Maurice J. van Eis

Identification of Orally Available Naphthyridine Protein Kinase D Inhibitors

A novel 2,6-naphthyridine was identified by high throughput screen (HTS) as a dual protein kinase C/D (PKC/PKD) inhibitor. PKD inhibition in the heart was proposed as a potential antihypertrophic mechanism with application as a heart failure therapy. As PKC was previously identified as the immediate upstream activator of PKD, PKD vs PKC selectivity was essential to understand the effect of PKD inhibition in models of cardiac hypertrophy and heart failure. The present study describes the modification of the HTS hit to a series of prototype pan-PKD inhibitors with routine 1000-fold PKD vs PKC selectivity. Example compounds inhibited PKD activity in vitro, in cells, and in vivo following oral administration. Their effects on heart morphology and function are discussed herein.

Identification of Potent and Selective Amidobipyridyl Inhibitors of Protein Kinase D

The synthesis and biological evaluation of potent and selective PKD inhibitors are described herein. The compounds described in the present study selectively inhibit PKD among other putative HDAC kinases. The PKD inhibitors of the present study blunt phosphorylation and subsequent nuclear export of HDAC4/5 in response to diverse agonists. These compounds further establish the central role of PKD as an HDAC4/5 kinase and enhance the current understanding of cardiac myocyte signal transduction. The in vivo efficacy of a representative example compound on heart morphology is reported herein.

2,6-Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes.

The present study describes a novel series of ATP-competitive PKC inhibitors based on the 2,6-naphthyridine template. Example compounds potently inhibit the novel Protein Kinase C (PKC) isotypes δ, ε, η, θ (in particular PKCε/η, and display a 10-100-fold selectivity over the classical PKC isotypes. The prototype compound 11 was found to inhibit PKCθ-dependent pathways in vitro and in vivo. In vitro, a-CD3/a-CD28-induced lymphocyte proliferation could be effectively blocked in 10% rat whole blood. In mice, 11 dose-dependently inhibited Staphylococcus aureus enterotoxin B-triggered IL-2 serum levels after oral dosing.

Novel ROCK inhibitors for the treatment of pulmonary arterial hypertension.

A novel class of selective inhibitors of ROCK1 and ROCK2 has been identified by structural based drug design. PK/PD experiments using a set of highly selective Rho kinase inhibitors suggest that systemic Rho kinase inhibition is linked to a reversible reduction in lymphocyte counts. These results led to the consideration of topical delivery of these molecules, and to the identification of a lead molecule 7 which shows promising PK and PD in a murine model of pulmonary hypertension after intra-tracheal dosing.

1,4-Addition of a Terminal Phosphinidene Complex to [5]Metacyclophane

Three novel aspects emerge for the reaction of [5]metacyclophane (1) with the (intermediate) phenylphosphinidene complex 2 to give the 7-phosphanorbornadiene 3. It is the first 1,4-addition of a phosphinidene complex to an unsaturated system, the first addition of a phosphinidene complex to a benzene ring, and the first [4+1] cycloaddition to an aromatic compound.

Discovery and profiling of a selective and efficacious syk inhibitor.

We describe the discovery of selective and potent Syk inhibitor 11, which exhibited favorable PK profiles in rat and dog and was found to be active in a collagen-induced arthritis model in rats. Compound 11 was selected for further profiling, but, unfortunately, in GLP toxicological studies it showed liver findings in rat and dog. Nevertheless, 11 could become a valuable tool compound to investigate the rich biology of Syk in vitro and in vivo.

Syk inhibitors with high potency in presence of blood.

We describe two series of Syk inhibitors which potently abrogate Syk kinase function in enzymatic assays, cellular assays and in primary cells in the presence of blood. Introduction of a 7-aminoindole substituent led to derivatives with good kinase selectivity and little or no hERG channel inhibition (3b, 10c).

1,4-Addition of a Phosphinidene Complex to Cisoid 1,3-Dienes

Abstract The first genuine 1,4-additions of the terminal phosphinidene complex PhPW(CO)5 (2) to 1,3-dienes 3 are reported. Two of the 1,4-adducts, 15 and 17, were characterised by X-ray crystal structure determinations. A cisoid conformation, but not coplanarity, of 3 appears to be a prerequisite for the occurrence of a 1,4-addition. The reaction of 2 with the sterically hindered 3B yields 66.5% of the 1,4-addition product 13, the highest percentage of 1,4-addition thus far observed for the reaction of an electrophilic species with a 1,3-diene. The product composition is almost independent of the temperature, implying that the usual preference for the 1,2-mode is mainly entropy controlled. Steric factors appear to be the main cause of the higher tendency towards 1,4-addition of phosphinidines as compared to carbenes.

Synthesis and anomalous structure–reactivity relationship of 8,11-dichloro[5]metacyclophan-3-one

Abstract The synthesis, structural characterisation, and reactivity of the title compound are reported. It was prepared in order to investigate the effects of incorporation of an sp2-centre in the bridge of a [5]metacyclophane on its structure and reactivity. An X-ray crystal structure of the cyclophanone demonstrates that the benzene ring is distorted to the same extent as in the hydrocarbon parent compound, while there is less strain in the bridge. Nevertheless, the cyclophanone displays a reduced reactivity in Diels–Alder reactions, which is tentatively ascribed to transition state effects. Calculations indicate that in spite of the close proximity between the ketone functionality and the benzene ring, there are no π–π interactions between them.

Sandwiching C70 between two crown ether-bound cations: regioselective synthesis, electrochemistry and cation binding properties of C70 bis-crown ether conjugates

Tetrakis-adducts of C70, featuring two covalently attached crown ethers, form stable 1 ∶ 1 and 1 ∶ 2 host–guest complexes with alkali metal cations. A large influence of cation complexation on the first reduction potential of the fullerene was observed.