Synthesis and evaluation of multisubstrate bicyclic pyrimidine nucleoside inhibitors of human thymidine phosphorylase.

A series of novel, multisubstrate, bicyclic pyrimidine nucleoside inhibitors of human thymidine phosphorylase (TP) is described. Thymidine phosphorylase has been implicated in angiogenesis and plays a significant role in tumor progression and metastasis. The presence and orientation of the phosphonate moiety (acting as a phosphate mimic) in these derivatives were critical for inhibitory activity. The most active compounds possessed a phosphonate group in an endo orientation. This was consistent with molecular modeling results that showed the endo isomer protein-ligand complex to be lower in energy than the exo complex.

First-in-class pan caspase inhibitor developed for the treatment of liver disease.

A series of oxamyl dipeptides were optimized for pan caspase inhibition, anti-apoptotic cellular activity and in vivo efficacy. This structure-activity relationship study focused on the P4 oxamides and warhead moieties. Primarily on the basis of in vitro data, inhibitors were selected for study in a murine model of alpha-Fas-induced liver injury. IDN-6556 (1) was further profiled in additional in vivo models and pharmacokinetic studies. This first-in-class caspase inhibitor is now the subject of two Phase II clinical trials, evaluating its safety and efficacy for use in liver disease.

Structure-activity relationships within a series of caspase inhibitors. Part 2: Heterocyclic warheads.

Various heterocyclic hetero-methyl ketones of the 1-naphthyloxyacetyl-Val-Asp backbone have been prepared. A study of their structure-activity relationship (SAR) related to caspase-1, -3, -6, and -8 is reported. Their efficacy in a cellular model of cell death is also discussed. Potent broad-spectrum caspase inhibitors have been identified.

Oxamyl dipeptide caspase inhibitors developed for the treatment of stroke.

Structural modifications were made to a previously described acyl dipeptide caspase inhibitor, leading to the oxamyl dipeptide series. Subsequent SAR studies directed toward the warhead, P2, and P4 regions of this novel peptidomimetic are described herein.

Structure-activity relationships within a series of caspase inhibitors: effect of leaving group modifications.

Various aryloxy methyl ketones of the 1-naphthyloxyacetyl-Val-Asp backbone have been prepared. A systematic study of their structure-activity relationship (SAR) related to caspases 1, 3, 6, and 8 is reported. Highly potent irreversible broad-spectrum caspase inhibitors have been identified. Their efficacy in cellular models of cell death and inflammation are also discussed.

Design of novel N-(2,4-dioxo-1,2,3,4-tetrahydro-thieno[3,2-d]pyrimidin-7-yl)-guanidines as thymidine phosphorylase inhibitors, and flexible docking to a homology model.

A novel class of thymidine phosphorylase (TP) inhibitors has been designed based on analogy to the enzyme substrate as well as known inhibitors. Flexible docking studies, using a homology model of human TP, of the designed N-(2,4-dioxo-1,2,3,4-tetrahydro-thieno[3,2-d]pyrimidin-7-yl)-guanidines as well as their synthetic precursors provide insight into the observed experimental trends in binding affinity.

Acyl dipeptides as reversible caspase inhibitors. Part 1: initial lead optimization.

Parallel synthesis was used to explore the SAR of a peptidomimetic caspase inhibitor. The most potent compound had nanomolar activity against caspases 1, 3, 6, 7, and 8.

Acyl dipeptides as reversible caspase inhibitors. Part 2: further optimization.

A new structural class of broad spectrum caspase inhibitors was optimized for its activity against caspases 1, 3, 6, 7, and 8. The most potent compound had low nanomolar broad spectrum activity, in particular, single digit nanomolar inhibitory activity against caspase 8.