3 research outputs found
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 H<sub>3</sub> Receptor Antagonist for the Treatment of Diabetes
A series of novel 2-piperidinopiperidine thiadiazoles
were synthesized
and evaluated as new leads of histamine H<sub>3</sub> 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<sub>1c</sub> 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