Showing papers in "Progress in Medicinal Chemistry in 1993"

Amidines and guanidines in medicinal chemistry.

Abstract: Publisher Summary This chapter focuses on amidines and guanidines in medicinal chemistry. The drugs are classified under their main physiological activities and within each group are arranged roughly in order of increasing molecular complexity. Many of the compounds have given temporary excitement to their discoverers and then been dropped—the commonest experience in medicinal chemistry. There are important, clinically used, medicines in all the major categories of therapeutic action discussed in the chapter. This simple and very unstable compound is not only a neurotransmitter in the brain, but acts in the dilation of blood vessels and activates leucocytes to attack tumour cells, fungi, and bacteria. In addition, nitric oxide can inhibit blood coagulation by preventing platelet aggregation and appears to be the regulator of the male erection. No doubt other functions will be discovered in the future, but the interesting finding for the present chapter is that the NO is formed by nitric oxide synthetase from arginine—the only essential amino acid which carries a guanidine group. Since most of the active guanidine drugs have at least one unsubstituted =NH or NH 2 group, it is interesting to speculate that they will be shown to act by giving nitric oxide as well.

Biological significance of manganese in mammalian systems.

Abstract: Publisher Summary This chapter discusses biological significance of manganese in mammalian systems. For manganese in mammalian systems, more information is now available on the sites of action and interaction at the molecular and cellular levels, due to an explosion of new findings within the past decade. Although, this has produced more viable hypotheses, manganese exhibits such a multiplicity and complexity of action that no single, unifying concept or model is likely to emerge. First, it is important to distinguish conceptually between ‘manganese activated (or inhibited)’ and ‘manganese containing’ enzyme systems—the latter being in the minority, with arginase and manganese superoxide dismutase being the best known examples. Manganese-activated systems are the general rule, typically having tight, rapidly reversible, manganese-specific sites involved with either catalytic or regulatory function. The limited number of redox enzymes reported to involve Mn(II) or Mn(III) directly in catalysis include catalase, a peroxidase, a hydroxylase, and manganese superoxide dismutase, all of which utilize one-electron redox reactions.

Semi-synthetic derivatives of erythromycin.

Abstract: Semi-synthetic derivatives of erythromycin have played an important role in antimicrobial chemotherapy. First generation derivatives such as 2'-esters and acid-addition salts significantly improved the chemical stability and oral bioavailability of erythromycin. A second generation of erythronolide-modified derivatives: roxithromycin, clarithromycin, azithromycin, dirithromycin and flurithromycin, have been synthesized and have exhibited significant improvements in pharmacokinetic and/or microbiological features. In addition, erythromycin itself has expanded its utility as an effective antibiotic against a variety of newly emerged pathogens. As a result of these developments, macrolide antibiotics have enjoyed a resurgence in clinical interest and use during the past half-dozen years, and semi-synthetic derivatives of erythromycin should continue to be important contributors to this macrolide renaissance. Despite these recent successes, other useful niches for macrolide antibiotics will remain unfilled. Consequently, the search for new semi-synthetic derivatives of erythromycin possessing even better antimicrobial properties should be pursued.

Approach to the chemotopography of the digitalis recognition matrix in Na+/K(+)-transporting ATPase as a step in the rational design of new inotropic steroids.

Abstract: Publisher Summary This chapter discusses approach to the chemotopography of the digitalis recognition matrix in Na+/K+ transporting ATPase as a step in the rational design of new inotropic steroids. The need for new inotropic drugs follows from the prevalence and mortality of congestive heart failure in the developed countries, and from the fact that the cardiac drugs currently available are clearly inadequate to restore health or even to minimize discomfort and disability. The most suitable method for the quantitative evaluation of the positive inotropic effect of a cardioactive steroid is at present the assessment of its influence on the isometric contraction curve, measured in isolated papillary muscles. To obtain reliable data for the comparison of the inotropic potency of the various cardioactive steroids, it is important to perform the experiments under identical conditions. All inhibitors of the Na+/K+ pump irrespective of their 'microscopic' inhibitory mechanism produce positive inotropic effects if they do not additionally affect other biochemical systems which preclude the manifestation of the inotropic action.

Inhibitors of enkephalin-degrading enzymes as potential therapeutic agents

Abstract: A limited number of enzymes such as membrane metalloendopeptidase (enkephalinase) and angiotensin converting enzyme appear to be involved in deactivation and modulation of circulatory regulatory peptides Peptides such as the enkephalins are also involved in a large number of physiological processes This multiplicity of physiological roles has made it difficult to establish the therapeutic role of enkephalin-degrading enzyme inhibitors Other factors such as difficulty in quantification and thus measurement of processes involved in pain and mental illness have also hindered the process of establishing any therapeutic role of enkephalin-degrading enzyme inhibitors in these conditions However, they have proved to be useful pharmacological 'tools' The most likely therapeutic role at present appears to be in the treatment of cardiovascular disorders As a 'profile' of pharmacological actions of enkephalin-degrading enzymes emerges, it is becoming apparent that bioavailability rather than a high degree of specificity or inhibitory potency may be the most important factor This may be used to an advantage in future developments by the use of less specific or combined inhibitors in the form of prodrugs, designed to be active at specific sites such as the central nervous system

Recent advances in the chemistry and biology of retinoids.

Abstract: Publisher Summary This chapter focuses on the role of retinoic acid in cell differentiation as it relates to disease, particularly of cancers and the chemoprevention or treatments thereof, much investigational work has been exerted towards determining the role of retinoids, retinoid nuclear receptors, and homeobox genes in development, morphogenesis, and organogenesis. Retinoids (analogues of vitamin A, retinol) comprise a unique class of anti-tumour agents able to convert a transformed, undifferentiated, neoplastic cell to a normal, terminally differentiated cell phenotype. With the discovery of this cytodifferentiating carcinostatic activity began a surge in the synthesis of new analogues in order to improve the therapeutic efficacy relative to the accepted standard, retinoic acid, a retinol metabolite and the most potent naturally occuring retinoid. Synthetic efforts are exerted to maximize anti-cancer activity while minimizing the toxic effects exhibited in animals and humans, collectively termed hypervitaminosis A. Over a period spanning more than ten years hundreds of retinoids have been synthesized and methods have been developed to evaluate their biological and/or therapeutic potential. Several proteins are found to bind retinoids and are shown to be important in their transport.