Adam Kois

THE DISCOVERY AND STRUCTURE-ACTIVITY RELATIONSHIPS OF NONPEPTIDE, LOW MOLECULAR WEIGHT ANTAGONISTS SELECTIVE FOR THE ENDOTHELIN ETB RECEPTOR

The systematic modification of the ETA selective N-(5-isoxazolyl)benzene-sulfonamide endothelin antagonists to give ETB selective antagonists is reported. The reversal in selectivity was brought about by substitution of the 4-position with aryl and substituted aryl groups. Of all the aromatic substituents studied, the para-tolyl group gave rise to the most active and selective ETB antagonist. Larger substituents caused a decrease in both ETB activity and selectivity. A similar trend was observed by substitution at the 5-position of the N-(5-isoxazolyl)-2-thiophenesulfonamide ETA receptor antagonists. The para-tolyl group was again found to be optimal for the ETB activity and selectivity. The structural features that were found to be favorable for binding to the ETB receptor, that is, the presence of a linear, conjugated π-system of definite shape and size, have been successfully incorporated into the design of ETB selective polycyclic aromatic sulfonamides antagonists.

Thiophenesulfonamides as endothelin receptor antagonists

Abstract The synthesis and in vitro binding affinities of a series of thiophenesulfonamides as ETA selective endothelin receptor antagonists is described. The most potent inhibitor displayed an IC50 of 43 nM and 3 μM to ETA and ETB receptors, respectively.

Aminopurine based JNK inhibitors for the prevention of ischemia reperfusion injury.

In this Letter we describe the optimization of an aminopurine lead (1) with modest potency and poor overall kinase selectivity which led to the identification of a series of potent, selective JNK inhibitors. Improvement in kinase selectivity was enabled by introduction of an aliphatic side chain at the C-2 position. CC-359 (2) was selected as a potential clinical candidate for diseases manifested by ischemia reperfusion injury.

Halogen substitution at the isoxazole ring enhances the activity of N-(isoxazolyl)sulfonamide endothelin antagonists

Abstract Replacement of the 4-methyl group in a series of N-(3,4-dimethylisoxazolyl)benzenesulfonamide endothelin antagonists with a bromine or chlorine atom resulted in a three- to ten-fold increase in the binding affinity for both the ETA and ETB receptors. This potentiation in activities was also observed for naphthalene and biphenylsulfonamide endothelin antagonists.