Dual metalloprotease inhibitors. IV. Utilization of thiazepines and thiazines as constrained peptidomimetic surrogates in mercaptoacyl dipeptides

The Application of Freidinger Lactams and their Analogs in the Design of Conformationally Constrained Peptidomimetics

“…Robl and co-workers at Bristol-Myers Squibb published several series of benzo-fused Freidinger lactams 41 as conformationally restricted mimetics of mercaptoacetyl-AlaPro (40) possessing dual ACE/NEP inhibitory properties [42][43][44][45]. The group also investigated conformationally constrained bicyclic [44,46] and even tricyclic dipeptide mimetics [46,47] which led to the discovery of omapatrilat BMS-186716; (42), a potent ACE/NEP inhibitor [47].…”

“…Renin is an aspartic protease that is produced mainly in the juxtaglomerular apparatus in the kidney. It is a highly specific proteolytic enzyme which cleaves the circulating -globulin angiotensinogen (45) produced by the liver, to form the decapeptide angiotensin I. Despite tremendous efforts to develop selective renin inhibitors from the 1980s no drug acting through this mechanism has yet reached the market [52].…”

New .alpha.-Thiol Dipeptide Dual Inhibitors of Angiotensin-I-Converting Enzyme and Neutral Endopeptidase EC 3.4.24.11

“…(2) to cyclic Boc-protected amino acids by the classical DCC/HOBt method.25'26 Deprotection of the Bocprotected dipeptides with anhydrous HCI gas in methylene chloride afforded the amine hydrochloride salts (4). Coupling of the -mercaptoacyl acids27 (5) to the dipeptide amine hydrochlorides (4) under the standard DCC/HOBt method gave poor yields (<15%) and led to significant racemization of the -thiol center.…”

“…Recently considerable interest has been devoted to the development of dual-acting inhibitors of the membranebound zinc metalloproteases, angiotensin-I converting enzyme and neutral endopeptidase EC 3.4.24.11. [1][2][3][4][5][6][7][8][9][10][11][12] These two ectoenzymes are involved in the metabolism of a variety of regulatory peptides which play an important role in blood pressure control and fluid homeostasis. Angiotensin-I converting enzyme (ACE) is part of the enzymatic cascade of the renin-angiotensin-aldosterone system (RAAS) and catalyzes the conversion of the decapeptide angiotensin-I to the octapeptide angiotensin-II.…”

Synthesis, spectral characterization, and in vitro antibacterial and antifungal activities of novel 1,3-thiazine-2-amines comprising morpholine nucleus

“…2-Amino-1,3-thiazines and their derivatives are chemically and pharmaceutically interesting entities, and have been used as antimicrobial agents 1 , as cannabinoid receptor agonists 2 , in the discovery of CB2 receptors 3 , in the phagocytic activity of human neutrophils 4 , as vasopressin receptor antagonists 5 , and have central nervous system (CNS) and antioxidant properties 6 , analgesic and anti-inflammatory activities 7 , antifilarial properties 8 , metalloprotease inhibition activity 9 , and antihypertensive activity 10 . The presence of the N-C-S linkage is believed to account for the extensive biological activities of the thiazine nucleus.…”