Marc Adler

Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A4 hydrolase.

Leukotriene B(4) (LTB(4)) is a potent pro-inflammatory mediator that has been implicated in the pathogenesis of multiple diseases, including psoriasis, inflammatory bowel disease, multiple sclerosis and asthma. As a method to decrease the level of LTB(4) and possibly identify novel treatments, inhibitors of the LTB(4) biosynthetic enzyme, leukotriene A(4) hydrolase (LTA(4)-h), have been explored. Here we describe the discovery of a potent inhibitor of LTA(4)-h, arylamide of glutamic acid 4f, starting from the corresponding glycinamide 2. Analogs of 4f are then described, focusing on compounds that are both active and stable in whole blood. This effort culminated in the identification of amino alcohol 12a and amino ester 6b which meet these criteria.

The Structure of a 19-Residue Fragment from the C-loop of the Fourth Epidermal Growth Factor-like Domain of Thrombomodulin

The solution structure has been determined for a 19-residue peptide that is fully folded at room temperature. The sequence of this peptide is based on the C-loop, residues 371-389, of the fourth epidermal growth factor-like domain of thrombomodulin, a protein that acts as a cofactor for the thrombin activation of protein C. Despite its small size, the peptide forms a compact structure with almost no repeating secondary structure. The results indicate the structure is held together by hydrophobic interactions, which in turn stabilize the two β-turns in the structure. The first β-turn in the C-loop represents a conserved motif that is found in the published structures of five other epidermal growth factor-like proteins. The critical role of Phe376 in the stabilization of the first β-turn is consistent with mutagenesis data with soluble thrombomodulin. The results also show that a small subdomain of a larger protein can fold independently, and therefore it could act as an initiation site for further folding.

Novel cinnoline-based inhibitors of LRRK2 kinase activity.

Leucine rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinsons disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of cinnoline-3-carboxamides that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays. These compounds are also shown to be potent inhibitors in a cellular assay and to have good to excellent CNS penetration.

Discovery of 4-alkylamino-7-aryl-3-cyanoquinoline LRRK2 kinase inhibitors

Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with familial Parkinsons disease (PD). The kinase activity of this complex protein is increased by pathogenic mutations. Inhibition of LRRK2 kinase activity has therefore emerged as a promising approach for the treatment of PD. Herein we report our findings on a series of 4-alkylamino-7-aryl-3-cyanoquinolines that exhibit kinase inhibitory activity against both wild type and G2019S mutant LRRK2. Activity was determined in both biochemical and cellular assays. Compound 14 was further evaluated in an in vivo pharmacodynamic study and found to significantly inhibit Ser935 phosphorylation after oral dosing.

Triazolopyridazine LRRK2 kinase inhibitors

Leucine-rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinsons disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of [1,2,4]triazolo[4,3-b]pyridazines that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays and show an unprecedented selectivity towards the G2019S mutant. A structural rational for the observed selectivity is proposed.

Removal of dispersive baseline distortions caused by strong water signals

A baseline correction routine that eliminates dispersive tails extending from the water tr noise band in 2D NMR spectra has been developed. Streaks along the w2 axis (Fig. la) spreading from the w2 position of the water resonance are among the most perturbing artifacts in 2D NMR spectra where the water signal is reduced by presaturation. In our experience, these streaks have dispersive lineshapes and cannot be eliminated with conventional baseplane correction routines, such as polynomial fits. They also add significantly to the apparent noise in the entire 2D spectra. To properly correct for these distortions, an w;’ term has been added to the polynomial baseline correction routine of our 2D processing software (FTNMR, Hare Research, Inc.). This term estimates the amount of the dispersive component. The actual correction baseplane is constructed as a sum of a constant offset, a linear term, and a dispersive component where the weight of the latter is calculated from the contribution of the w;’ term. With this procedure we have achieved major improvements of the quality of the spectra and of the apparent signal-to-noise in 2D protein spectra in water recorded with presaturation. Presaturation of the water signal was the first method to record 2D NMR spectra in H20 (1, 2), and it is still the most common technique for recording 2D NMR spectra of proteins in H20. During the recycle delay between accumulations, a long selective pulse is applied to the water resonance. Usually, the transmitter and the decoupler are set to the water frequency in order to minimize distortions in 2D spectra. Phase coherence of transmitter and decoupler is important for good water suppression. Nevertheless, this technique leaves residual artifacts. An example is shown in Figs. 1 and 2. In the 1 D spectra of a 5 mM solution of the protein kistrin (3) collected with this technique, the water peak was roughly 50 times higher than the largest methyl signals. A NOESY spectrum acquired under these conditions has large ridges parallel to w2 (Fig. la). As shown in Fig. 2, these ridges are due to large dispersive artifactual signals centered at the water frequency. A conventional polynomial baseline correction cannot accurately reproduce a dispersive lineshape. Also, this technique is very sensitive to the choice of reference points for the polynomial fit. Since the reference points for the polynomial fit can only be used from regions of the spectrum where there are no resonances, this procedure is not very practical for crowded protein spectra. An alternative procedure has been

Identification of orally bioavailable, non-amidine inhibitors of Urokinase Plasminogen Activator (uPA)

In this Letter we report the synthesis and evaluation of a series of non-amidine inhibitors of Urokinase Plasminogen Activator (uPA). Starting from compound 1, a significant change provided compounds in which the amidine, binding in the S1 pocket, was replaced with a primary amine. Further modifications led to the identification of potent, selective, and orally bioavailable uPA inhibitors.

Discovery of selective urokinase plasminogen activator (uPA) inhibitors as a potential treatment for multiple sclerosis

We report here the design and synthesis of a novel series of benzylamines that are potent and selective inhibitors of uPA with promising oral availability in rat. Further evaluation of one representative (ZK824859) of the new structural class showed that this compound lowered clinical scores when dosed in either acute or chronic mouse EAE models, suggesting that uPA inhibitors of this type could be useful for the treatment of multiple sclerosis.