with 3,5-dibromo analogues in particular having increased potency combined with oral bioavailability. Diphenyl thioether derivatives also have improved potency but are less orally active. At the 1-position, the D enantiomer retains selectivity, but removal of the alpha-amino group to give a propionic acid results in loss of selective thyromimetic activity.

Thyroid hormone analogues. Synthesis of 3'-substituted 3,5-diiodo-L-thyronines and quantitative structure-activity studies of in vitro and in vivo thyromimetic activities in rat liver and heart.

Twenty-nine novel 3'-substituted derivatives of the thyroid hormone 3,3',5-triiodo-L-thyronine (T3) have been synthesized by using established methods and by a new route involving manipulation of a 3'-formyl intermediate. In vitro hormone receptor binding (to intact nuclei) and in vivo thyromimetic activity (induction of mitochondrial 3-phosphoglycerate oxidoreductase, GPDH) were measured in rat liver and heart for these new analogues and for the 18 previously reported 3'-substituted 3,5-diiodo-L-thyronines. Analysis of the binding data using theoretical conformational and quantitative structure-affinity methods implies that the 3'-substituent recognition site on the thyroid hormone receptor is hydrophobic and limited in depth to the length of the natural iodo substituent, but has sufficient width to accommodate a phenyl or cyclohexyl group. Receptor binding is reduced by approximately 10-fold in 3'-acyl derivatives which form strong intramolecular acceptor hydrogen bonds with the adjacent 4'-hydroxyl. The compounds studied showed no differences in their relative affinities for heart and liver nuclei, suggesting that receptors in these tissues are similar. However, the relationships between thyromimetic activity (induction of GPDH) and nuclear binding showed some tissue differences. A high correlation between activity and binding is observed for full agonists in the heart, but an equally significant correlation for the liver data is only seen when 3'-substituent bulk (molar refractivity) is included in the analysis. These results suggest the possibility that differential tissue penetration or access to receptors may occur in vivo.

A thyromimetic that decreases plasma cholesterol levels without increasing cardiac activity.

A number of agents that mimic the ability of the thyroid hormone, T3, to decrease plasma cholesterol levels are described; one is as effective as T3 at reducing cholesterol levels and stimulating liver function, but has very little effect on cardiac function and is thus less likely to be toxic. The agent may be useful in the treatment of atherosclerosis.

Dipole moment in relation to H2 receptor histamine antagonist activity for cimetidine analogues.

The activities of a series of H2 receptor histamine antagonists structurally related to cimetidine (1) have been compared to investigate the effect of replacing the cyanoguanidine moiety by other neutral, dipolar groups. Antagonist activity, as measured in vitro on the histamine-stimulated guinea pig right atrium, was found to be very sensitive to relatively minor structural changes. Differences in H2 antagonist activity are accounted for by dipole moment orientation and lipophilicity and are rationalized in terms of an optimum requirement for alignment of a hydrogen-bonding moiety in the antagonist with respect to the receptor and desolvation effects at the receptor. The most active compound in the series is the 2-amino-3-nitropyrrole derivative 5, which combines a near-optimal dipole orientation with high lipophilicity.

3'-Acetyl-3,5-diiodo-L-thyronine: a novel highly active thyromimetic with low receptor affinity.

The 4'-phenolic hydroxyl group of thyroid hormones plays an important role in receptor binding, and it has been suggested that the interaction of this hydroxyl group with the receptor involves hydrogen bonding via donation of the acidic hydrogen in a trans disposition to the 3'-substituent of the hormones. In order to test this hypothesis we have synthesised, and measured the hepatic receptor affinity and thyromimetic activity of 3'-acetyl-3,5-diiodo-L-thyronine (3'-Ac-T2), a compound in which the formation of such a receptor-phenol hydrogen bond is precluded by the presence of a strong intramolecular hydrogen bond between the 3'-acetyl- and 4'-hydroxyl groups. In confirmation of the hypothesis, 3'-Ac-T2 has a low affinity (0.5% of that of 3,5,3'-triiodo-L-thyronine, T3) for the T3-receptor in isolated rat hepatic nuclei. By contrast the thyromimetic activity (assessed by its ability to induce rat hepatic glycerol-3-phosphate dehydrogenase and increase the qO2 of liver slices) was roughly equal to that of T3. This apparent discrepancy was resolved when it was found that the capacity of 3'-Ac-T2 to occupy hepatic receptors after in vivo administration, was about 100 times greater than predicted from its in vitro affinity. The reason for this difference between in vivo and in vitro nuclear binding is unknown at the present time.

Potential histamine H2-receptor antagonists. 4. Benzylhistamines.

