Institute of Medicinal Chemistry

Japan

Institute of Medicinal Chemistry

Japan
SEARCH FILTERS
Time filter
Source Type

Galal O.,Institute of Medicinal Chemistry | Podlogar J.,Institute of Medicinal Chemistry | Verspohl E.J.,Institute of Medicinal Chemistry
Journal of Pharmacy and Pharmacology | Year: 2013

Objectives Asymmetric dimethylarginine (ADMA) is a non-selective nitric oxide (NO) synthase inhibitor associated with cardiovascular and metabolic disorders. This study aimed to investigate ADMA with respect to both diabetes and respiratory disease. Methods Glucose was determined by hexokinase method, insulin by a radioimmunoassay. Griess test was used for NO assay and cytokinines were assayed by ELISA. Ciliary beat frequency was determined by high speed video using a microscope. Key findings ADMA induced an increase in blood glucose and plasma insulin levels in rats; the ratio of these effects indicates the induction of a diabetic situation (insulin resistance). l-arginine increased blood glucose and initially slightly decreased plasma insulin. A pretreatment with ADMA abolished these effects. ADMA shows similar effects in vitro (insulin-secreting cell line, INS-1 cells). l-arginine increased production of NO, which was reversed by ADMA (INS-1 cells). ADMA also reduced NO production positively modulated by various substances, namely metformin, ciglitazone, losartan and nateglinide, but nevertheless inhibited insulin release induced by these compounds. ADMA stimulated the production of cytokines such as interleukin (IL-6) and macrophage inflammatory protein-2 (MIP-2) (rat IL-8 analogue) from INS-1 cells. 5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR), a direct adenosine monophosphate protein kinase (AMPK) activator and anti-inflammatory agent, induced NO production and reduced cytokine release. In contrast to diabetes parameters, ADMA had no effect of on the respiratory system (cytokine secretion from BEAS-2B cells (IL-8, regulated on activation, normal T cell expressed and secreted, and tumour necrosis factor-α), ciliary beat frequency and smooth muscle contraction of rat trachea). Conclusions ADMA has a pathophysiological impact leading to a diabetic situation but has no impact on the respiratory system. © 2012 Royal Pharmaceutical Society.


Hardigan T.,Georgia Regents University | Spitler K.,University of Iowa | Matsumoto T.,Institute of Medicinal Chemistry | Carrillo-Sepulveda M.A.,Georgia Regents University
Pflugers Archiv European Journal of Physiology | Year: 2015

Activation of Toll-like receptor 3 (TLR3), a pattern recognition receptor of the innate immune system, is associated with vascular complications. However, whether activation of TLR3 alters vascular contractility is unknown. We, therefore, hypothesized that TLR3 activation augments vascular contractility and activates vascular smooth muscle cell (VSMC) contractile apparatus proteins. Male mice were treated with polyinosinic-polycytidylic acid (Poly I:C group, 14 days), a TLR3 agonist; control mice received saline (vehicle, 14 days). At the end of protocol, blood pressure was measured by tail cuff method. Aortas were isolated and assessed for contractility experiments using a wire myograph. Aortic protein content was used to determine phosphorylated/total interferon regulatory factor 3 (IRF3), a downstream target of TLR3 signaling, and ERK1/2 using Western blot. We investigated the TLR3/IRF3/ERK1/2 signaling pathway and contractile-related proteins such as phosphorylated/total myosin light chain (MLC) and caldesmon (CaD) in aortic VSMC primary cultures. Poly I:C-treated mice exhibited (vs. vehicle-treated mice) (1) elevated systolic blood pressure. Moreover, Poly I:C treatment (2) enhanced aortic phenylephrine-induced maximum contraction, which was suppressed by PD98059 (ERK1/2 inhibitor), and (3) increased aortic levels of phosphorylated IRF3 and ERK1/2. Stimulation of mouse aortic VSMCs with Poly I:C resulted in increased phosphorylation of IRF3, ERK1/2, MLC, and CaD. Inhibition of ERK1/2 abolished Poly I:C-mediated phosphorylation of MLC and CaD. Our data provide functional evidence for the role of TLR3 in vascular contractile events, suggesting TLR3 as a potential new therapeutic target in vascular dysfunction and regulation of blood pressure. © 2015, Springer-Verlag Berlin Heidelberg.


