Regina M. Black

Fluorinated piperidine acetic acids as γ-secretase modulators

We report herein a novel series of difluoropiperidine acetic acids as modulators of gamma-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective beta-difluorination with Selectfluor. Compounds 1f and 2c were selected for in vivo assessment and demonstrated selective lowering of Abeta42 in a genetically engineered mouse model of APP processing. Moreover, in a 7-day safety study, rats treated orally with compound 1f (250mg/kg per day, AUC(0-24)=2100microMh) did not exhibit Notch-related effects.

The basal SAR of a novel insulin receptor activator.

The synthesis and SAR of analogues prepared from novel insulin receptor activator 1 are described. Changes to the dihydroxyquinone core were not tolerated while functionalization of the two indoles contained in 1 resulted in little effect upon activation of the insulin receptor.

Pneumocandin antifungal lipopeptides. The phenolic hydroxyl is required for 1,3-β-glucan synthesis inhibition.

Abstract Pneumocandin B 0 1 undergoes selective oxidation / reduction chemistry at the homotyrosine ( hty ) residue. Removal of the phenolic hydroxyl gives >140-fold loss in activity against a Candida albicans 1,3-β-glucan synthetase enzyme preparation and a significant loss of antifungal activity. Inversion of the C4- hty hydroxyl causes about a 70-fold decrease in potency, while removal of this hydroxyl yields a more potent inhibitor.

Reduction studies of antifungal echinocandin lipopeptides. One step conversion of echinocandin B to Echinocandin C

Abstract Sodium cyanoborohydride in trifluoroacetic acid selectively reduced the C5-orn and C4-htyr carbinols to methylene groups in echinocandin lipopeptides. The selective reduction of either hydroxyl is also described. The first conversion of echinocandin B to echinocandin C was accomplished.

Synthesis and structure-activity relationships of novel 3′-Hty-substituted pneumocandins

Abstract A series of pneumocandin B 0 analogs substituted at the 3′ -position of the homotyrosine (Hty) residue have been prepared and evaluated for their inhibition of 1,3-β-( d )-glucan synthesis and for their antifungal activity against C. albicans . Cationic analogs displayed enhanced antifungal properties. The phenolic hydroxyl is involved in a critical hydrogen-bond at the binding site of the enzyme.

Design of a novel pyrrolidine scaffold utilized in the discovery of potent and selective human β3 adrenergic receptor agonists.

A novel class of human β(3)-adrenergic receptor agonists was designed in effort to improve selectivity and metabolic stability versus previous disclosed β(3)-AR agonists. As observed, many of the β(3)-AR agonists seem to need the acyclic ethanolamine core for agonist activity. We have synthesized derivatives that constrained this moiety by introduction of a pyrrolidine. This unique modification maintains human β(3) functional potency with improved selectivity versus ancillary targets and also eliminates the possibility of the same oxidative metabolites formed from cleavage of the N-C bond of the ethanolamine. Compound 39 exhibited excellent functional β(3) agonist potency across species with good pharmacokinetic properties in rat, dog, and rhesus monkeys. Early de-risking of this novel pyrrolidine core (44) via full AMES study supports further research into various new β(3)-AR agonists containing the pyrrolidine moiety.

The fungal cell wall as a drug discovery target: SAR of novel echinocandin analogs

Abstract Serious fungal infections are an escalating problem due to the increase in the immunocompromised patient population. Amphotericin B remains the drug of choice for life-threatening infections despite a high incidence of severe adverse reactions. While the newer azoles represent a class of safer drugs, they are fungistatic and are not ideal for deep-seated mycoses. There is a need for safer agents with a novel mode of action. The echinocandins and pneumocandins belong to a class of fungicidal lipopeptides that inhibit the synthesis of β-1,3-D-glucan in a number of pathogenic fungi, most importantly, Candida and Aspergillus species. Cationic derivatives of the pneumocandins such as L-733560, are nanomolar inhibitors of β-1,3-D-glucan synthesis and potent agents in vivo. Optimization of their properties led to identification of L-743872 which is under clinical investigation.