143958-73-0Relevant academic research and scientific papers
Structure-activity relationships, pharmacokinetics, and pharmacodynamics_ of the Kir6.2/Sur1-specific channel opener VU0071063
Kharade, Sujay V.,Sanchez-Andres, Juan Vicente,Fulton, Mark G.,Shelton, Elaine L.,Blobaum, Anna L.,Engers, Darren W.,Hofmann, Christopher S.,Dadi, Prasanna K.,Lantier, Louise,Jacobson, David A.,Lindsley, Craig W.,Denton, Jerod S.
supporting information, p. 350 - 359 (2019/09/12)
Glucose-stimulated insulin secretion from pancreatic b-cells is controlled by ATP-regulated potassium (KATP) channels composed of Kir6.2 and sulfonylurea receptor 1 (SUR1) subunits. The KATP channel-opener diazoxide is FDA-approved for treating hyperinsulinism and hypoglycemia but suffers from off-target effects on vascular KATP channels and other ion channels. The development of more specific openers would provide critically needed tool compounds for probing the therapeutic potential of Kir6.2/SUR1 activation. Here, we characterize a novel scaffold activator of Kir6.2/SUR1 that our group recently discovered in a high-throughput screen. Optimization efforts with medicinal chemistry identified key structural elements that are essential for VU0071063-dependent opening of Kir6.2/SUR1. VU0071063 has no effects on heterologously expressed Kir6.1/SUR2B channels or ductus arteriole tone, indicating it does not open vascular KATP channels. VU0071063 induces hyperpolarization of b-cell membrane potential and inhibits insulin secretion more potently than diazoxide. VU0071063 exhibits metabolic and pharmacokinetic properties that are favorable for an in vivo probe and is brain penetrant. Administration of VU0071063 inhibits glucose-stimulated insulin secretion and glucose-lowering in mice. Taken together, these studies indicate that VU0071063 is a more potent and specific opener of Kir6.2/SUR1 than diazoxide and should be useful as an in vitro and in vivo tool compound for investigating the therapeutic potential of Kir6.2/SUR1 expressed in the pancreas and brain.
Fragment Discovery for the Design of Nitrogen Heterocycles as Mycobacterium tuberculosis Dihydrofolate Reductase Inhibitors
Shelke, Rupesh U.,Degani, Mariam S.,Raju, Archana,Ray, Mukti Kanta,Rajan, Mysore G. R.
, p. 602 - 613 (2016/08/28)
Fragment-based drug design was used to identify Mycobacterium tuberculosis (Mtb) dihydrofolate reductase (DHFR) inhibitors. Screening of ligands against the Mtb DHFR enzyme resulted in the identification of multiple fragment hits with IC50 values in the range of 38–90 μM versus Mtb DHFR and minimum inhibitory concentration (MIC) values in the range of 31.5–125 μg/mL. These fragment scaffolds would be useful for anti-tubercular drug design.
FUSED BICYCLIC HETEROCYCLES USEFUL AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS
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Page/Page column 44-45, (2012/09/21)
The present invention is directed to novel bicyclic heterocycles of structural formula (I) which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzy
Effects of Alkyl Substitutions of Xanthine Skeleton on Bronchodilation
Sakai, Ryosuke,Konno, Kayo,Yamamoto, Yasunori,Sanae, Fujiko,Takagi, Kenzo,et al.
, p. 4039 - 4044 (2007/10/02)
Structure-activity relationships in a series of 1,3,7-trialkyl-xanthine were studied with guinea pigs.Relaxant actions in the tracheal muscle were increased with alkyl chain length at the 1- and 3-positions of the xanthine skeleton, but decreased by alkylation at the 7-position.Positive chronotropic actions in the right atrium were potentiated with 3-alkyl chain length but tended to decrease with 1-alkylation and diminish by 7-substitution.Consequently, while the 1- and 3-substitutions were equally important for the tracheal smooth muscle relaxation, the substitution at the 1-position was more important than the 3-substitution for bronchoselectivity.The 7-alkylation may be significant to cancel heart stimulation.There were good correlations between the smooth muscle relexant action and the cyclic AMP-PDE inhibitory activity in 3-substituents and the affinity for adenosine (A1)receptors in 1-,3-, and 7-substituents.This suggests that not only the cyclic AMP-PDE inhibitory activity but also the adenosine antagonistic activity is important in the bronchodilatory effects of alkylxanthines.Among these xanthine derivatives, 1-butyl-3-propylxanthine and its 7-methylated derivative showed high bronchoselectivity in the in vitro and in vivo experiments compared to theophylline and enprofylline and may be new candidates for bronchodilator.
