Peter Hans Dorff

A SOLID PHASE CBZ CHLORIDE EQUIVALENT : A NEW MATRIX SPECIFIC LINKER

Abstract Treatment of TentaGel S resin (1) with phosgene provides matrix linked chloroformate (2), which is converted to the corresponding carbamoylated derivatives 3a and 3b. Alternatively, Wang resin provides the imidazolide (7a), which is readily transformed to amides and esters by treatment with nitrogen and carbon nucleophiles, respectively.

Metabolism-Directed Design of Oxetane-Containing Arylsulfonamide Derivatives as γ-Secretase Inhibitors

A metabolism-based approach toward the optimization of a series of N-arylsulfonamide-based γ-secretase inhibitors is reported. The lead cyclohexyl analogue 6 suffered from extensive oxidation on the cycloalkyl motif by cytochrome P450 3A4, translating into poor human liver microsomal stability. Knowledge of the metabolic pathways of 6 triggered a structure-activity relationship study aimed at lowering lipophilicity through the introduction of polarity. This effort led to several tetrahydropyran and tetrahydrofuran analogues, wherein the 3- and 4-substituted variants exhibited greater microsomal stability relative to their 2-substituted counterparts. Further reduction in lipophilicity led to the potent γ-secretase inhibitor and 3-substituted oxetane 1 with a reduced propensity toward oxidative metabolism, relative to its 2-substituted isomer. The slower rates of metabolism with 3-substituted cyclic ethers most likely originate from reductions in lipophilicity and/or unfavorable CYP active site interactions with the heteroatom. Preliminary animal pharmacology studies with a representative oxetane indicate that the series is generally capable of lowering Aβ in vivo. As such, the study also illustrates the improvement in druglikeness of molecules through the use of the oxetane motif.

Preparation and reactions of chiral propargylic amines

Abstract Exposure of chiral amino aldehydes ( 1 ) to dimethyl diazophosphonate ( 4 ) affords propargylic amines ( 2 ) of high optical purity. Chain extension of these intermediates is readily accomplished via hydrozirconation of the acetylene moiety and subsequent Ni(II) catalyzed Michael addition to a variety of Michael acceptors.

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.

Novel solid-phase preparation of 2,6,9-trisubstituted purines for combinatorial library generation

Abstract A novel procedure for the preparation of 2,6,9-trisubstituted purine libraries has been developed.

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.