Investigation of the S3 site of thrombin: design, synthesis and biological activity of 4-substituted 3-amino-2-pyridones incorporating P1-argininals.

A novel scaffold for P4-P2 dipeptide mimics containing a rigid pyridone spacer was designed based on a virtual library strategy. Several selected nonpeptidic 4-aralkyl or 4-alkylpyridones incorporating a P1-argininal sequence were prepared. The modeling studies, synthesis and biological activities of these unique pyridone derivatives are reported herein.

Assessing homeless mentally ill persons for permanent housing: screening for safety.

Although placement in community housing is a frequent intervention with populations of seriously mentally ill homeless individuals, there has been little formal investigation of the criteria used by clinicians in screening individuals for such placement. In this paper, we describe screening a population of 303 homeless people with severe mental illness for placement in independent apartments. We assess subjects' level of risk along multiple dimensions and determine the contribution of each risk dimension to the final safety decision. In addition, we evaluate the validity of the risk measures with other measures of clinical condition. Two-thirds of the sample were judged as safe for independent living. Assaultiveness was the most frequent risk identified, followed by self-destructiveness, substance abuse, and medication non-compliance. The final safety decision was associated most strongly with assaultiveness, self-destructiveness, and medication non-compliance. We conclude that it is possible to assess risk with measures that are available from shelter and medical records, and call for more research on the role of medication non-compliance in safety decisions and for longitudinal research to validate risk assessments.

Crystallographic structure of a peptidyl keto acid inhibitor and human alpha-thrombin.

The low molecular weight alpha-keto amide inhibitor CVS-1347, benzyl-SO2-Met(O2)-Pro-Arg(CO)((CONH)CH2)-phenyl, is a slow, tight binding inhibitor of alpha-thrombin amidolytic activity having a Ki = 1.28 x 10(-10) M. A complex between human alpha-thrombin and a hydrolysis product of CVS-1347 has been determined and refined using crystallography. The crystals belong to monoclinic space group C2 with cell dimensions of a = 71.08, b = 72.05 and c = 72.98 A and beta = 100.8 degrees. The structure was solved using isomorphous replacement methods and refined with resolution limits of (8.00-1.76) A to an R-value of 0.162. The Pro-Arg core of the inhibitor binds in the S2 and S1 subsites respectively, as is usually observed for Pro-Arg thrombin inhibitors. The Met(O2) side chain does not make any close contacts with the enzyme but influences the conformation of Glu192; the N-terminal benzylsulfonyl group makes an aromatic-aromatic contact with Trp215 in the hydrophobic part of the active site. The alpha-keto carboxylic acid of the proteolyzed inhibitor binds with the carboxylate group in the oxyanion hole, demonstrating that this region can accommodate an anion in a protease-peptide complex. The alpha-keto carbonyl group interacts closely with the two most important residues in the active site: the carbon atom is within a covalent bond distance of the active site Ser195 O gamma and the carbonyl oxygen is hydrogen bonded to His57.(ABSTRACT TRUNCATED AT 250 WORDS)

Heteroaryl-fused 2-phenylisothiazolone inhibitors of cartilage breakdown.

The synthesis, biological evaluation, and structure-activity relationships of a series of N-phenyl heteroaryl-fused isothiazolones are described. These isothiazolones have been shown to exhibit potent, dose-dependent inhibition of IL-1 beta-induced breakdown of proteoglycan in a cartilage organ culture assay. This effect is likely due to inhibition of MMP activation and a consequent reduction in MMP activity following IL-1 beta stimulation. Thus these compounds potentially represent simple, non-peptidic disease-modifying agents for the treatment of arthritic diseases. To examine the effects of structure on in vitro activity, three general features of the molecules were varied, substituents on the pendant N-phenyl group, the position of ring fusion to the isothiazolone, and substituents on the fused ring peri to the isothiazolone sulfur.