Kwan-Young Jung

Benzofuroindole Analogues as Potent BKCa Channel Openers

Potassium channels belong to a ubiquitous and heterogeneous protein family, selectively permitting K ions to move across the cell membrane. These channels play an important role in adjusting cellular excitability through maintaining the optimum set of conditions for K ion concentration, which is related to the membrane potential and membrane resistance. The different families of K channels are classified by several influencing factors. Calcium-activated potassium channels belong to a family in which channel opening is determined by a rise in the intracellular calcium concentrations and regulated by transmembrane voltage and phosphorylation states. Calcium-activated potassium channels are further divided into three major types, which can be distinguished electropysiologically by their different single-channel conductance. The BKCa or Maxi-K channel has the particular function of large single-channel conductance (100–250 pS), whereas the other two major types of calciumdependent potassium channels have small (2–25 pS; SKCa) and intermediate conductance (25–100 pS; IKCa). [4–5] Among these three kinds of channel, BKCa channels are been particularly appealing as a therapeutic target because of the extensive K efflux and membrane hyperpolarization, which come from the large single-channel conductance, and their expression in a range of excitable and non-excitable cell types, including neurons and muscles. The roles of BKCa channels include shaping action potentials, regulating neuronal excitability, and neurotransmitter release in the nervous system. The therapeutic applications that target BKCa channels are more evident in pathological conditions such as the potential neurotoxic cascade introduced by excess Ca entry, which could be limited or interrupted by BKCa channel activators or openers. Thus, designing chemical openers of BKCa channels could be a strategy for the development of drugs to treat neuronal damage resulting from traumatic and ischemic events or neurodegenerative processes. Moreover, the relaxation effects of smooth muscle by BKCa-channel openers could be utilized to develop drugs to treat cardiovascular diseases including hypertension, airway smooth-muscle-related diseases, such as asthma, and erectile dysfnctions. Among the prototypical BKCa-channel openers BMS-204352 (1), the quinolinone analogue 2, and the substituted benzofuroindole analogue 3 (Scheme 1), compound 1 was reported to shift the BKCa channel activation curve selectively toward less-positive membrane potentials in a dose-dependent

Synthesis of potent chemical inhibitors of dynamin GTPase.

Dynamin is a key regulatory protein in clathrin mediated endocytosis. Compared to genetic or immunological tools, small chemical dynamin inhibitors such as dynasore have the potential to study the dynamic nature of endocytic events in cells. Dynasore inhibits dynamin GTPase activity and transferrin uptake at IC(50) approximately 15 microM but use in some biological applications requires more potent inhibitor than dynasore. Here, we chemically modified the side chains of dynasore and found that two derivatives, DD-6 and DD-11 more potently inhibited transferrin uptake (IC(50): 4.00 microM for DD-6, 2.63 microM for DD-11) and dynamin GTPase activity (IC(50): 5.1 microM for DD-6, 3.6 microM for DD-11) than dynasore. The effect was reversible and they were washed more rapidly out than dynasore. TIRF microscopy showed that they stabilize the clathrin coats on the membrane. Our results indicated that new dynasore derivatives are more potent inhibitor of dynamin, displaying promise as leads for the development of more effective analogues for broader biological applications.

Synthesis and biological evaluation of thienopyrimidine derivatives as GPR119 agonists

A series of thienopyrimidine derivatives was synthesized and evaluated for their GPR119 agonistic ability. Several thienopyrimidine derivatives containing R(1) and R(2) substituents displayed potent GPR119 agonistic activity. Among them, compound 5d, which is a prototype, showed good in vitro activity with an EC50 value of 3 nM and human and rat liver microsomal stability. Compound 5d exhibited no CYP inhibition and induction, Herg binding, or mutagenic potential. Compound 5d showed increase insulin secretion in beta TC-6 cell and lowered the glucose excursion in mice in an oral glucose-tolerance test.

Synthesis and biological evaluation of thiazole derivatives as GPR119 agonists

A series of 4-(phenoxymethyl)thiazole derivatives was synthesized and evaluated for their GPR119 agonistic effect. Several 4-(phenoxymethyl)thiazoles with pyrrolidine-2,5-dione moieties showed potent GPR119 agonistic activities. Among them, compound 27 and 32d showed good in vitro activity with an EC50 value of 49 nM and 18 nM, respectively with improved human and rat liver microsomal stability compare with MBX-2982. Compound 27 &32d did not exhibit significant CYP inhibition, hERG binding, and cytotoxicity. Moreover, these compounds lowered the glucose excursion in mice in an oral glucose-tolerance test.

Design, synthesis, and biological evaluation of aryl N-methoxyamide derivatives as GPR119 agonists

A series of N-methoxyamide derivatives was identified and evaluated as GPR119 agonists. Several N-methoxyamides with thienopyrimidine and pyridine scaffolds showed potent GPR119 agonistic activities. Among them, compound 9c displayed good in vitro activity and potency. Moreover, compound 9c lowered glucose excursion in mice in an oral glucose tolerance test and increased GLP-1 secretion in intestinal cells.