Patric James Hahn

Use of solid supported nucleophiles and electrophiles for the purification of non-peptide small molecule libraries

Abstract Solid supported nucleophiles and electrophiles are employed to expedite the work-up and purification of a variety of amine alkylations acylacylations. These solid suported scavengers are particularly advantageous for the construction of non-peptide libraries in a parallel array format.

Rapid purification of small molecule libraries by ion exchange chromatography

Abstract Amines and acylated amines are synthesized in traditional solution phase reactions, then rapidly purified by ion exchange chromatography to yield pure products. In some instances, impurities devoid of ionizable functionality can be covalently modified prior to purification. The generic purification sequence is applicable to a variety of reactions, and is amenable to automation with commercially available equipment.

Rapid parallel synthesis applied to the optimization of a series of potent nonpeptide neuropeptide Y-1 receptor antagonists

Abstract This study describes the integrated application of parallel synthesis and computational chemistry to the design of potent nonpeptide antagonists for the neuropeptide Y-1 (NPY1) receptor. A lead molecule was modeled in the active site of the NPY1 receptor, and a potentially fruitful region for analog construction was identified. Synthesis of suitable scaffolds followed by solution phase generation of a small library of analogs produced a compound with 5-fold improvement in binding over the already potent lead. This new compound was shown to be an unanticipated side product of the parallel synthesis reaction.

Discovery of the First α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Antagonist Dependent upon Transmembrane AMPA Receptor Regulatory Protein (TARP) γ-8

Transmembrane AMPA receptor regulatory proteins (TARPs) are a family of scaffolding proteins that regulate AMPA receptor trafficking and function. TARP γ-8 is one member of this family and is highly expressed within the hippocampus relative to the cerebellum. A selective TARP γ-8-dependent AMPA receptor antagonist (TDAA) is an innovative approach to modulate AMPA receptors in specific brain regions to potentially increase the therapeutic index relative to known non-TARP-dependent AMPA antagonists. We describe here, for the first time, the discovery of a noncompetitive AMPA receptor antagonist that is dependent on the presence of TARP γ-8. Three major iteration cycles were employed to improve upon potency, CYP1A2-dependent challenges, and in vivo clearance. An optimized molecule, compound (-)-25 (LY3130481), was fully protective against pentylenetetrazole-induced convulsions in rats without the motor impairment associated with non-TARP-dependent AMPA receptor antagonists. Compound (-)-25 could be utilized to provide proof of concept for antiepileptic efficacy with reduced motor side effects in patients.