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Yoshimura M.,Formulation Research Institute | Yoshimura M.,Nagoya City University | Miyake M.,Formulation Research Institute | Kawato T.,Medicinal Chemistry Research Laboratories | And 5 more authors.
Crystal Growth and Design | Year: 2017

The objectives of this study are to enhance the oral bioavailability of cilostazol (CLZ), which is a poorly soluble compound, by cocrystallization and to evaluate the correlation between the calculated solubility of the cocrystal by the solubility product (Ksp) and the complexation constant (K11) and the performance of the cocrystal. Cocrystals of CLZ with 4-hydroxybenzoic acid (4HBA), 2,4-dihydroxybenzoic acid (2,4DHBA), and 2,5-dihydroxybenzoic acid (2,5DHBA) were prepared. Stoichiometric 1:1 structures were formed in the crystal packing of the three cocrystals according to single crystal X-ray diffraction. The calculated solubilities of the CLZ-4HBA cocrystal, CLZ-2,4DHBA cocrystal, and CLZ-2,5DHBA cocrystal were 9.5-fold, 14.5-fold, and 34.3-fold higher than that of CLZ, respectively. Interestingly, the supersaturated dissolution profile in the nonsink condition was inversely correlated with the calculated solubility of the cocrystals, and the CLZ-4HBA cocrystal, which mildly enhanced the solubility compared to the other cocrystals, effectively prolonged the supersaturation. The in vivo performance correlated with the in vitro dissolution profile, and the bioavailability of the CLZ-4HBA cocrystal in beagles was also significantly enhanced even when compared to the amorphous solid dispersion. The cocrystallization of CLZ could be an effective means to enhance the bioavailability, but excessive solubility enhancement was not preferable for the CLZ cocrystal. ©2016 American Chemical Society.


Ogawa S.,Medicinal Chemistry Research Laboratories | Ogawa S.,University of Tsukuba | Watanabe T.,Medicinal Chemistry Research Laboratories | Sugimoto I.,Medicinal Chemistry Research Laboratories | And 9 more authors.
ACS Medicinal Chemistry Letters | Year: 2016

To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists with a unique prostacyclin-like scaffold. Further optimization of the ω chain was performed to improve EP2 agonist activity and subtype selectivity. Phenoxy derivative 18a showed potent agonist activity and excellent subtype selectivity. Furthermore, a series of compounds were identified as G protein-biased EP2 receptor agonists. These are the first examples of biased ligands of prostanoid receptors. © 2016 American Chemical Society.


Nomura S.,Medicinal Chemistry Research Laboratories | Yamamoto Y.,Medicinal Chemistry Research Laboratories | Matsumura Y.,Medicinal Chemistry Research Laboratories | Ohba K.,Medicinal Chemistry Research Laboratories | And 7 more authors.
ACS Medicinal Chemistry Letters | Year: 2014

Inhibition of the renal sodium glucose cotransporter (SGLT) increases urinary glucose excretion (UGE) and thus reduces blood glucose levels during hyperglycemia. To explore the potential of new antihyperglycemic agents, we synthesized and determined the human SGLT2 (hSGLT2) inhibitory potential of novel substituted 3-benzylindole-N-glucosides 6. Optimization of 6 resulted in the discovery of 3-(4-cyclopropylbenzyl)-4-fluoroindole-N-glucoside 6a-4 (TA-1887), a highly potent and selective hSGLT2 inhibitor, with pronounced antihyperglycemic effects in high-fat diet-fed KK (HF-KK) mice. Our results suggest the potential of indole-N-glucosides as novel antihyperglycemic agents through inhibition of renal SGLT2. © 2013 American Chemical Society.


Awazu Y.,Inflammation Drug Discovery Unit | Mizutani A.,Oncology Drug Discovery Unit | Nagase Y.,Scientific Intelligence | Tsuchiya S.,Extra Value Generation and General Medicine Drug Discovery Unit | And 10 more authors.
Cancer Science | Year: 2013

We recently reported that TAK-593, a novel imidazo[1,2-b]pyridazine derivative, is a highly potent and selective inhibitor of the vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) receptor tyrosine kinase families. Moreover, TAK-593 exhibits a uniquely long-acting inhibitory profile towards VEGF receptor 2 (VEGFR2) and PDGF receptor β (PDGFRβ). In this study, we demonstrated that TAK-593 potently inhibits VEGF- and PDGF-stimulated cellular phosphorylation and proliferation of human umbilical vein endothelial cells and human coronary artery smooth muscle cells. TAK-593 also potently inhibits VEGF-induced tube formation of endothelial cells co-cultured with fibroblasts. Oral administration of TAK-593 exhibited strong anti-tumor effects against various human cancer xenografts along with good tolerability despite a low level of plasma exposure. Even after the blood and tissue concentrations of TAK-593 decreased below the detectable limit, a pharmacodynamic marker (phospho VEGFR2) was almost completely suppressed, indicating that its long duration of enzyme inhibition might contribute to the potent activity of TAK-593. Immunohistochemical staining indicated that TAK-593 showed anti-proliferative and pro-apoptotic effects on tumors along with a decrease of vessel density and inhibition of pericyte recruitment to microvessels in vivo. Furthermore, dynamic contrast-enhanced magnetic resonance imaging revealed that TAK-593 reduced tumor vessel permeability prior to the onset of anti-tumor activity. In conclusion, TAK-593 is an extremely potent VEGFR/PDGFR kinase inhibitor whose potent anti-angiogenic activity suggests therapeutic potential for the treatment of solid tumors. © 2013 Japanese Cancer Association.


