Steven Wayne Goldstein

Tetrahydroquinoline derivatives as CRTH2 antagonists

A series of tetrahydroquinoline-derived inhibitors of the CRTH2 receptor was discovered by a high throughput screen. Optimization of these compounds for potency and pharmacokinetic properties led to the discovery of potent and orally bioavailable CRTH2 antagonists.

CP-99,711: a non-peptide glucagon receptor antagonist

Abstract CP-99,711, identified in a screening program, displaces [125I]-glucagon from its rat liver receptor. We describe here the synthesis of this compound and its characterization as a functional glucagon receptor antagonist.

Discovery and Optimization of a Novel Spiropyrrolidine Inhibitor of β-Secretase (BACE1) through Fragment-Based Drug Design

The aspartyl protease β-secretase, or BACE, has been demonstrated to be a key factor in the proteolytic formation of Aβ-peptide, a major component of plaques in the brains of Alzheimers disease (AD) patients, and inhibition of this enzyme has emerged as a major strategy for pharmacologic intervention in AD. An X-ray-based fragment screen of Pfizers proprietary fragment collection has resulted in the identification of a novel BACE binder featuring spiropyrrolidine framework. Although exhibiting only weak inhibitory activity against the BACE enzyme, the small compound was verified by biophysical and NMR-based methods as a bona fide BACE inhibitor. Subsequent optimization of the lead compound, relying heavily on structure-based drug design and computational prediction of physiochemical properties, resulted in a nearly 1000-fold improvement in potency while maintaining ligand efficiency and properties predictive of good permeability and low P-gp liability.

Solid phase synthesis of phosphinopeptoids as transition state analog inhibitors

Abstract A procedure for preparing novel phosphinopeptoids, 1 , on a solid support is described. The key step in the synthesis includes a conjugate addition of the trivalent form of a protected aminomethylphosphinic acid ( 5 ) to a resin-bound acrylate.

α-Azido acids in heterocyclic synthesis

Abstract 2-Aminobenzophenones and acetophenones were N-acylated with α-azido carboxylic acids to give the corresponding anilides. Reductive cyclization provided 3-substituted-2H-1,4-benzodiazepin-2-ones in good (46–99%) yields.