Russell Joseph Deorazio

5-Functionalized indazoles as glucocorticoid receptor agonists

An indazole based series of glucocorticoid receptor agonists is reported. The SAR exploration of this scaffold yielded compounds with nanomolar affinity for the glucocorticoid receptor with indications of selectivity for the preferred transrepression mechanism; in vivo efficacy was observed in the mouse LPS induced TNFalpha model for compound 28.

The design and synthesis of novel SGLT2 inhibitors: C-glycosides with benzyltriazolopyridinone and phenylhydantoin as the aglycone moieties.

The sodium glucose co-transporter 2 (SGLT2) has received considerable attention in recent years as a target for the treatment of type 2 diabetes mellitus. This report describes the design, synthesis and structure-activity relationship (SAR) of C-glycosides with benzyltriazolopyridinone and phenylhydantoin as the aglycone moieties as novel SGLT2 inhibitors. Compounds 5p and 33b demonstrated high potency in inhibiting SGLT2 and high selectivity against SGLT1. The in vitro ADMET properties of these compounds will also be discussed.

Discovery of 2-substituted benzoxazole carboxamides as 5-HT3 receptor antagonists

A new class of 2-substituted benzoxazole carboxamides are presented as potent functional 5-HT(3) receptor antagonists. The chemical series possesses nanomolar in vitro activity against human 5-HT(3)A receptors. A chemistry optimization program was conducted and identified 2-aminobenzoxazoles as orally active 5-HT(3) receptor antagonists with good metabolic stability. These novel analogues possess drug-like characteristics and have potential utility for the treatment of diseases attributable to improper 5-HT(3) receptor function, especially diarrhea predominant irritable bowel syndrome (IBS-D).

Synthesis and structure–activity relationship of substitutions at the C-1 position of Δ9-tetrahydrocannabinol

A novel series of Delta9-tetrahydrocannabinol (Delta9-THC) analogues were synthesized to determine their potential as cannabinoid receptor modulators. Chemistry focused on conversion of the phenol of Delta9-THC to other functionality through palladium catalyzed reactions with an intermediate triflate 2. Two analogues with sub 100 nM affinity for the CB1 and CB2 receptors were identified.

Stereospecific α-d-mannosylation

Abstract The stereospecific formation of α- d -mannosyl glycosidic linkages has been achieved in high yield using tetra- O -pivaloyl-α- d -mannopyranosyl fluoride and boron trifluoride diethyl etherate in dichloromethane. Examples of the α- d -mannosylation of primary, secondary, benzylic and phenolic hydroxyl groups are described.

Preparation of 3β‐Acetoxy‐17a‐Oxo‐Androst‐5‐Ene‐7,17‐Dione, a Biologically Active Impurity Isolated from the Production of 3β‐Acetoxyandrost‐5‐Ene‐7,17‐Dione

Abstract An impurity isolated during the kilo‐lab preparation of 3β‐acetoxyandrost‐5‐ene‐7,17‐dione was identified as 3β‐acetoxy‐17a‐oxo‐androst‐5‐ene‐7,17‐dione. This novel D‐ring secosteroid was postulated to be a Baeyer–Villiger oxidation by‐product of the preparation reaction. A genuine sample was prepared by the selective peracid‐mediated Baeyer–Villiger reaction on 3β‐acetoxyandrost‐5‐ene‐7,17‐dione (7‐oxo‐DHEA acetate), confirming the novel structure.

A Simple Strategy for the Preparation of 6-Substituted 3H-Benzoxazol-2-ones and 3H-Benzothiazol-2-ones

Abstract The double metallation of 6-bromo-3H-benzothiazol-2-one and 6-bromo-3H-benzoxazol-2-one with methyl magnesium bromide and alkyllithium bases is described. Alkylation with a variety of electrophiles occurs at the 6-position of the heterocycles in good yields.