1. 9,9-Dimethyl-9-silafluorene
Hans-Wolfram Lerner, Michael Bolte, Jan Mewes Acta Crystallogr Sect E Struct Rep Online . 2009 Feb 4;65(Pt 3):o451. doi: 10.1107/S1600536809003614.
The title compound, C(14)H(14)Si, crystallizes with two almost identical mol-ecules (r.m.s. deviation = 0.080 Å for all non-H atoms) in the asymmetric unit. All atoms of the silafluorene moiety lie in a common plane (r.m.s. deviations = 0.049 and 0.035 Å for the two mol-ecules in the asymmetric unit). The Si-C(meth-yl) bonds are significantly shorter [1.865 (4)-1.868 (4) Å] than the Si-C(aromatic) bonds [1.882 (3)-1.892 (3) Å]. Owing to strain in the five-membered ring, the endocyclic C-Si-C angles are reduced to 91.05 (14) and 91.21 (14)°.
2. Secretory System Components as Potential Prophylactic Targets for Bacterial Pathogens
Wieslaw Swietnicki Biomolecules . 2021 Jun 15;11(6):892. doi: 10.3390/biom11060892.
Bacterial secretory systems are essential for virulence in human pathogens. The systems have become a target of alternative antibacterial strategies based on small molecules and antibodies. Strategies to use components of the systems to design prophylactics have been less publicized despite vaccines being the preferred solution to dealing with bacterial infections. In the current review, strategies to design vaccines against selected pathogens are presented and connected to the biology of the system. The examples are given forY. pestis,S. enterica,B. anthracis,S. flexneri, and other human pathogens, and discussed in terms of effectiveness and long-term protection.
3. Dose-dependent exposure and metabolism of GNE-892, a β-secretase inhibitor, in monkeys: contributions by P450, AO, and P-gp
Joseph P Lyssikatos, Ryan Takahashi, Kevin W Hunt, Shuguang Ma, Kelly Regal, Cornelis E C A Hop, Nicholas C Kallan, Michael Siu, Xingrong Liu, Qin Yue, Yijun Yi, S Cyrus Khojasteh, Heasook Kim-Kang Eur J Drug Metab Pharmacokinet . 2015 Jun;40(2):171-85. doi: 10.1007/s13318-014-0198-5.
(R)-2-Amino-1,3',3'-trimethyl-7'-(pyrimidin-5-yl)-3',4'-dihydro-2'H-spiro[imidazole-4,1'-naphthalen]-5(1H)-one (GNE-892) is an orally administered inhibitor of β-secretase 1 (β-site amyloid precursor protein cleaving enzyme 1, BACE1) that was developed as an intervention therapy against Alzheimer's disease. A clinical microdosing strategy was being considered for de-risking the potential pharmacokinetic liabilities of GNE-892. We tested whether dose-proportionality was observed in cynomolgus monkey as proof-of-concept for a human microdosing study. With cryopreserved monkey hepatocytes, concentration-dependency for substrate turnover and the relative contribution of P450- versus AO-mediated metabolism were observed. Characterization of the kinetics of these metabolic pathways demonstrated differences in the affinities of P450 and AO for GNE-892, which supported the metabolic profiles that had been obtained. To test if this metabolic shift occurred in vivo, mass balance studies in monkeys were conducted at doses of 0.085 and 15 mg/kg. Plasma exposure of GNE-892 following oral administration was more than 20-fold greater than dose proportional at the high-dose. P-gp-mediated efflux was unable to explain the discrepancy. The profiles of metabolites in circulation and excreta were indicative that oxidative metabolism limited the exposure to unchanged GNE-892 at the low dose. Further, the in vivo data supported the concentration-dependent metabolic shift between P450 and AO. In conclusion, microdosing of GNE-892 was not predictive of pharmacokinetics at a more pharmacologically relevant dose due to saturable absorption and metabolism. Therefore, it is important to consider ADME liabilities and their potential concentration-dependency when deciding upon a clinical microdosing strategy.