As part of our studies aimed at designing histamine H2-receptor antagonists, the effect on histaminergic activity of introducing benzyl substituents at various positions in the histamine molecule is described. New synthetic methods are reported for the novel 4-benzyl-, beta-benzyl- and 4,N tau-dibenylhistamines and the reported 2-benzylhistamine. The novel N tau-benzylhistamine was synthesized by the versatile route reported by us for the synthesis of N tau-methylhistamine. These benzylhistamines, together with the reported N alpha- and N pi-benzylhistamines, were tested for agonist and antagonist activity at both H1 and H2 receptors. The results obtained indicate that introduction of a benzyl group into the histamine molecule causes a marked reduction in H1- or H2-agonist activity, and none of the compounds showed consistent antagonist activity. Evidently, the sterically demanding benzyl substituent is not easily accommodated in the agonist binding mode and is unable to locate a lipophilic receptor region for potential hydrophobic binding.

Characterization and development of cimetidine as a histamine H2-receptor antagonist.

The concept of two classes of histamine receptor, H1 and H2, is introduced and the chemical derivation of histamine H2-receptor antagonists is outlined briefly. Starting from the structure of histamine, chemical modification led eventually to burimamide, the first described histamine H2-receptor antagonist. Further stepwise modifications ultimately afforded metiamide and cimetidine. In vitro studies show that cimetidine is a specific competitive histamine H2-receptor antagonist. In vivo, it is a potent inhibitor of histamine-stimulated gastric acid secretion in rats and dogs after both intravenous and oral administration. It is equally potent as an inhibitor of pentagastrin-stimulated secretion. The evidence suggests that cimetidine inhibits gastric acid secretion through blockade of histamine H2-receptors in the gastric mucosa. Cimetidine has been shown to have low acute toxicity. Repeated dose studies of up to 24 months in rats and up to 12 months in dogs have been carried out and the results are presented and discussed. There is no known toxic effect which would limit the usefulness of cimetidine in man.

Cyanoguanidine-thiourea equivalence in the development of the histamine H2-receptor antagonist, cimetidine.

In the histamine H2-receptor antagonist metiamide (2a) isosteric replacement of thione sulfur (=S) by carbonyl oxygen (=O) or imino nitrogen (=NH) affords the urea 2c and guanidine 2d which are antagonists of decreased potency. The guanidine is very basic and at physiological pH is completely protonated. However, introduction of strongly electronegative substituents into the guanidine group reduces basicity and gives potent H2-receptor antagonists, viz. the cyanoguanidine 2b (cimetidine, "Tagamet") and nitroguanidine 2e. A correspondence between the activity of thioureas and cyanoguanidines is demonstrated for a series of structures 1-4. The close correspondence between cyanoguanidine and thiourea in many physicochemical properties and the pharmacological equivalence of these groups in H2-receptor antagonists leads to the description of cyanoguanidine and thiourea as bioisosteres. Acid hydrolysis of the cyanoguanidine 2b yields the carbamoylguanidine 2f at ambient temperatures and the guanidine 2d at elevated temperatures. Cimetidine is slightly more active than metiamide in vivo as an inhibitor of histamine-stimulated gastric acid secretion and has clinical use in the treatment of peptic ulcer and associated gastrointestinal disorders.

Potential histamine H2-receptor antagonists. 3. Methylhistamines.

Syntheses are described for all the mono- and some di- and trimethylhistamines. New methods are given for the known Npi, Ntau-, Nalpha-, 2-, and 4-methylhistamines and for the novel compounds, beta-methyl-, 4,Nalpha-dimethyl-, and 4,Nalpha,Nalpha-trimethylhistamines. Agonist activities are reported for stimulation of histamine H1 (guinea-pig ileum) and H2 (rat gastric acid secretion) receptors. H2-Receptor agonist activities indicate that a methyl group is more readily accommodated at the 4 and Nalpha positions than elsewhere in the histamine molecule and that receptor binding is substantially retained with a methyl substituent in these positions. Thus, for the design of potential antagonists, two sites are identified as being worthwhile exploring for the introduction of lipophilic substituents.

Some chemical aspects of histamine H2-receptor antagonists.

Certain chemical properties, which may determine the biological actions of the recently discovered histamine H2-receptor antagonists burimamide and metiamide, are identified, partly by considering the derivation of these antagonists. Examples are given of attempts to design antagonists using histamine as starting point. A partial agonist was eventually obtained through modifying the side chain of histamine but retaining the imidazole ring. Further developments led to the synthesis of uncharged thioureido analogues and to the discovery of the antagonist, burimamide. Consideration of the relative concentration of imidazole tautomers led to the replacement of a methylene group (-CH2-) with an isosteric thioether (-S-) link in the side chain, and incorporation of a methyl group in the imidazole ring; these changes afforded metiamide, an orally active antagonist. These developments emphasize that the imidazole ring appears to have a special importance at H2 receptors. Burimamide and metiamide are hydrophilic molecules that resemble histamine in having an imidazole ring but differ in the side chain which, though polar, is uncharged. By contrast, the H1-receptor antihistaminic drugs are lipophilic molecules; their resemblance to histamine is in having a positively charged ammonium side chain. These substantial chemical differences between the respective antagonists probably determine their selectivity in distinguishing between the two types of histamine receptor. Furthermore, the very low lipophilicities of these H2-receptor antagonists probably account for the lack of central nervous system and local anesthetic effects normally associated with the use of antihistaminic drugs.