分类: 生物学 >> 生态学 提交时间: 2017-11-17
摘要: A novel dipeptidyl peptidase IV inhibitor hit (5, IC50 = 0.86 mu M) was structurally derived from our recently disclosed preclinical candidate 4 by replacing the cyanobenzyl with a butynyl based on pharmacophore hybridization. A hit-to-lead optimization effort was then initiated to improve its potency. Most N-substituted analogs exhibited good in vitro activity, and compound 180 (IC50 = 1.55 nM) was identified to be a potent dipeptidyl peptidase IV inhibitor with a significantly improved pharmacokinetic properties (bioavailablity: 41% vs 82.9%; T-1/2: 2 h vs 4.9 h). (C) 2013 Elsevier Ltd. All rights reserved.
分类: 天文学 >> 天文学 提交时间: 2023-02-19
摘要: We exploit James Webb Space Telescope (JWST) NIRCam observations from the GLASS-JWST-Early Release Science program to investigate galaxy stellar masses at z>7. We first show that JWST observations reduce the uncertainties on the stellar mass by a factor of at least 5-10, when compared with the highest quality data sets available to date. We then study the UV mass-to-light ratio, finding that galaxies exhibit a two orders of magnitude range of M/L_UV values for a given luminosity, indicative of a broad variety of physical conditions and star formation histories. As a consequence, previous estimates of the cosmic star stellar mass density - based on an average correlation between UV luminosity and stellar mass - can be biased by as much as a factor of ~6. Our first exploration demonstrates that JWST represents a new era in our understanding of stellar masses at z>7, and therefore of the growth of galaxies prior to cosmic reionization.
分类: 生物学 >> 生态学 提交时间: 2017-11-17
摘要: We previously reported a highly potent DPP-IV inhibitor 6 with low in vivo efficacy. While trying to maintain consistent in vitro and in vivo biological activity, we initiated a pharmacokinetic property-driven optimization to improve the metabolic stability and permeability of inhibitor 6. A simple scaffold replacement of thienopyrimidine with pyrrolopyrimidine (21a) led to significantly improved metabolic stability (4% vs. 65% remaining). Further modification of the pyrrolopyrimidine scaffold to produce compound 21j resulted in much better oral bioavailability than 6. Importantly, compound 21j exhibits greater in vivo efficacy than does 6 and Alogliptin and is worthy of further development. (C) 2012 Elsevier Masson SAS. All rights reserved.