Dennis R. Berry

Indole inhibitors of human nonpancreatic secretory phospholipase A2. 3. Indole-3-glyoxamides.

Phospholipases (PLAs) produce rate-limiting precursors in the biosynthesis of various types of biologically active lipids involved in inflammatory processes. Increased levels of human nonpancreatic secretory phospholipase A2 (hnps-PLA2) have been detected in several pathological conditions. An inhibitor of this enzyme could have therapeutic utility. A broad screening program was carried out to identify chemical structures which could inhibit hnps-PLA2. One of the lead compounds generated by the screening program was 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid (13a). We describe the syntheses, structure−activity relationships, and pharmacological activities of a series of indole-3-acetamides and related compounds derived from this lead. This SAR was undertaken with the aid of X-ray crystal structures of complexes between the inhibitors and hnps-PLA2 which were of great value in directing the SAR.

Synthesis and structure-activity relationships of benzophenones as inhibitors of cathepsin D

Abstract Non peptide inhibitors of cathepsin D, an aspartyl protease that has been implicated in many disease states including Alzheimers disease, were prepared and evaluated. The most potent inhibitor of cathepsin D in this series was found to be (Z)-5-[[4-(4-benzoyl-3-hydroxy-2-propylphenoxy) methylphenyl]methylene]-2-thioxo-4-thiazolidinone ( 3f , IC 50 = 210 nM).

Platelet glycoprotein IIb–IIIa receptor (GPIIb–IIIa) antagonists derived from amidinoindoles

Abstract A series of substituted amidinoindoles have been prepared as mimics of the RGD sequence and were studied as antagonists of the platelet glycoprotein IIb–IIIa receptor (GPIIb–IIIa). The agents were potent and selective antagonists of GPIIb–IIIa. Compared to their acyclic counterparts, the amidinoindole series bound with 10- to 20-fold greater affinity, indicating the advantages of added conformational restriction and/or hydrophobicity in the basic region of RGD mimics.

Enzymatic removal of a cephalosporin methyl ester blocking group

Abstract Over 7000 microorganisms were screened to find an enzyme source for the hydrolysis of a C 4 methyl ester blocking group on 7-aminodesacetoxycephalosporanic acid (7-ADCA). Only one culture, Streptomyces capillispira Mertz and Higgens nov. sp., produced an enzyme that catalysed the reaction. Enzyme synthesis in a defined mineral salts medium was repressed by NH 3 and amino acids. Under optimum fermentation conditions, the maximum rate of substrate hydrolysis was 6 × 10 −10 mol min −1 mg −1 cell. The enzyme was recovered from the mycelia and partially purified by gel filtration. Kinetic studies by pH-stat titration indicated that the pH optimum was 7.5–8.5, the temperature optimum was 25–30°C, and the substrate K m value was 2.3 mg ml −1 . The reaction products, 7-ADCA and methanol, were weak competitive inhibitors of the enzyme with K 1 values of 6.63 and 0.188 mg ml −1 , respectively. The enzyme also hydrolysed cefaclor and cephalexin methyl esters but did not hydrolyse cephalosporin ethyl esters. With further improvements in enzyme yields and stability, enzymatic deblocking of cephalosporins could provide an alternative to chemical deblocking processes.

Characterization of LY806303 as a potent and selective inhibitor of thrombin

Abstract Methyl 3-(2-methyl-1-oxopropoxy)[1]benzothieno[3,2-b]furan-2-carboxylate (LY806303; 1) has been characterized as a novel, potent and selective inhibitor thrombin.