Edwin J. Iwanowicz

A mild and efficient method for the preparation of guanidines

Abstract A mild and efficient method for the preparation of guanidines by reaction of an acylated thiourea with an amine followed by removal of the acyl group(s) from the intermediate acylguanidine is reported.

Rapid synthesis of triazine inhibitors of inosine monophosphate dehydrogenase

A series of novel triazine-based small molecule inhibitors (IV) of inosine monophosphate dehydrogenase was prepared. The synthesis and the structure-activity relationships (SAR) derived from in vitro studies are described.

Derivatives of 5-amidine indole as inhibitors of thrombin catalytic activity

Abstract Substituted 5-amidine indoles were constructed based upon a computational analysis of putative modes of binding to thrombin utilizing coordinates from the crystal structure of BMS-183,507-α-thrombin complex. These analogs display competitive kinetics for the inhibition of human α-thrombin. The most potent member of this series 17, shows marked potency for thrombin with an inhibition constant, Ki of 260 nM.

Identification of novel and potent isoquinoline aminooxazole-Based IMPDH inhibitors

Screening of our in-house compound collection led to the discovery of 5-bromo-6-amino-2-isoquinoline 1 as a weak inhibitor of IMPDH. Subsequent optimization of 1 afforded a series of novel 2-isoquinolinoaminooxazole-based inhibitors, represented by 17, with single-digit nanomolar potency against the enzyme.

Reaction of quinoxalin-2-ones with TosMIC reagent: synthesis of imidazo[1,5-a]quinoxalin-4-ones

Abstract Imidazo[1,5-a]quinoxalin-4-ones were prepared in four steps starting from 1,2-phenylenediamines using a new strategy for the construction of the ring system. A key step in this new method involves the reaction of quinoxalin-2-ones with TosMIC (tosylmethyl isocyanide).

Inhibitors of inosine monophosphate dehydrogenase: SARs about the N-[3-Methoxy-4-(5-oxazolyl)phenyl moiety

The first reported structure-activity relationships (SARs) about the N-[3-methoxy-4-(5-oxazolyl)phenyl moiety for a series of recently disclosed inosine monophosphate dehydrogenase (IMPDH) inhibitors are described. The syntheses and in vitro inhibitory values for IMPDH II, and T-cell proliferation (for select analogues) are given.

Discovery and initial SAR of imidazoquinoxalines as inhibitors of the Src-family kinase p56Lck

We have identified a novel series of 1,5-imidazoquinoxalines as inhibitors of Lck with excellent potency (IC50s<5 nM) as well as good cellular activity against T-cell proliferation (IC50s<1 microM). Structure-activity studies demonstrate the requirement for the core heterocycle in addition to an optimal 2,6-disubstituted aniline group.

α-hydroxy- and α-ketoester functionalized thrombin inhibitors

Abstract α-Hydroxy- and α-ketoester functionalized D-Phe-Pro-Lys tripeptides were found to be potent thrombin active site inhibitors. The ketoester derivatives were characterized by slow binding kinetics. The most potent of the series was 9 (BMS 181, 412) with an overall inhibition constant Ki* of 0.0017 μM.

3-Cyanoindole-based inhibitors of inosine monophosphate dehydrogenase: synthesis and initial structure–Activity relationships

A series of novel small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH), based upon a 3-cyanoindole core, were explored. IMPDH catalyzes the rate determining step in guanine nucleotide biosynthesis and is a target for anticancer, immunosuppressive and antiviral therapy. The synthesis and the structure-activity relationships (SAR), derived from in vitro studies, for this new series of inhibitors is given.

A survey of cyclic replacements for the central diamide moiety of inhibitors of inosine monophosphate dehydrogenase.

A series of heterocyclic replacements for the central diamide moiety of 1, a potent small molecule inhibitor of inosine monophosphate dehydrogenase (IMPDH) were explored The synthesis and the structure-activity relationships (SARs), derived from in vitro studies, for these new series of inhibitors is given.