Gregory H. Merriman

Structure-based library design and the discovery of a potent and selective mast cell β-tryptase inhibitor as an oral therapeutic agent

A solid phase combinatorial library was designed based on X-ray structures and in-silico models to explore an inducible S4+ pocket, which is formed by a simple side-chain rotation of Tyr95. This inducible S4+ pocket is unique to β-tryptase and does not exist for other trypsin-like serine proteases of interest. Therefore, inhibitors utilizing this pocket have inherent advantages for being selective against other proteases in the same family. A member of this library was found to be a potent and selective β-tryptase inhibitor with a suitable pharmacokinetic profile for further clinical evaluation.

The enantioselective synthesis and antiinflammatory activity of novel aryl-sphingolipid PKC inhibitors

Abstract Recently we identified three promising topically active antiinflammatory agents ( 2 , 3 , and 4 ) from a series of racemic aryl-sphingolipids that inhibit protein kinase C (PKC). We now wish to report the enantioselective synthesis of the aforementioned leads and their comparative biological profile. The individual enantiomers examined are equipotent to their racemate in vitro and in vivo .

Aryl-fused sphingolipids as novel PKC inhibitors with topical antiinflammatory activity

Abstract Novel aryl-fused sphingolipids, in which aryl-/heteroaryl-moieties were incorporated into the allylic 4,5,6-positions of sphingosine, were prepared and found to possess good in vitro PKC inhibitory activity. (3-(1-Dodecynyl)phenyl)- and (4- and (5-(1-dodecynyl)-2-thienyl)-2-amino-1,3-propanediols were found to have topical antiinflammatory activity comparable to sphingosine.