Kathleen M. Rupprecht

Benzamide derivatives as blockers of Kv1.3 ion channel

The voltage-gated potassium channel, Kv1.3, is present in human T-lymphocytes. Blockade of Kv1.3 results in T-cell depolarization, inhibition of T-cell activation, and attenuation of immune responses in vivo. A class of benzamide Kv1.3 channel inhibitors has been identified. The structure-activity relationship within this class of compounds in two functional assays, Rb_Kv and T-cell proliferation, is presented. In in vitro assays, trans isomers display moderate selectivity for binding to Kv1.3 over other Kv1.x channels present in human brain.

The medicinal chemistry of FK-506

Substantial strides have been made in the past decade in the discovery of potent immunosuppressants that are effective in the prevention of rejection in organ transplantation and in the treatment of autoimmune diseases. The past three years have witnessed stunning breakthroughs in the elucidation of the common mechanism of immunosuppressive action of FK-506 and cyclosporin A (CsA). FK-506 is 50- to 100-fold more potent than CsA in its immunosuppressive activity in vitro and in vivo, but retains the toxic side effects of CsA. This review describes the medicinal chemical evaluation of FK-506 with the objective of identifying positions on the macrolactam that can be altered without substantially reducing immunosuppressive activity. Suitable modification at such positions may reduce toxicity, thereby improving the overall therapeutic index and broadening the patient population that can be treated for autoimmune-related diseases.

ω-Aminoalkyl β-glycosides of N-acetylmuramyl-l-alanyl-d-isoglutamine, and their conjugates with meningococcal group C polysaccharide

The 6-aminohexyl beta-glycoside of N-acetylmuramyl-L-alanyl-D-isoglutamine and its spacer-arm-linked analog (3.8 nm) were synthesized from 2-methyl-(3,4,6-tri-O-acetyl-1,2-dideoxy-alpha-D-glucopyrano)-[2,1-d]-2- oxazoline, and coupled with meningococcal group C polysaccharide in attempts to enhance the immunogenicity of the polysaccharide antigen.

MK-7128, a novel CB1 receptor inverse agonist, improves scopolamine-induced learning and memory deficits in mice.

Cannabinoid receptors (CBRs) play an important role in a variety of physiological functions and have been considered drug targets for obesity and psychiatric disorders. In particular, the CB1R is highly expressed in brain regions crucial to learning and memory processes, and several lines of evidence indicate that pharmacological blockade of this receptor could have therapeutic applications in the treatment of cognitive disorders. In this study, we investigated whether MK-7128 (0.1, 0.3, and 1 mg/kg, orally), a novel and selective CB1R inverse agonist, could improve learning and memory deficits induced by scopolamine (1 mg/kg, subcutaneously) in mice. The investigators also assessed CB1R occupancy in the brain to ensure target engagement of MK-7128, and showed that MK-7128 significantly improved both Y-maze spontaneous alternation and object habituation performance in scopolamine-treated mice and inhibits the binding of radioiodinated AM251 in murine cortex and hippocampus. These data indicate that MK-7128 improves cognitive performance in a model of cholinergic hypofunction and suggest that efficacy is achieved at relatively low levels of CB1R occupancy in the brain. Our results extend earlier findings suggesting a role of CB1Rs in the modulation of memory processes and a potential therapeutic application for CB1R inverse agonists in cognitive disorders.

Synthetic studies on the immunosuppressive agent FK-506: Enantioselective synthesis of a C22C34 fragment

Abstract The C28C32 cyclohexyl group of the natural product, FK-506, was prepared enantioselectively from the iodolactone by replacement of iodide with retention of configuration . The C27C28 trisubstituted olefin was introduced stereoselectively via a classical aldol/elimination sequence employing titanium enolate methodology. Elaboration of this chemistry has led to a synthesis of a C22C34 fragment of the natural product.

Synthetic studies on the immunosuppressive agent FK-506: Construction of the polycarbonyl region

Abstract The C10C17 fragment of the natural product, FK-506, has been stereoselectively synthesized from L-gulose. Methods for elaboration to the C1C17 fragment and installation of the C9 carbonyl group are described.

Chapter 14. CCR3 antagonists for the treatment of respiratory diseases

Publisher Summary This chapter focuses on the role played by CCR3 antagonists in the treatment of respiratory diseases. CCR3 is a member of the G-protein coupled receptor superfamily whose members contain seven transmembrane α-helical domains. CCR3 was the third β-chemokine receptor cloned and characterized in a family of close to 20 members. As one of the most promiscuous chemokine receptors identified to date, CCR3 can be activated by as many as 11 chemokine agonists. Three of these CCR3 β-chemokine agonists—eotaxin, eotaxin-2, and eotaxin3—are CCR3-selective, while the remaining CCR3 β-chemokine agonists bind to and activate other chemokine receptors. CCR3 has recently been shown to be expressed on a much wider diversity of ceils involved in airway inflammation. These cells include basophils, mast cells, airway epithelial cells, and TH 2 T-lymphocytes. In addition to chemotaxis, the triggering of CCR3 on target cells with 8-chemokines leads to a series of complex biochemical and physiological processes, including chemokine secretion, intracellular calcium mobilization, integrin up-regulation, etc. Studies demonstrate substantial evidence for the beta-chemokine/CCR3 axis playing a significant role in the clinical pathophysiology of allergic airway diseases.