Philippe G. Nantermet

A facile three-step synthesis of 1,2-amino alcohols using the Ellman homochiral tert-butylsulfinamide

Abstract Addition of organometallic reagents to tert -butylsulfinimines derived from tert -butyldimethylsiloxyacetaldehyde stereoselectively generates protected 1,2-amino alcohols. Removal of the acid labile protecting groups affords amino alcohols in high yield. The predominant diastereomer is opposite to that predicted by the traditional Ellman model; therefore, a chelation model invoking rapid E / Z isomerization of the imine is proposed to rationalize the observed selectivity.

Pharmacokinetic optimization of 3-amino-6-chloropyrazinone acetamide thrombin inhibitors. Implementation of P3 pyridine N-oxides to deliver an orally bioavailable series containing P1 N-benzylamides.

In this manuscript we demonstrate that a modification principally directed toward the improvement of the aqueous solubility (i.e., introduction a P3 pyridine N-oxide) of the previous lead compound afforded a new series of potent orally bioavailable P1 N-benzylamide thrombin inhibitors. An expedited investigation of the P1 SAR with respect to oral bioavailability, plasma half-life, and human liver microsome stability revealed 5 as the best candidate for advanced evaluation.

Unexpected enhancement of thrombin inhibitor potency with o-aminoalkylbenzylamides in the P1 position.

Thrombin inhibitors incorporating o-aminoalkylbenzylamides in the P1 position were designed, synthesized and found to have enhanced potency and selectivity in several different structural classes. X-ray crystallographic analysis of compound 24 bound in the alpha-thrombin-hirugen complex provides an explanation for these unanticipated results.

Discovery of a nonpeptidic small molecule antagonist of the human platelet thrombin receptor (PAR-1)

The synthesis and biological evaluation of a series of nonpeptidic small molecule antagonists of the human platelet thrombin receptor (PAR-1) are described. Optimization of the 5-amino-3-arylisoxazole lead resulted in an approximate 100-fold increase in potency. The most potent of these compounds (54) inhibits platelet activation with IC(50)s of 90 nM against the thrombin receptor agonist peptide (TRAP) and 510 nM against thrombin as the agonist. Further, antagonist 54 fully blocks platelet aggregation stimulated by 1 nM thrombin for 10 min.

Discovery and initial structure-activity relationships of trisubstituted ureas as thrombin receptor (PAR-1) antagonists.

Thrombin is the most potent agonist of platelet activation, and its effects are predominantly mediated by platelet thrombin receptors. Therefore, antagonists of the thrombin receptor have potential utility for the treatment of thrombotic disorders. Screening of combinatorial libraries revealed 2 to be a potent antagonist of the thrombin receptor. Modifications of this structure produced 11k, which inhibits thrombin receptor stimulated secretion and aggregation of platelets.

Design and synthesis of potent and selective macrocyclic thrombin inhibitors

A series of potent and selective proline- and pyrazinone-based macrocyclic thrombin inhibitors is described. Detailed SAR studies led to the incorporation of specific functional groups in the tether that enhanced functional activity against thrombin and provided exquisite selectivity against trypsin and tPA. X-ray crystallography and molecular modeling studies revealed the inhibitor-enzyme interactions responsible for this selectivity.

SAR of tertiary carbinamine derived BACE1 inhibitors: Role of aspartate ligand amine pKa in enzyme inhibition

The optimization of tertiary carbinamine derived inhibitors of BACE1 from its discovery as an unstable lead to low nanomolar cell active compounds is described. Five-membered heterocycles are reported as stable and potency enhancing linkers. In the course of this work, we have discovered a clear trend where the activity of inhibitors at a given assay pH is dependent on pK(a) of the amino group that interacts directly with the catalytic aspartates. The potency of compounds as inhibitors of Alphabeta production in a cell culture assay correlated much better with BACE1 enzyme potency measured at pH 7.5 than at pH 4.5.

Rapid P1 SAR of brain penetrant tertiary carbinamine derived BACE inhibitors

This Letter describes the one pot synthesis of tertiary carbinamine 3 and related analogs of brain penetrant BACE-1 inhibitors via the alkylation of the Schiff base intermediate 2. The methodology developed for this study provided a convenient and rapid means to explore the P1 region of these types of inhibitors, where the P1 group is installed in the final step using a one-pot two-step protocol. Further SAR studies led to the identification of 10 which is twofold more potent in vitro as compared to the lead compound. This inhibitor was characterized in a cisterna magna ported rhesus monkey model, where significant lowering of CSF Abeta40 was observed.

Evolution of tertiary carbinamine BACE-1 inhibitors: Aβ reduction in rhesus CSF upon oral dosing

Evolution of Tertiary Carbinamine BACE-1 Inhibitors: Ab Reduction in Rhesus CSF upon Oral Dosing Philippe G. Nantermet,* Hemaka A. Rajapakse, Mathew G. Stanton, Shaun R. Stauffer, James C. Barrow, Allison R. Gregro, Keith P. Moore, Melissa A. Steinbeiser, John Swestock, Harold G. Selnick, Samuel L. Graham, Georgia B. McGaughey, Dennis Colussi, Ming-Tain Lai, Sethu Sankaranarayanan, Adam J. Simon, Sanjeev Munshi, Jacquelynn J. Cook, Marie A. Holahan, Maria S. Michener, and Joseph P. Vacca

Recent Advances Toward Pain Therapeutics

Publisher Summary This chapter focuses on recent advances toward pain therapeutics. Two of the most promising novel targets actively pursued for chronic pain are the voltage-gated sodium (Nav) channels—in particular Nav 1.3, 1.7, and 1.8—and nerve growth factor (NGF/tropomyosin-related kinase receptor A (TrkA). Both of these targets are predominantly localized in the periphery. The achievement of good target selectivity with small molecules is also a common challenge of both pathways. A summary of recent drug development for these two pathways, highlighting recent developments and progress made toward finding truly selective inhibitors, is provided in the chapter. In contrast to sodium channels and NGF/TrkA, fatty acid amide hydrolase (FAAH) is believed to play a significant role in both the periphery and the central nervous system. The chapter covers some recently disclosed novel noncovalent inhibitors and clinical data that raise questions about the validity of the target. The treatment of chronic pain is potentially on the cusp of entering a new era with a number of novel mechanistic approaches in clinical development. Many of these novel mechanisms present unique medicinal chemistry challenges in developing safe and effective medicines.