Cyprian O. Ogbu

Tryptase Inhibition Blocks Airway Inflammation in a Mouse Asthma Model

Release of human lung mast cell tryptase may be important in the pathophysiology of asthma. We examined the effect of the reversible, nonelectrophilic tryptase inhibitor MOL 6131 on airway inflammation and hyper-reactivity in a murine model of asthma. MOL 6131 is a potent selective nonpeptide inhibitor of human lung mast cell tryptase based upon a β-strand template (Ki = 45 nM) that does not inhibit trypsin (Ki = 1,061 nM), thrombin (Ki = 23, 640 nM), or other serine proteases. BALB/c mice after i.p. OVA sensitization (day 0) were challenged intratracheally with OVA on days 8, 15, 18, and 21. MOL 6131, administered days 18–21, blocked the airway inflammatory response to OVA assessed 24 h after the last OVA challenge on day 22; intranasal delivery (10 mg/kg) had a greater anti-inflammatory effect than oral delivery (10 or 25 mg/kg) of MOL 6131. MOL 6131 reduced total cells and eosinophils in bronchoalveolar lavage fluid, airway tissue eosinophilia, goblet cell hyperplasia, mucus secretion, and peribronchial edema and also inhibited the release of IL-4 and IL-13 in bronchoalveolar lavage fluid. However, tryptase inhibition did not alter airway hyper-reactivity to methacholine in vivo. These results support tryptase as a therapeutic target in asthma and indicate that selective tryptase inhibitors can reduce allergic airway inflammation.

Highly efficient and versatile synthesis of libraries of constrained β-strand mimetics

The general approach of using a bicyclic template to produce inhibitors of the protease superfamily of enzymes has been investigated. The Diels-Alder cycloaddition reaction on solid support has been found to be highly efficient for the synthesis of libraries of compounds that mimic the β-strand secondary structure of proteins. Several potent and selective inhibitors of proteases have been discovered.

Tricarbonyl(tropone)iron as a useful functionalized enone equivalent

Abstract Tricarbonyl(tropone)iron has been shown to undergo reactions that are characteristic of an isolated enone.

Bicyclic β-Strand Templates: Epimerization and Biological Activity of Non-Electrophilic Serine Protease Inhibitors

Previously, we have demonstrated the utility of Diels-Alder cycloaddition in the solid-phase organic synthesis of proteolytic enzyme inhibitors [1]. In the reported syntheses of s-strand mimetics using this methodology, the assumption was that the classic concerted addition of the diene resulted in two enantiomers with the cis configuration. The C5 position of the s-strand mimetic corresponding to the Ca position of the natural amino acid now appears to be epimerizable, either under basic conditions, or elevated temperature. The resulting template enantiomers could have different biological activities as a result of different presentation of side chains, but also as a result of overall change in the conformation of template.