ABSTRACT
Hydroxy urea moieties are introduced as a new class of bradykinin B(1) receptor antagonists. First, the SAR of the lead compound was systematically explored. Subsequent optimization resulted in the identification of several biaryl-based hydroxyurea bradykinin B(1) receptor antagonists with low-nanomolar activity and very high oral bioavailability in the rat.
Subject(s)
Bradykinin B1 Receptor Antagonists , Hydroxyurea/chemistry , Hydroxyurea/metabolism , Receptor, Bradykinin B1/metabolism , Animals , Biological Availability , Caco-2 Cells , Fibroblasts/drug effects , Fibroblasts/metabolism , Humans , Hydroxyurea/administration & dosage , Male , Protein Binding/drug effects , Rats , Rats, WistarABSTRACT
The synthesis and SAR of two series of bradykinin B(1) receptor antagonists is described. The benzamide moiety proved to be a suitable replacement for the aryl ester functionality of biaryl based antagonists. In addition, it was found that semicarbazides can effectively replace cyclopropyl amino acids. The compounds with the best overall profile were biaryl semicarbazides which display high antagonistic activity, low Caco-2 efflux and high oral bioavailability in the rat.
Subject(s)
Benzamides/chemistry , Bradykinin B1 Receptor Antagonists , Semicarbazides/chemistry , Animals , Benzamides/metabolism , Benzamides/pharmacology , Caco-2 Cells , Humans , Male , Microsomes/drug effects , Microsomes/metabolism , Rats , Rats, Wistar , Receptor, Bradykinin B1/metabolism , Semicarbazides/metabolism , Semicarbazides/pharmacologyABSTRACT
Efforts to find new bradykinin B(1) receptor antagonists identified 2-aminobenzimidazole as a novel core. Subsequent transformation into five-membered diaminoheterocycle derivatives and their synthesis and SAR is described. This resulted in compounds with low nanomolar activity.
Subject(s)
Benzimidazoles/chemistry , Bradykinin B1 Receptor Antagonists , Benzimidazoles/metabolism , Benzimidazoles/pharmacology , Cell Line , Diamines/chemistry , Diamines/metabolism , Diamines/pharmacology , Fibroblasts/drug effects , Fibroblasts/metabolism , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/metabolism , Heterocyclic Compounds/pharmacology , Humans , Receptor, Bradykinin B1/metabolism , Structure-Activity RelationshipABSTRACT
The first total synthesis of (+)-astrophylline (2) has been achieved, starting from readily available enantiomerically pure (+)-(1R,4S)-4-hydroxycyclopent-2-enyl acetate (11). A novel ruthenium-catalyzed ring-closing ring-opening ring-closing metathesis of carbocyclic olefins of general type 5 was the key step, providing the stereochemically well-defined bis-piperidyl skeleton of the target molecule. A [2,3]-Wittig-Still rearrangement of 9 was also employed as the critical transformation in the stereocontrolled generation of the 1,2-trans configuration of the cyclopentene intermediate 6c. Our early synthetic efforts toward 1,2-trans cyclopentene derivatives of type 6, as well as the synthetic pathway to an optimized 13-step total synthesis of 2 (12% overall yield), are reported.
