Angiotensin Converting Enzyme Inhibitors: A Class of Potent Antihypertensive Agents pp. 63-96
Authors: (Sharad Kumar Panday, Jagdish Prasad, Manohar Bhushan Pathak, Department of Applied Chemistry, Faculty of Engineering and Technology, M. J. P. Rohilkhand University, Bareilly, U. P., India)
Abstract: Hypertension, a major cause of heart-diseases is caused by malfunction of one or more of the complex set of mechanisms controlling blood pressure. In last four decades specific agents interacting with these regulatory mechanisms have become available. Introduction in early eighties of Captopril, a rationally designed potent inhibitor of Angiotensin converting enzymes (ACE), heralded a new era in antihypertensive therapy. Since then rapid strides have been made in understanding of the active site and the spatial requirements for ACE inhibitors. This chapter has been aimed to report the existing knowledge and to enable researchers all over the world to exploit further with an objective to develop better therapeutic agents. Bio receptors being chiral, interactions with organic molecules are strongly influenced by the chirality of the substrate. The two enantiomers of a drug are some times known to elicit differential and in some cases even opposite responses, amply heightened by work on ACE inhibitors. The present trend, in drug research, is to design and synthesize molecules with designated chirality. ACE inhibitors represent a class of rationally designed drugs based on the comprehensive knowledge of the enzyme and its binding sites and had led to great revolution in antihypertensive therapy. ACE is a Zn++ containing metalloenzyme similar to carboxypeptidases, whose binding sites have been studied properly and a hypothetical model incorporating all the binding sites have been developed. Based on the hypothetical model for ACE binding sites and the role which it plays in living organism, attempts have been made to develop potent inhibitors of ACE with an objective to control blood pressure. Early researches on ACE inhibitors started with snake venom peptides, showing antihypertensive activity. Though these could not be used as drugs due to high toxicity but certainly opened an avenue to look for development of antihypertensive agents on these lines. Further researches coupled with structure activity relationship (SAR) studies led to development of various ACE inhibitors and ultimately in early eighty‘s first rationally designed drug ―Captopril‖ was introduced in market. Since then various other drugs acting through same mechanism and controlling blood pressure effectively have come out.