ABSTRACT
The 4-amino-5-azaindole as an amidino-benzimidazole replacement is described. A series of potent and selective analogs were discovered and showed desirable ex vivo efficacy as measured by PT.
Subject(s)
Factor VIIa/antagonists & inhibitors , Indoles/chemical synthesis , Indoles/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Factor VIIa/metabolism , Indoles/chemistry , Molecular Structure , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
The discovery and development of 5-azaindole factor VIIa inhibitors will be described.
Subject(s)
Aza Compounds/chemical synthesis , Aza Compounds/pharmacology , Factor VIIa/antagonists & inhibitors , Indoles/chemical synthesis , Indoles/pharmacology , Aza Compounds/chemistry , Crystallography, X-Ray , Factor VIIa/chemistry , Factor VIIa/metabolism , Indoles/chemistry , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
Within the trypsin family of coagulation proteases, obtaining highly selective inhibitors of factor VIIa has been challenging. We report a series of factor VIIa (fVIIa) inhibitors based on the 5-amidino-2-(2-hydroxy-biphenyl-3-yl)-benzimidazole (1) scaffold with potency for fVIIa and high selectivity against factors IIa, Xa, and trypsin. With this scaffold class, we propose that a unique hydrogen bond interaction between a hydroxyl on the distal ring of the biaryl system and the backbone carbonyl of fVIIa lysine-192 provides a basis for enhanced selectivity and potency for fVIIa.
Subject(s)
Factor VIIa/antagonists & inhibitors , Binding Sites , Factor Xa Inhibitors , Humans , Hydrogen Bonding , Protein Binding , Prothrombin/antagonists & inhibitors , Structure-Activity Relationship , Trypsin/metabolismABSTRACT
The rational design and synthesis of beta-amino-alpha-hydroxy amide derivatives as reversible inhibitors of methionine aminopeptidase-2 (MetAP2) with anti-proliferative activity against human umbilical vein endothelial cells (HUVECs) is described.
Subject(s)
Amides/chemical synthesis , Aminopeptidases/antagonists & inhibitors , Drug Design , Endothelium, Vascular/drug effects , Endothelium, Vascular/enzymology , Glycoproteins/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Amides/pharmacology , Aminopeptidases/metabolism , Animals , Cattle , Glycoproteins/metabolism , Humans , Methionyl Aminopeptidases , Protease Inhibitors/pharmacologyABSTRACT
Two new alkaloids, polycarpine (1) and N,N-didesmethylgrossularine-1 (4), have been isolated from extracts of the ascidian Polycarpa aurata collected in Chuuk, Federated States of Micronesia. Three degradation products of 1 were also isolated. The structures of 1, 2, and 4 were determined by X-ray crystallography. The dimeric disulfide 1 inhibited the enzyme inosine monophosphate dehydrogenase, but the inhibition could be reversed by addition of excess dithiothreitol suggesting that 1 reacts with sulfhydryl groups on the enzyme.
