Molecular modeling of the myosin-S1(A1) isoform.

Type II myosin is the molecular motor which drives contraction upon cyclic interaction with filamentous actin while consuming ATP. The contemporary crystallographic structure of the myosin subfragment-1 (S1) of myosin covers both the motor domain of the heavy chain (MHC) as well as the essential (ELC) and regulatory light chains (RLC). A part of the N-terminus of the ELC is, however, missing in the 3D-models of Type II myosin.

Rational design of novel, potent small molecule pan-selectin antagonists.

This report describes the first results of a rational hit-finding strategy to design novel small molecule antiinflammatory drugs targeting selectins, a family of three cellular adhesion molecules. Based on recent progress in understanding of molecular interaction between selectins and their natural ligands as well as progress in clinical development of synthetic antagonists like 1 (bimosiamose, TBC1269), this study was initiated to discover small molecule selectin antagonists with improved pharmacological properties. Considering 1 as template structure, a ligand-based approach followed by focused chemical synthesis has been applied to yield novel synthetic small molecules (MWr < 500) with a trihydroxybenzene motif, bearing neither peptidic nor glycosidic components, with nanomolar in vitro activity.

Tolerability and pharmacokinetics of inhaled bimosiamose disodium in healthy males.

Aims: The aim of these first-in-human studies was to investigate the tolerability and the pharmacokinetics of bimosiamose disodium (TBC1269Z) administered by inhalation.

Methods: Two randomized, double-blind, placebo-controlled Phase I trials were performed in healthy males. In a single-dose escalating study 48 subjects received doses of 2-140 mg bimosiamose disodium by inhalation and in a multiple-dose study 32 subjects received 8-70 mg bimosiamose disodium twice daily.

Pan-selectin antagonism improves psoriasis manifestation in mice and man.

The selectin family of vascular cell adhesion molecules is comprised of structurally related carbohydrate binding proteins, which mediate the initial rolling of leukocytes on the activated vascular endothelium. Because this process is one of the crucial events in initiating and maintaining inflammation, selectins are proposed to be an attractive target for the development of new antiinflammatory therapeutics. Here, we demonstrate that the synthetic pan-selectin antagonist bimosiamose is effective in pre-clinical models of psoriasis as well as in psoriatic patients.