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Nariai T.,Dainippon Sumitomo | Fujita K.,Dainippon Sumitomo | Mori M.,Dainippon Sumitomo | Katayama S.,Chemistry Research Laboratories | And 2 more authors.
Journal of Cardiovascular Pharmacology | Year: 2012

The purpose of this study was to evaluate the effects of SM-368229, a novel mineralocorticoid receptor (MR) antagonist with partial agonistic activity, and spironolactone (SPI) on systolic blood pressure (SBP) and serum potassium in spontaneously hypertensive rats. SM-368229 given for 2 weeks prevented the increase in SBP without serum potassium elevation, but the treatment with SPI prevented SBP increase with serum potassium elevation. To elucidate the contribution of partial agonistic activity of SM-368229 for MR in the mitigation of serum potassium elevation, we studied the relationships between sodium balance decrease, as an index of antimineralocorticoid action, and serum potassium elevation in adrenalectomized and/or potassium-loaded rats, using SM-368229 and its derivatives (DSR-11861 and DSR-14397) showing different partial agonist activities for MR (12%, 0%, and 36%, respectively). DSR-11861 and SPI reversed sodium balance and increased serum potassium. SM-368229 also reversed sodium balance but did not show apparent serum potassium increase. Although DSR-14397 did not show serum potassium increase, its antimineralocorticoid action was very weak. These findings indicate that serum potassium elevation is negatively related to partial agonistic activities for MR, and SM-368229 shows antihypertensive efficacy with minimal effect on serum potassium level, probably due to its partial agonistic property. Copyright © 2012 by Lippincott Williams & Wilkins. Source


Huertos M.A.,Chemistry Research Laboratories | Weller A.S.,Chemistry Research Laboratories
Chemical Science | Year: 2013

We demonstrate that [Rh(η6-FC6H 5)(Ph2PCH2CH2CH2PPh 2)][BArF 4] is a competent catalyst for the dehydrocoupling of H3B·PR2H to give H 3B·PR2BH2·PR2H (R = Ph, tBu). The isolation of intermediates (R = tBu, Ph) and kinetic/isotopic labelling experiments (for R = Ph) point to a mechanism, for R = Ph, in which the rate-limiting process for dehydrocoupling involves B-H activation, while the turnover limiting process for catalysis involves the substitution of the oligomeric product at the metal, which forms a strong chelate complex with a Rh(iii) centre, by H3B·PPh 2H. When R = tBu no chelate product complex forms, and it is speculated that the dehydrocoupling process now becomes turnover limiting. These observations provide, for the first time we believe, data on the P-B bond forming events that are central to the dehydrocoupling and dehydropolymerisation of phosphine-boranes. This journal is © The Royal Society of Chemistry 2013. Source


Hawkins A.,Chemistry Research Laboratories | Jakubec P.,Chemistry Research Laboratories | Ironmonger A.,Glaxosmithkline | Dixon D.J.,Chemistry Research Laboratories
Tetrahedron Letters | Year: 2013

Application of a novel palladium-catalysed stereoselective arylative allene spirocyclisation cascade as the key step for the construction of the ACE tricyclic core of manzamine A is described. Source


Tanaka D.,Chemistry Research Laboratories | Tsuda Y.,Chemistry Research Laboratories | Shiyama T.,Chemistry Research Laboratories | Nishimura T.,Chemistry Research Laboratories | And 5 more authors.
Journal of Medicinal Chemistry | Year: 2011

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. © 2010 American Chemical Society. Source


Adams G.M.,Chemistry Research Laboratories | Chadwick F.M.,Chemistry Research Laboratories | Pike S.D.,Chemistry Research Laboratories | Weller A.S.,Chemistry Research Laboratories
Dalton Transactions | Year: 2015

The CH2Cl2 complex [Rh(tBuPONOP)(κ1-ClCH2Cl)][BArF 4] is reported, that also acts as a useful synthon for other complexes such as N2, CO and H2 adducts; while the analogous PNP complex undergoes C-Cl activation. This journal is © The Royal Society of Chemistry 2015. Source

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