Kenneth J. Shaw

Design, synthesis, and in vitro biological activity of benzimidazole based factor Xa inhibitors

Inhibitors based on the benzimidazole scaffold showed subnanomolar potency against Factor Xa with 500-1000-fold selectivity against thrombin and 50-100-fold selectivity against trypsin. The 2-substituent on the benzimidazole ring had a strong impact on the FXa inhibitory activity. Crystallography studies suggest that the 2-substituent may have a conformational effect favoring the extended binding conformation.

Structure-activity relationships of substituted benzothiophene-anthranilamide factor Xa inhibitors

Compound 1 was identified by high throughput screening as a novel, potent, non-amidine factor Xa inhibitor with good selectivity against thrombin and trypsin. A series of modifications of the three aromatic groups of 1 was investigated. Substitution of chlorine or bromine for fluorine on the aniline ring led to the discovery of subnanomolar factor Xa inhibitors. Positions on the anthranilic acid ring that can accommodate further substitution were also identified.

Crystallographic analysis of potent and selective factor Xa inhibitors complexed to bovine trypsin.

Factor Xa is a serine protease which activates thrombin (factor IIa) and plays a key regulatory role in the blood-coagulation cascade. Factor Xa is, therefore, an important target for the design of anti-thrombotics. Both factor Xa and thrombin share sequence and structural homology with trypsin. As part of a factor Xa inhibitor-design program, a number of factor Xa inhibitors were crystallographically studied complexed to bovine trypsin. The structures of one diaryl benzimidazole, one diaryl carbazole and three diaryloxypyridines are described. All five compounds bind to trypsin in an extended conformation, with an amidinoaryl group in the S1 pocket and a second basic/hydrophobic moiety bound in the S4 pocket. These binding modes all bear a resemblance to the reported binding mode of DX-9065a in bovine trypsin and human factor Xa.

Synthesis and biological evaluation of piperazine-based derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)

Compound 1 was identified by high throughput screening as a novel PAI-1 inhibitor. Optimization of the B and C-segments of 1 resulted in a series of structurally simplified compounds with improved potency. The synthesis and SAR data of these compounds are presented here.

Design, synthesis, and in vitro biological activity of indole-based factor Xa inhibitors

A series of indole and carbazole based inhibitors of factor Xa (FXa) has been investigated. The most potent compound inhibits FXa with a Ki of 0.2 nM and has 900- and 750-fold selectivity over thrombin and trypsin, respectively.

Design, synthesis, and biological activity of novel factor Xa inhibitors: 4-aryloxy substituents of 2,6-diphenoxypyridines.

A novel series of triaryloxypyridines have been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. Inhibitor 5e has a K(I) against factor Xa of 0.12nM and is greater than 8000- and 2000-fold selective over two related serine proteases, thrombin and trypsin, respectively. The 4-position of the central pyridine has been identified as a site that tolerates various substitutions without deleterious effects on potency and selectivity. This suggests that the 4-position of the pyridine ring is an ideal site for chemical modifications to identify inhibitors with improved pharmacokinetic characteristics. This investigation has resulted in inhibitor 5d, which has an oral availability of 6% in dogs. The synthesis, in vitro activity, and in vivo profile of this class of inhibitors is outlined.

Benzimidazole-Based fXa inhibitors with improved thrombin and trypsin selectivity

Optimization of the benzimidazole-based fXa inhibitors for selectivity versus thrombin and trypsin was achieved by substitution on the benzimidazole ring and replacement of the naphthylamidine group. Substitution of a nitro group at the 4-position on the benzimidazole improves both potency against fXa and selectivity versus thrombin. Alternatively, replacement of the naphthylamidine with either a biphenylamidine or propenylbenzamidine not only improves fXa potency and selectivity versus thrombin, but selectivity versus trypsin as well.

Design and synthesis of aminophenol-based factor Xa inhibitors

A novel potent and selective aminophenol scaffold for fXa inhibitors was developed from a previously reported benzimidazole-based naphthylamidine template. The aminophenol template is more synthetically accessible than the benzimidazole template, which simplified the introduction of carboxylic acid groups. Substitution of a propenyl-para-hydroxy-benzamidine group on the aminophenol template produced selective, sub-nanomolar fXa inhibitors. The potency of the inhibitors is partially explained with the aid of a trypsin complex crystal structure.

Chapter 1. New Anxiolytics

Publisher Summary While the disease state of anxiety is not yet fully understood, the structure elucidation of the macromolecular complex consisting of chloride channel, barbiturate receptor, gamma-aminobutyric acid (GABA) receptor, and benzodiazepine (BZ) receptor has increased the likelihood that the specificity of future therapeutics can be improved. The existence of GABA A and GABA B receptors and the subtyping of the BZ receptor into w 1 , w 2 , and w 3 subtypes through selective ligands and molecular biology have further raised hopes that a much improved anxiolytic can be discovered. In addition, accumulating evidence has continued to support the original electrophysiological findings that first suggested that cholecystokinin (CCK) may have a role in inducing anxiety. The reported beneficial effects of 5-HT 1 , 5-HT 2 , and 5-HT 3 receptor subtype ligands in anxiety have kept alive interest in serotonin (5-HT) as a modulator of anxiety. The chapter discusses the research interest in an area where, compared to other central nervous system (CNS) diseases, existing therapy is relatively safe and effective. Anxiety disorders can have serious consequences. Panic disorders are treated with monoamine oxidase inhibitors, benzodiazepines, and tricyclic antidepressants. Clomipramine, a tricyclic, has been approved by the FDA for obsessive–compulsive disorder. The chapter describes the molecular biology of GABA A receptors and presents a study on the benzodiazepine receptor subtypes, relative binding affinities of selected benzodiazepine receptor ligands, as well as details on benzodiazepine full, partial, and inverse agonists and other benzodiazepine ligands, along with the features and properties of CCK receptors and the contribution of the changes in brain serotonin levels to anxiety. The serotonin uptake inhibitors, chemistry, clinical pharmacology, pharmacokinetics, and adverse effects have also been described in detail in the chapter.