ABSTRACT
Three zinc metallopeptidases are implicated in the regulation of fluid homeostasis and vascular tone and represent interesting targets for the treatment of chronic heart failure. We have previously reported the synthesis of a triple inhibitor able to simultaneously inhibit neprilysin (NEP, EC 3.4.24.11), angiotensin-converting enzyme (ACE, EC 3.4.15.1) and endothelin-converting enzyme (ECE-1, EC 3.4.24.71) with nanomolar potency towards NEP and ACE and a lesser affinity for ECE. Here, we report the optimization and biological activities of analogs derived from lead compound 1 (2S)-2-[(2R)-2-((1S)-5-bromo-indan-1-yl)-3-mercapto-propionylamino]-3- (1H-indol-3-yl)-propionic acid by a structural approach. Among several inhibitors, compound 21, (2S)-2-[(2R)-2-((1S)-5-bromo-indan-1-yl)-3-mercapto-propionylamino]-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionic acid was selected by taking into account its good molecular adaptation with the recently published structures of the three vasopeptidases. This optimization procedure led to an improved pharmacologic activity when compared with 1.
Subject(s)
Alanine/chemistry , Alanine/pharmacology , Angiotensin-Converting Enzyme Inhibitors/chemistry , Aspartic Acid Endopeptidases/antagonists & inhibitors , Indans/chemistry , Indans/pharmacology , Neprilysin/antagonists & inhibitors , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Tryptophan/analogs & derivatives , Alanine/analogs & derivatives , Alanine/chemical synthesis , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Endothelin-Converting Enzymes , Indans/chemical synthesis , Male , Metalloendopeptidases/antagonists & inhibitors , Metalloendopeptidases/metabolism , Molecular Structure , Peptidyl-Dipeptidase A/metabolism , Protease Inhibitors/chemical synthesis , Rats , Rats, Wistar , Structure-Activity Relationship , Sulfhydryl Compounds/chemistry , Tryptophan/chemistry , Vascular Diseases/therapyABSTRACT
The first synthesis of siderophore conjugates of two macrolide antibiotics, spiramycin 1 and neospiramycin 2, which are unable to penetrate the outer membrane of gram-negative bacteria are described. These novel conjugates were prepared by regioselective acylation of a hydroxyl function of 1 and 2 with a dihydroxybenzoic Fe(III) complexing ligand linked via a carboxyl group containing spacer to the macrolide antibiotics. The preliminary biological evaluation of these novel conjugates under standard and iron depleted conditions has shown that their antibacterial activity was comparable to that of spiramycin 1 and neospiramycin 2.