-
Yuko Shinagawa,
Teruhiko Inoue,
Takeo Katsushima,
Toshihiro Kiguchi,
Taku Ikenogami,
Naoki Ogawa,
Kenji Fukuda,
Kazuyuki Hirata,
Kazuhito Harada,
Masaki Takagi,
Takashi Nakagawa,
Shuichi Kimura,
Yushi Matsuo,
Mariko Maekawa,
Mikio Hayashi,
Yuki Soejima,
Mitsuru Takahashi,
Masanori Shindo, Hiromasa Hashimoto
[show abstract]
[hide abstract]
ABSTRACT: Short-acting oral calcilytics, calcium-sensing receptor (CaSR) antagonists, have been considered as alternatives for parathyroid hormone (PTH), an injectable bone anabolic drug used in the treatment of osteoporosis. Previously, we identified aminopropandiol 1, which transiently stimulated endogenous PTH secretion in rats. However, the inhibition of cytochrome P450 (CYP) 2D6 and the low bioavailability of 1 remain to be solved. Attempts to change the physicochemical properties of the highly lipophilic amine 1 by introduction of a carboxylic acid group as well as further structural modifications led to the discovery of the highly potent biphenylcarboxylic acid 15, with a markedly reduced CYP2D6 inhibition and a significantly improved bioavailability. Compound 15 evoked a rapid and transient elevation of endogenous PTH levels in rats after oral administration in a dose-dependent manner at a dose as low as 1 mg/kg. The PTH secretion pattern correlated with the pharmacokinetic profile and agreed well with that of the exogenous PTH injection which exerts a bone anabolic effect.Keywords (keywords): Calcium-sensing receptor (CaSR) antagonist; calcilytics; PTH; short-acting; osteoporosis; cytochrome P450 inhibition
12/2010;
-
[show abstract]
[hide abstract]
ABSTRACT: Synthesis and structure-activity relationship studies on a new aminopropandiol class of derivatives as calcium-sensing receptor antagonists are described. Modification of the phenolic moiety of a calcilytic compound NPS 2143 led to the identification of an orally available compound (R,R)-31 which demonstrated a rapid and transient stimulation of PTH release in rats.
Bioorganic & medicinal chemistry letters 06/2010; 20(12):3809-13. · 2.65 Impact Factor
-
Shintaro Hirashima,
Takahiro Oka,
Kazutaka Ikegashira,
Satoru Noji,
Hiroshi Yamanaka,
Yoshinori Hara,
Hiroyuki Goto,
Ryo Mizojiri,
Yasushi Niwa,
Toru Noguchi,
Izuru Ando,
Satoru Ikeda, Hiromasa Hashimoto
[show abstract]
[hide abstract]
ABSTRACT: Following the discovery of JTK-109 (1) as a potent inhibitor of hepatitis C virus NS5B RNA-dependent RNA polymerase, [(a) Hirashima, S.; Suzuki, T.; Ishida, T.; Noji, S.; Yata, S.; Ando, I.; Komatsu, M.; Ikeda, S.; Hashimoto, H. J. Med. Chem.2006, 49, 4721. (b) Hashimoto, H.; Mizutani, K.; Yoshida, A. Int. Patent Appl. WO 01/47883, 2001.] further studies toward the improvement of the cellular potency have been performed. A greater than 40-fold improvement was achieved through replacing the biphenyl moiety with a 2-morpholinophenyl group and the benzimidazole ring with the tetracyclic scaffold to afford compound 7 with an excellent replicon potency (EC(50)=7.6 nM).
Bioorganic & Medicinal Chemistry Letters 07/2007; 17(11):3181-6. · 2.55 Impact Factor
-
Kazutaka Ikegashira,
Takahiro Oka,
Shintaro Hirashima,
Satoru Noji,
Hiroshi Yamanaka,
Yoshinori Hara,
Tsuyoshi Adachi,
Jun-Ichiro Tsuruha,
Satoki Doi,
Yasunori Hase,
Toru Noguchi,
Izuru Ando,
Naoki Ogura,
Satoru Ikeda, Hiromasa Hashimoto
[show abstract]
[hide abstract]
ABSTRACT: We report a new series of hepatitis C virus NS5B RNA polymerase inhibitors containing a conformationally constrained tetracyclic scaffold. SAR studies led to the identification of 6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indoles (19 and 20) bearing a basic pendent group with high biochemical and cellular potencies. These compounds displayed a very small shift in cellular potency when the replicon assay was performed in the presence of human serum albumin.
Journal of Medicinal Chemistry 12/2006; 49(24):6950-3. · 5.25 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Following the discovery of a new series of benzimidazole derivatives bearing a diarylmethyl group as inhibitors of hepatitis C virus NS5B RNA-dependent RNA polymerase (HCV NS5B RdRp),1,2 we extended the structure-activity relationship (SAR) study to analogues bearing a substituted biphenyl group and succeeded in a significant advancement of activity. Starting from compound 1, optimization of the A, B, and C rings afforded potent inhibitors with low nanomolar potency against genotype 1b NS5B. The compounds, which have a substituent with a carbonyl function at the 4-position of the B-ring, efficiently blocked subgenomic viral RNA replication in the replicon cell assay at low submicromolar concentrations. Among the new compounds, compound 10n (JTK-109) exhibited favorable pharmacokinetic profiles, high selectivity for NS5B, and good safety profiles, suggesting the potential for a clinical candidate in the treatment of hepatitis C.
Journal of Medicinal Chemistry 08/2006; 49(15):4721-36. · 5.25 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A series of 1-cycloalkyl-2-phenyl-1H-benzimidazole-5-carboxylic acid derivatives was synthesized and evaluated for inhibitory activity against HCV NS5B RNA-dependent RNA polymerase (RdRp). A SAR study was performed and led to identify the 2-[(4-diarylmethoxy)phenyl]-benzimidazoles as potent inhibitors. They inhibit subgenomic HCV RNA replication in the replicon cells at low micromolar concentrations (EC(50) as low as 1.1microM). They are selective against DNA polymerases (IC(50)>10microM) and exhibit low cytotoxicity.
Bioorganic & Medicinal Chemistry Letters 04/2006; 16(7):1859-63. · 2.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A series of 4-(4-cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamide derivatives were synthesized and evaluated for their abilities to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) enzymes. In this series, substituent effects at the ortho position to the sulfonamide group on the phenyl ring were examined. Most substituents reduced or lost both COX-2 and COX-1 activities. In contrast, introduction of a fluorine atom preserved COX-2 potency and notably increased COX1/COX-2 selectivity. This work led to the identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522 [9d, 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide], which is currently in phase II clinical trials for the treatment of rheumatoid arthritis, osteoarthritis, and acute pain.
Journal of Medicinal Chemistry 04/2002; 45(7):1511-7. · 5.25 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A series of 4-aryl/cycloalkyl-5-phenyloxazole derivatives was synthesized and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1). These compounds were found to be potent and selective COX-2 inhibitors.
Bioorganic & Medicinal Chemistry Letters 02/2002; 12(1):65-8. · 2.55 Impact Factor
