Joan Eileen Sabalski

Antiobesity-like effects of the 5-HT2C receptor agonist WAY-161503.

WAY-161503 ((4aR)-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one), a 5-HT(2B/C) receptor agonist, was characterized in vitro using stable Chinese hamster ovary cell lines expressing each of the human 5-HT2 receptors and in vivo in animal models of obesity. WAY-161503 displaced both agonist ([125I]2,5-dimethoxy-4-iodoamphetamine (DOI)) and antagonist ([3H]mesulergine) radioligand binding to the human 5-HT2C receptor with derived Ki values of 3.3 +/- 0.9 and 32 +/- 6 nM, respectively. Relative to 5-HT2C receptor binding, WAY-161503 was approximately 6-fold less potent at human 5-HT2A receptors ([125I]DOI) with a derived Ki value of 18 nM and 20-fold less potent at human 5-HT2B receptors ([3H]5-HT) with a derived Ki value of 60 nM. In functional studies, WAY-161503 was a full agonist in stimulating 5-HT2C-receptor-coupled [3H]inositol phosphate (IP) formation and calcium mobilization with EC50 values of 8.5 nM and 0.8 nM, respectively. WAY-161503 was also a 5-HT2B agonist (EC50s of 6.9 and 1.8 nM for IP and calcium, respectively). In IP studies, WAY-161503 was a weak 5-HT(2A) partial agonist (EC50, 802 nM) yet potently stimulated calcium mobilization (EC50, 7 nM) in 5-HT2A receptor-expressing cells. Functionally, WAY-161503 also stimulated the phospholipase A2-coupled arachidonic acid release in 5-HT2C receptor expressing cells albeit with lower potency (EC50, 38 nM) and efficacy (Emax, 77%) compared with activation of the PLC pathway. In vivo, WAY-161503 produced dose-dependent decreases in 2-h food intake in 24 h fasted normal Sprague-Dawley rats, diet-induced obese mice, and obese Zuker rats with ED50 values of 1.9 mg/kg, 6.8 mg/kg, and 0.73 mg/kg, respectively. The reduction in food intake in normal Sprague-Dawley rats was reversed by administration of the 5-HT2C receptor antagonist SB-242084. Following chronic administration (10 days) in growing Sprague-Dawley rats, WAY-161503 decreased food intake and attenuated body weight gain. Finally, following chronic administration (15 days) of WAY-161503 to obese Zuker rats, the rats maintained a 30% decrease in food intake over the 15-day period combined with a 25 g decrease in body weight relative to vehicle-treated controls demonstrating a lack of tolerance to its anorectic effects.

Synthesis and 5-hydroxytryptamine (5-HT) activity of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5-(6H)ones and 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalines.

A series of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5-(6H)ones and 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalines was shown to exhibit 5-HT2C agonist binding and functional activity. Compound 21R inhibited food intake over 2 h in fasted, male Sprague Dawley rats with ED50 values of 2 mg/kg (i.p.) and 10 mg/kg (p.o.).

Identification and SAR of squarate inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2)

A novel series of inhibitors for mitogen activated protein kinase-activated protein kinase 2 (MK-2) are reported. These squarate based inhibitors were identified via a high-throughput screen. An MK2 co-structure with the starting ligand was obtained and a structure based approach was followed to optimize potency and selectivity.

Synthesis and structure―activity relationship of a novel series of heterocyclic sulfonamide γ-secretase inhibitors

gamma-Secretase inhibitors have been shown to reduce the production of beta-amyloid, a component of the plaques that are found in brains of patients with Alzheimers disease. A novel series of heterocyclic sulfonamide gamma-secretase inhibitors that reduce beta-amyloid levels in cells is reported. Several examples of compounds within this series demonstrate a higher propensity to inhibit the processing of amyloid precursor protein compared to Notch, an alternative gamma-secretase substrate.

Identification and initial optimization of inhibitors of Clostridium difficile (C. difficile) toxin B (TcdB)

The discovery, synthesis and preliminary structure-activity relationship (SAR) of a novel class of inhibitors of Clostridium difficile (C. difficile) toxin B (TcdB) is described. A high throughput screening (HTS) campaign resulted in the identification of moderately active screening hits 1-5 the most potent of which was compound 1 (IC50 = 0.77 µM). In silico docking of an early analog offered suggestions for structural modification which resulted in the design and synthesis of highly potent analogs 13j(IC50 = 1 nM) and 13 l(IC50 = 7 nM) which were chosen as leads for further optimization.