Kimberly Suzanne Para

Design and synthesis of morpholine derivatives. SAR for dual serotonin & noradrenaline reuptake inhibition.

Single enantiomer (SS) and (RR) 2-[(phenoxy)(phenyl)methyl]morpholine derivatives 5, 8-23 are inhibitors of monoamine reuptake. Target compounds were prepared using an enantioselective synthesis employing a highly specific enzyme-catalysed resolution of racemic n-butyl 4-benzylmorpholine-2-carboxylate (26) as the key step. Structure-activity relationships established that serotonin and noradrenaline reuptake inhibition are functions of stereochemistry and aryl/aryloxy ring substitution. Consequently, selective SRI, selective NRI and dual SNRIs were all identified. One of these compounds, a potent and selective dual SNRI, (SS)-5a was selected as a candidate for further pre-clinical evaluation.

Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging.

Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes in diabetes, oncology, and neurology. N-(3-(1H-1,2,4-triazol-1-yl)propyl)-5-(3-chloro-4-methoxyphenyl)oxazole-4-carboxamide (PF-04802367 or PF-367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK-3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation in vitro and in vivo. Whereas the kinetics of PF-367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF-367 is ideal for discovery of radiopharmaceuticals for GSK-3 in the central nervous system. A (11) C-isotopologue of PF-367 was synthesized and preliminary PET imaging studies in non-human primates confirmed that we have overcome the two major obstacles for imaging GSK-3, namely, reasonable brain permeability and displaceable binding.

Nonpeptidic HIV protease inhibitors: 3-(S-benzyl substituted)-4-hydroxy-6-(phenyl substituted)-2H-pyran-2-one with an inverse mode of binding

Abstract Systematic substitutions on 6-phenyl and 3-SCH 2 Ph rings of inhibitor 1 , were carried out to optimize the inhibitory activity against HIV PR. These studies lead to 3-Sbenzyl esters with enhanced potency. The X-ray crystal structure of 32 bound to HIV PR revealed that the 3-SCH 2 phenyl group is occupying the P 2 ′ pocket, which is contrary to the binding mode of 1 (derivative lacking ortho isopropyl ester group). In the latter case, benzyl group occupies the P 1 ′ pocket.