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Development of Domain‐Selective Angiotensin I‐Converting Enzyme Inhibitors
Author(s) -
REDELINGHUYS PIERRE,
NCHINDA ALOYSIUS T.,
STURROCK EDWARD D.
Publication year - 2005
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1352.035
Subject(s) - bradykinin , angiotensin converting enzyme , renin–angiotensin system , chemistry , ectodomain , angiotensin ii , enzyme , pharmacology , homeostasis , biochemistry , endocrinology , biology , blood pressure , receptor
Somatic angiotensin‐converting enzyme (ACE) is an essential component of the renin‐angiotensin system and consequently plays a key role in blood pressure and electrolyte homeostasis. Thus, ACE inhibitors are widely used in the treatment of cardiovascular disease, causing a decrease in the production of angiotensin II and an increase in the circulating vasodilator bradykinin. The ectodomain of ACE consists of two parts (N and C domains), each bearing an active site that differs in substrate and inhibitor specificity. Advances in the elucidation of the functional roles of these two domains and an expanded view of the renin‐angiotensin system underscore the need for the next generation of domain‐selective inhibitors with improved pharmacologic profiles. Moreover, recent breakthroughs in determining the crystal structure of testis ACE (identical to the C domain) and its homologue ACE2 provide new mechanistic insights into the interactions of ACE inhibitors and substrates with active site pockets. This review summarizes the structural basis and recent synthetic chemistry approaches to the development of novel domain‐selective inhibitors.