Daniel G.M. Roberts

Derivatives of 5-amidine indole as inhibitors of thrombin catalytic activity

Abstract Substituted 5-amidine indoles were constructed based upon a computational analysis of putative modes of binding to thrombin utilizing coordinates from the crystal structure of BMS-183,507-α-thrombin complex. These analogs display competitive kinetics for the inhibition of human α-thrombin. The most potent member of this series 17, shows marked potency for thrombin with an inhibition constant, Ki of 260 nM.

ARGATROBAN ANALOGS : SYNTHESIS, THROMBIN INHIBITORY ACTIVITY AND CELL PERMEABILITY OF AMINOHETEROCYCLIC GUANIDINE SURROGATES

Abstract A series of Argatroban analogs, 3–6 , in which the guanidino group was replaced by amino-substituted heterocycles of decreasing basicity were prepared and evaluated for their ability to inhibit human α-thrombin. Basicity was found to be important in determining inhibitory potency. Aminopyridine analog 3b (pK a ∼7) afforded the most potent inhibition (I 50 =0.47 μM) and exhibited enhanced Caco-2 cell permeability.

α-hydroxy- and α-ketoester functionalized thrombin inhibitors

Abstract α-Hydroxy- and α-ketoester functionalized D-Phe-Pro-Lys tripeptides were found to be potent thrombin active site inhibitors. The ketoester derivatives were characterized by slow binding kinetics. The most potent of the series was 9 (BMS 181, 412) with an overall inhibition constant Ki* of 0.0017 μM.

Molecular design and structure-activity relationships leading to the potent, selective, and orally active thrombin active site inhibitor BMS-189664.

A series of structurally novel small molecule inhibitors of human alpha-thrombin was prepared to elucidate their structure-activity relationships (SARs), selectivity and activity in vivo. BMS-189664 (3) is identified as a potent, selective, and orally active reversible inhibitor of human alpha-thrombin which is efficacious in vivo in a mouse lethality model, and at inhibiting both arterial and venous thrombosis in cynomolgus monkey models.

Thrombin active site inhibitors: chemical synthesis, in vitro and in vivo pharmacological profile of a novel and selective agent BMS-189090 and analogues.

A series of structurally novel small molecule inhibitors of human alpha-thrombin was prepared to elucidate their structure- activity relationships (SAR), selectivity and activity in vivo. BMS-189090 (5) is identified as a potent, selective, and reversible inhibitor of human alpha-thrombin that is efficacious in vivo in a mice lethality model, and in inhibiting both arterial and venous thrombosis in a rat model.

The Secondary Drying and the Fate of Organic Solvents for Spray Dried Dispersion Drug Product

PurposeTo understand the mechanisms of secondary drying of spray-dried dispersion (SDD) drug product and establish a model to describe the fate of organic solvents in such a product.MethodsThe experimental approach includes characterization of the SDD particles, drying studies of SDD using an integrated weighing balance and mass spectrometer, and the subsequent generation of the drying curve. The theoretical approach includes the establishment of a Fickian diffusion model.ResultsThe kinetics of solvent removal during secondary drying from the lab scale to a bench scale follows Fickian diffusion model. Excellent agreement is obtained between the experimental data and the prediction from the modeling.ConclusionsThe diffusion process is dependent upon temperature. The key to a successful scale up of the secondary drying is to control the drying temperature. The fate of primary solvents including methanol and acetone, and their potential impurity such as benzene can be described by the Fickian diffusion model. A mathematical relationship based upon the ratio of diffusion coefficient was established to predict the benzene concentration from the fate of the primary solvent during the secondary drying process.

Solid-phase synthesis of benzisothiazolones as serine protease inhibitors

An efficient solid-phase synthesis of benzisothiazolone-1,1-dioxide-based serine protease inhibitors involving alkylation of carboxylic acids with N-(bromomethyl)benzisothiazolone-1,1-dioxide has been developed. An example using this procedure for preparation of a library of human mast cell tryptase inhibitors is described.

Retro-binding thrombin active site inhibitors: Identification of an orally active inhibitor of thrombin catalytic activity

A series of retro-binding inhibitors of human alpha-thrombin was prepared to elucidate structure-activity relationships (SAR) and optimize in vivo performance. Compounds 9 and 11, orally active inhibitors of thrombin catalytic activity, were identified to be efficacious in a thrombin-induced lethality model in mice.