MACRO: A Combined Microchip-PCR and Microarray System for High-Throughput Monitoring of Genetically Modified Organisms

The monitoring of genetically modified organisms (GMOs) is a primary step of GMO regulation. However, there is presently a lack of effective and high-throughput methodologies for specifically and sensitively monitoring most of the commercialized GMOs. Herein, we developed a multiplex amplification on a chip with readout on an oligo microarray (MACRO) system specifically for convenient GMO monitoring. This system is composed of a microchip for multiplex amplification and an oligo microarray for the readout of multiple amplicons, containing a total of 91 targets (18 universal elements, 20 exogenous genes, 45 events, and 8 endogenous reference genes) that covers 97.1% of all GM events that have been commercialized up to 2012. We demonstrate that the specificity of MACRO is ∼100%, with a limit of detection (LOD) that is suitable for real-world applications. Moreover, the results obtained of simulated complex samples and blind samples with MACRO were 100% consistent with expectations and the results of independently performed real-time PCRs, respectively. Thus, we believe MACRO is the first system that can be applied for effectively monitoring the majority of the commercialized GMOs in a single test

Discovery of a Potent Thiadiazole Class of Histamine H₃ Receptor Antagonist for the Treatment of Diabetes

A series of novel 2-piperidinopiperidine thiadiazoles were synthesized and evaluated as new leads of histamine H₃ receptor antagonists. The 4-(5-([1,4′-bipiperidin]-1′-yl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)­morpholine (<b>5u</b>) displayed excellent potency and ex vivo receptor occupancy. Compound <b>5u</b> was also evaluated in vivo for antidiabetic efficacy in STZ diet-induced obesity type 2 diabetic mice for 2 or 12 days. Non-fasting glucose levels were significantly reduced as compared with vehicle-treated mice. In addition, <b>5u</b> dose dependently blocked the increase of HbA_1c after 12 days of treatment

Discovery of MK-8318, a Potent and Selective CRTh2 Receptor Antagonist for the Treatment of Asthma

A novel series of tricyclic tetrahydroquinolines were identified as potent and selective CRTh2 receptor antagonists. The agonism and antagonism switch was achieved through structure-based drug design (SBDD) using a CRTh2 receptor homologue model. The challenge of very low exposures in pharmacokinetic studies was overcome by exhaustive medicinal chemistry lead optimization through focused SAR studies on the tricyclic core. Further optimization resulted in the identification of the preclinical candidate 4-(cyclopropyl­((3<i>aS</i>,9<i>R</i>,9<i>aR</i>)-7-fluoro-4-(4-(trifluoromethoxy)­benzoyl)-2,3,3<i>a</i>,4,9,9<i>a</i>-hexahydro-1<i>H</i>-cyclopenta­[<i>b</i>]­quinolin-9-yl)­amino)-4-oxobutanoic acid (<b>15c</b>, <b>MK-8318</b>) with potent and selective CRTh2 antagonist activity and a favorable PK profile suitable for once daily oral dosing for potential treatment of asthma