Koga K.,Institute of Medicinal Chemistry | Hattori Y.,Institute of Medicinal Chemistry | Komori M.,Institute of Medicinal Chemistry | Narishima R.,Hoshi University | And 4 more authors.
Cancer Science | Year: 2010

Medullary thyroid carcinoma (MTC) is a rare endocrine tumor that frequently metastasizes, and treatment with irinotecan (CPT-11) is limited because of side effects. Mutations in the Rearranged during transfection (RET) proto-oncogene are considered the causative event of MTC. The objective of this study was to examine whether small interfering RNA (siRNA) and its combined treatment with CPT-11 could inhibit MTC cell growth in vitro and in vivo. The transfection of RET siRNA suppressed RET expression, reduced proliferation, and increased caspase-3/7 activity via the down-regulation of Bcl-2 expression. Combined treatments with CPT-11 or SN-38 significantly increased caspase 3/7 activity compared with RET siRNA, CPT-11 or SN-38 treatment alone. Importantly, intratumoral injection of RET siRNA along with intravenous injection of CPT-11 significantly inhibited the tumor growth of MTC xenografts via an increased apoptotic effect. These findings that RET siRNA enhanced sensitivity for CPT-11 will provide a novel strategy for the treatment of MTC with RET mutation. © 2010 Japanese Cancer Association.


Bertamino A.,University of Salerno | Ostacolo C.,University of Naples Federico II | Ambrosino P.,University of Molise | Musella S.,University of Naples Federico II | And 12 more authors.
Journal of Medicinal Chemistry | Year: 2016

Pharmacological modulation of the transient receptor potential melastatin type 8 (TRPM8) is currently under investigation as a new approach for the treatment of pain and other diseases. In this study, a series of N-substituted tryptamines was prepared to explore the structural requirements determining TRPM8 modulation. Using a fluorescence-based screening assay, we identified two compounds acting as an activator (2-(1H-indol-3-yl)-N-(4-phenoxybenzyl)ethanamine, 21) or an inhibitor (N,N-dibenzyl-2-(1H-indol-3-yl)ethanamine, 12) of calcium influx in HEK293 cells. In patch-clamp recordings, compound 21 displayed a significantly higher potency (EC50 = 40 ± 4 μM) and a similar efficacy when compared to menthol; by contrast, compound 12 produced a concentration-dependent inhibition of menthol-induced TRPM8 currents (IC50 = 367 ± 24 nM). Molecular modeling studies using a homology model of a single rat TRPM8 subunit identified a putative binding site located between the VSD and the TRP box, disclosing differences in the binding modes for the agonist and the antagonist. © 2016 American Chemical Society.


PubMed | University of Molise, University of Salerno, University of Naples Federico II, Institute of Medicinal Chemistry and University Miguel Hernández
Type: Journal Article | Journal: Journal of medicinal chemistry | Year: 2016

Pharmacological modulation of the transient receptor potential melastatin type 8 (TRPM8) is currently under investigation as a new approach for the treatment of pain and other diseases. In this study, a series of N-substituted tryptamines was prepared to explore the structural requirements determining TRPM8 modulation. Using a fluorescence-based screening assay, we identified two compounds acting as an activator (2-(1H-indol-3-yl)-N-(4-phenoxybenzyl)ethanamine, 21) or an inhibitor (N,N-dibenzyl-2-(1H-indol-3-yl)ethanamine, 12) of calcium influx in HEK293 cells. In patch-clamp recordings, compound 21 displayed a significantly higher potency (EC50 = 40 4 M) and a similar efficacy when compared to menthol; by contrast, compound 12 produced a concentration-dependent inhibition of menthol-induced TRPM8 currents (IC50 = 367 24 nM). Molecular modeling studies using a homology model of a single rat TRPM8 subunit identified a putative binding site located between the VSD and the TRP box, disclosing differences in the binding modes for the agonist and the antagonist.


