Sawada N

References (3)

Title : A practical use of ligand efficiency indices out of the fragment-based approach: ligand efficiency-guided lead identification of soluble epoxide hydrolase inhibitors - Tanaka_2011_J.Med.Chem_54_851
Author(s) : Tanaka D , Tsuda Y , Shiyama T , Nishimura T , Chiyo N , Tominaga Y , Sawada N , Mimoto T , Kusunose N
Ref : Journal of Medicinal Chemistry , 54 :851 , 2011
Abstract : Ligand efficiency is frequently used to evaluate fragment compounds in fragment-based drug discovery. We applied ligand efficiency indices in a conventional virtual screening-initiated lead generation study of soluble epoxide hydrolase inhibitors. From a considerable number of screening hits, we carefully selected a compound exhibiting relatively weak inhibitory activity but high ligand efficiency. This ligand efficiency-guided selection could reveal compounds possessing preferable lead-like characteristics in terms of molecular size and lipophilicity. The following hit-to-lead medicinal chemistry campaign successfully led to a more potent, ADMET-clean, lead-like compound preserving high ligand efficiency. Retrospective analyses, including consideration of the more recently proposed indices of ligand efficiency, shed light on the validity of our hit triage and hit-to-lead studies. The present work proposes a practical methodology for lead generation using the concept of ligand efficiency.
ESTHER : Tanaka_2011_J.Med.Chem_54_851
PubMedSearch : Tanaka_2011_J.Med.Chem_54_851
PubMedID: 21192659
Gene_locus related to this paper: human-EPHX2

Title : The forefront for novel therapeutic agents based on the pathophysiology of lower urinary tract dysfunction: pathophysiology of voiding dysfunction and pharmacological therapy - Takeda_2010_J.Pharmacol.Sci_112_121
Author(s) : Takeda M , Araki I , Mochizuki T , Nakagomi H , Kobayashi H , Sawada N , Zakohji H
Ref : J Pharmacol Sci , 112 :121 , 2010
Abstract : Normal lower urinary tract function consists of voiding and storage. During voiding, the pontine micturition reflex center orders the sacral parasympathetic nucleus to increase parasympathetic activity, resulting in urinary bladder detrusor contraction via activation of post-synaptic muscarinic receptors (M2/3) and in the relaxation of both urethral and prostatic smooth muscle by nitric oxide (NO). In addition, the rhabdosphincter relaxes by inhibition of the pudendal nucleus at the sacral portion. During the storage phase, increase in sympathetic activity relaxes the urinary bladder via activation of post-synaptic beta(3)-receptors and in the contraction of both urethral and prostatic smooth muscles via alpha(1)-adrenoceptor. Many factors influence voiding function, including lower urinary tract disorders (benign prostatic hyperplasia in males, urethral stricture) and neurological disorders (central and peripheral). Theories of pharmacotherapy for voiding dysfunction are 1) increase detrusor contractility and 2) decrease urethral resistance. The former includes agonists for muscarinic receptors and cholinesterase inhibitor; and the latter includes alpha(1)-adrenoceptor antagonists, NO donors, benzodiazepines, baclofen, dantrolene, and boturinum toxin.
ESTHER : Takeda_2010_J.Pharmacol.Sci_112_121
PubMedSearch : Takeda_2010_J.Pharmacol.Sci_112_121
PubMedID: 20134111

Title : Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue - Miwa_1998_Eur.J.Cancer_34_1274
Author(s) : Miwa M , Ura M , Nishida M , Sawada N , Ishikawa T , Mori K , Shimma N , Umeda I , Ishitsuka H
Ref : Eur J Cancer , 34 :1274 , 1998
Abstract : Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel oral fluoropyrimidine carbamate, which is converted to 5-fluorouracil (5-FU) selectively in tumours through a cascade of three enzymes. The present study investigated tissue localisation of the three enzymes in humans, which was helpful for us to design the compound. Carboxylesterase was almost exclusively located in the liver and hepatoma, but not in other tumours and normal tissue adjacent to the tumours. Cytidine (Cyd) deaminase was located in high concentrations in the liver and various types of solid tumours. Finally, thymidine phosphorylase (dThdPase) was also more concentrated in various types of tumour tissues than in normal tissues. These unique tissue localisation patterns enabled us to design capecitabine. Oral capecitabine would pass intact through the intestinal tract, but would be converted first by carboxylesterase to 5'-deoxy-5-fluorocytidine (5'-dFCyd) in the liver, then by Cyd deaminase to 5'-deoxy-5-fluorouridine (5'-dFUrd) in the liver and tumour tissues and finally by dThdPase to 5-FU in tumours. In cultures of human cancer cell lines, the highest level of cytotoxicity was shown by 5-FU itself, followed by 5'-dFUrd. Capecitabine and 5'-dFCyd had weak cytotoxic activity only at high concentrations. The cytotoxicity of the intermediate metabolites 5'-dFCyd and 5'-dFCyd was suppressed by inhibitors of Cyd deaminase and dThdPase, respectively, indicating that these metabolites become effective only after their conversion to 5-FU. Capecitabine, which is finally converted to 5-FU by dThdPase in tumours, should be much safer and more effective than 5-FU, and this was indeed the case in the HCT116 human colon cancer and the MX-1 breast cancer xenograft models.
ESTHER : Miwa_1998_Eur.J.Cancer_34_1274
PubMedSearch : Miwa_1998_Eur.J.Cancer_34_1274
PubMedID: 9849491