Inhibition of noroviruses by piperazine derivatives.

There is currently an unmet need for the development of small-molecule therapeutics for norovirus infection. The piperazine scaffold, a privileged structure embodied in many pharmacological agents, was used to synthesize an array of structurally-diverse derivatives which were screened for anti-norovius activity in a cell-based replicon system. The studies described herein demonstrate for the first time that functionalized piperazine derivatives possess anti-norovirus activity. Furthermore, these studies have led to the identification of two promising compounds (6a and 9l) that can be used as a launching pad for the optimization of potency, cytotoxicity, and drug-like characteristics.

Dual function inhibitors of relevance to chronic obstructive pulmonary disease.

The general strategy and rationale underlying the design of COPD therapeutics that possess protease inhibitory activity and are also capable of releasing a species that attenuates inflammation by inhibiting caspase-1, are described. The synthesis and in vitro biochemical evaluation of a dual function molecule that sequentially inhibits HNE and caspase-1 in a time-dependent manner is reported.

Design, synthesis, and evaluation of inhibitors of Norwalk virus 3C protease.

The first series of peptidyl aldehyde inhibitors that incorporate in their structure a glutamine surrogate has been designed and synthesized based on the known substrate specificity of Norwalk virus 3C protease. The inhibitory activity of the compounds with the protease and with a norovirus cell-based replicon system was investigated. Members of this class of compounds exhibited noteworthy activity both in vitro and in a cell-based replicon system.

Potent inhibition of Norwalk virus by cyclic sulfamide derivatives.

A new class of compounds that exhibit anti-norovirus activity in a cell-based system and embody in their structure a cyclosulfamide scaffold has been identified. The structure of the initial hit (compound 2a, ED(50) 4 µM, TD(50) 50 µM) has been prospected by exploiting multiple points of diversity and generating appropriate structure-activity relationships.

Effects of structure on inhibitory activity in a series of mechanism-based inhibitors of human neutrophil elastase.

A structurally-diverse series of carboxylate derivatives based on the 1,2,5-thiadiazolidin-one 1,1 dioxide scaffold were synthesized and used to probe the S' subsites of human neutrophil elastase (HNE) and neutrophil proteinase 3 (Pr 3). Several compounds are potent inhibitors of HNE but devoid of inhibitory activity toward Pr 3, suggesting that the S' subsites of HNE exhibit significant plasticity and can, unlike Pr 3, tolerate various large hydrophobic groups. The results provide a promising framework for the design of highly selective inhibitors of the two enzymes.

Utilization of the 1,2,3,5-thiatriazolidin-3-one 1,1-dioxide scaffold in the design of potential inhibitors of human neutrophil proteinase 3.

The S' subsites of human neutrophil proteinase 3 (Pr 3) were probed by constructing diverse libraries of compounds based on the 1,2,3,5-thiatriazolidin-3-one 1,1-dioxide using combinational and click chemistry methods. The multiple points of diversity embodied in the heterocyclic scaffold render it well-suited to the exploration of the S' subsites of Pr 3. Molecular modeling studies suggest that further exploration of the S' subsites of Pr 3 using the aforementioned heterocyclic scaffold may lead to the identification of highly selective, reversible competitive inhibitors of Pr 3.

Design, synthesis, and in vitro evaluation of potential West Nile virus protease inhibitors based on the 1-oxo-1,2,3,4-tetrahydroisoquinoline and 1-oxo-1,2-dihydroisoquinoline scaffolds.

The 1-oxo-1, 2, 3, 4-tetrahydroisoquinoline and 1-Oxo-1, 2-dihydroisoquinoline scaffolds were utilized in the design and solution phase synthesis of focused libraries of compounds for screening against West Nile Virus (WNV) protease. Exploratory studies have led to the identification of a WNV protease inhibitor (a 1-oxo-1, 2-dihydroisoquinoline-based derivative, 12j) which could potentially serve as a launching pad for a hit-to-lead optimization campaign. The identified hit was devoid of any inhibitory activity toward a panel of mammalian serine proteases.

Mechanism-based inhibitors of serine proteases with high selectivity through optimization of S' subsite binding.

A series of mechanism-based inhibitors designed to interact with the S' subsites of serine proteases was synthesized and their inhibitory activity toward the closely-related serine proteases human neutrophil elastase (HNE) and proteinase 3 (PR 3) was investigated. The compounds were found to be time-dependent inhibitors of HNE and were devoid of any inhibitory activity toward PR 3. The results suggest that highly selective inhibitors of serine proteases whose primary substrate specificity and active sites are similar can be identified by exploiting differences in their S' subsites. The best inhibitor (compound 16) had a k(inact)/K(I) value of 4580 M(-1)s(-1).

Inhibitors of human neutrophil elastase based on a highly functionalized N-amino-4-imidazolidinone scaffold.

A series of compounds based on the N-amino-4-imidazolidinone scaffold was synthesized and screened against human neutrophil elastase (HNE). These studies lead to the identification of a selective, low micromolar reversible competitive inhibitor of HNE.