Hu Y.-G.,Institute of Medicinal Chemistry | Xu J.,Institute of Medicinal Chemistry | Gao H.-T.,Institute of Medicinal Chemistry | Ma Z.,Institute of Medicinal Chemistry
Journal of Heterocyclic Chemistry | Year: 2010

(Chemical Equation Presented) Carbodiimide, obtained from aza-Wittig reaction of iminophosphorane with 4-fluorophenyl isocyanate, reacted with various nucleophiles under mild conditions to give a series of 2-substituted-3-(4-fluorophenyl)-benzofuro [3,2-d] pyrimidin-4(3H)-ones in satisfactory yield. Their structures were confirmed using NMR, EI-Ms, IR, and elementary analysis, and compound 7b was further analyzed by single-crystal. The preliminary bioassays indicated that these compounds showed moderate fungicidal activities against six kinds of fungi at a concentration of 50 mg/L. © 2010 HeteroCorporation.


Liu Y.-N.,Institute of Medicinal Chemistry | Wang J.-J.,Shandong University | Ji Y.-T.,Institute of Medicinal Chemistry | Zhao G.-D.,Institute of Medicinal Chemistry | And 4 more authors.
Journal of Medicinal Chemistry | Year: 2016

By targeting a new binding region at the interface between αβ-tubulin heterodimers at the colchicine binding site, we designed a series of 7-substituted 1-methyl-1,4-dihydroindeno[1,2-c]pyrazoles as potential tubulin polymerization inhibitors. Among the compounds synthesized, 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)acetamide 6a and 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)-N-hydroxyacetamide 6n showed noteworthy low nanomolar potency against HepG2, Hela, PC3, and MCF-7 cancer cell lines. In mechanism studies, 6a inhibited tubulin polymerization and disorganized microtubule in A549 cells by binding to tubulin colchicine binding site. 6a arrested A549 cells in G2/M phase that was related to the alterations in the expression of cyclin B1 and p-cdc2. 6a induced A549 cells apoptosis through the activation of caspase-3 and PARP. In addition, 6a inhibited capillary tube formation in a concentration-dependent manner. In nonsmall cell lung cancer xenografts mouse model, 6a suppressed tumor growth by 59.1% at a dose of 50 mg/kg (ip) without obvious toxicity, indicating its in vivo potential as anticancer agent. © 2016 American Chemical Society.


PubMed | Institute of Medicinal Chemistry
Type: Journal Article | Journal: Acta crystallographica. Section E, Structure reports online | Year: 2011

In the title compound, C(20)H(18)N(2)O(4), all non-H atoms of the three fused rings of the benzofuro[3,2-d]pyrimidine system are almost coplanar (r.m.s. deviation 0.021). The dihedral angle between the fused ring system and the benzene ring is 1.47(12). Intra-molecular and inter-molecular C-HO hydrogen bonds together with weak C-H inter-actions stabilize the structure.


PubMed | Institute of Medicinal Chemistry
Type: Journal Article | Journal: Acta crystallographica. Section E, Structure reports online | Year: 2011

In the title compound, C(9)H(9)ClN(4)OS, the two rings enclose a dihedral angle of 84.67(11). Inter-molecular C-HO and C-HN hydrogen bonds stabilize the crystal packing.


PubMed | Institute of Medicinal Chemistry
Type: Journal Article | Journal: Acta crystallographica. Section E, Structure reports online | Year: 2011

In the title compound, C(20)H(32)N(2)O(2)S(2), the cyclo-hexene ring is disordered over two half-boat conformations with occupancy factors of 0.71:0.29. One n-butyl chain is also disordered over two positions with occupancy factors of 0.83:0.17. The mol-ecular conformation is stabilized by an intra-molecular N-HO hydrogen bond.

Loading Institute of Medicinal Chemistry collaborators
Loading Institute of Medicinal Chemistry collaborators