Rikimaru K.,Takeda Pharmaceutical | Rikimaru K.,Medicinal Chemistry Research Laboratories | Wakabayashi T.,Takeda Pharmaceutical | Wakabayashi T.,Medicinal Chemistry Research Laboratories | And 38 more authors.
Bioorganic and Medicinal Chemistry | Year: 2012

Herein, we describe the design, synthesis, and structure-activity relationships of novel benzylpyrazole acylsulfonamides as non-thiazolidinedione (TZD), non-carboxylic-acid-based peroxisome proliferator-activated receptor (PPAR) γ agonists. Docking model analysis of in-house weak agonist 2 bound to the reported PPARγ ligand binding domain suggested that modification of the carboxylic acid of 2 would help strengthen the interaction of 2 with the TZD pocket and afford non-carboxylic-acid-based agonists. In this study, we used an acylsulfonamide group as the ring-opening analog of TZD as an isosteric replacement of carboxylic acid moiety of 2; further, preliminary modification of the terminal alkyl chain on the sulfonyl group gave the lead compound 3c. Subsequent optimization of the resulting compound gave the potent agonists 25c, 30b, and 30c with high metabolic stability and significant antidiabetic activity. Further, we have described the difference in binding mode of the carboxylic-acid-based agonist 1 and acylsulfonamide 3d. © 2011 Elsevier Ltd. All rights reserved.


Itadani S.,Medicinal Chemistry Research Laboratories | Takahashi S.,Medicinal Chemistry Research Laboratories | Ima M.,Medicinal Chemistry Research Laboratories | Sekiguchi T.,Medicinal Chemistry Research Laboratories | And 3 more authors.
ACS Medicinal Chemistry Letters | Year: 2014

The benzoxazine derivative, (2S)-4-(3-carboxypropyl)-8-{[4-(4-phenylbutoxy)benzoyl]amino}-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (19, ONO-2050297), was identified as the first potent dual CysLT1 and CysLT2 antagonist with IC50 values of 0.017 ∼M (CysLT1) and 0.00087 ∼M (CysLT2), respectively. © 2014 American Chemical Society.


Yanagisawa A.,Kyowa Hakko Kirin Co. | Yanagisawa A.,Medicinal Chemistry Research Laboratories | Taga M.,Kyowa Hakko Kirin Co. | Atsumi T.,Kyowa Hakko Kirin Co. | And 7 more authors.
Organic Process Research and Development | Year: 2011

A short and practical synthesis of the PDE4 inhibitor K-34 (1) was developed. This synthesis was achieved in four steps and with a 58% overall yield. The unique spiro acetal was created with exceptionally high yield by utilizing the neighbor carboxylic acid assistance. This synthesis also features efficient ketone construction with 4-pyridinylmethyl anion 9 and ester 18, in which overreaction should be prohibited by quick in situ enolate formation. The overall synthesis was carried out under mild conditions and used a simple procedure suitable for large-scale production. © 2011 American Chemical Society.


Yanagisawa A.,Kyowa Hakko Kirin Co. | Yanagisawa A.,Medicinal Chemistry Research Laboratories | Nishimura K.,Kyowa Hakko Kirin Co. | Ando K.,Kyowa Hakko Kirin Co. | And 6 more authors.
Organic Process Research and Development | Year: 2010

A practical and scalable synthesis of a PDE4 inhibitor KW-4490 (1) was developed. This improved synthesis features the construction of the 1-arylcyclohexene (9) by the Diels-Alder reaction followed by a newly established Brnsted acid-promoted hydrocyanation. Subsequent crystallization-induced dynamic resolution enabled the high-yield production of the desired cis-isomer (cis-8). The synthesis was achieved in seven steps in 37% overall yield. © 2010 American Chemical Society.


Uchida R.,Kitasato University | Yokota S.,Kitasato University | Matsuda D.,Kitasato University | Matsumoto A.,Kitasato University | And 4 more authors.
Journal of Antibiotics | Year: 2014

A small molecule named habiterpenol produced by actinomycete Phytohabitans suffuscus 3787-5 was found to abrogate bleomycin-induced G2 arrest in Jurkat cells. Habiterpenol showed no cytotoxic effect on Jurkat cells even at 273 μM; however, the compound inhibited bleomycin-induced G2 arrest in Jurkat cells with an IC50 value of 3.55 μM, while it showed no effect on colchicine-induced M arrest even at 273 μM. These results indicated that habiterpenol selectively abrogated bleomycin-induced G2 arrest in Jurkat cells. © 2014 Japan Antibiotics Research Association All rights reserved 0021-8820/14.

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