ABSTRACT
The oxetan-3-yl and azetidin-3-yl substituents have previously been identified as privileged motifs within medicinal chemistry. An efficient approach to installing these two modules into aromatic systems, using a nickel-mediated alkyl-aryl Suzuki coupling, is presented.
Subject(s)
Azetidines/chemical synthesis , Benzene Derivatives/chemical synthesis , Ethers, Cyclic/chemical synthesisABSTRACT
The nonsteroidal anti-inflammatory drugs flurbiprofen and ibuprofen were modified in an attempt to alter the kinetics of inhibitor binding by COX-1. Contrary to prior predictions, a halogen substituent is not sufficient to confer slow tight-binding behavior. Conversion of the carboxylate moiety of flurbiprofen to an ester or amide abolishes slow tight-binding behavior, regardless of halogenation state.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cyclooxygenase Inhibitors/pharmacology , Isoenzymes/antagonists & inhibitors , Propionates/chemistry , Propionates/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Binding, Competitive , Carboxylic Acids/chemistry , Cyclooxygenase 1 , Cyclooxygenase Inhibitors/chemistry , Flurbiprofen/chemistry , Flurbiprofen/metabolism , Flurbiprofen/pharmacology , Halogens/chemistry , Ibuprofen/analogs & derivatives , Ibuprofen/pharmacology , Kinetics , Prostaglandin-Endoperoxide Synthases , Sheep , Structure-Activity RelationshipABSTRACT
Prostaglandin H2 synthase (EC 1.14.99.1) is an integral membrane enzyme containing a cyclooxygenase site, which is the target for the non-steroidal anti-inflammatory drugs, and a spatially distinct peroxidase site. Previous crystallographic studies of this clinically important drug target have been hindered by low resolution. We present here the 2.0 A resolution X-ray crystal structure of ovine prostaglandin H2 synthase-1 in complex with alpha-methyl-4-biphenylacetic acid, a defluorinated analog of the non-steroidal anti-inflammatory drug flurbiprofen. Detergent molecules are seen to bind to the protein's membrane-binding domain, and their positions suggest the depth to which this domain is likely to penetrate into the lipid bilayer. The relation of the enzyme's proximal heme ligand His388 to the heme iron is atypical for a peroxidase; the iron-histidine bond is unusually long and a substantial tilt angle is observed between the heme and imidazole planes. A molecule of glycerol, used as a cryoprotectant during diffraction experiments, is seen to bind in the peroxidase site, offering the first view of any ligand in this active site. Insights gained from glycerol binding may prove useful in the design of a peroxidase-specific ligand.
