Center for Molecular Innovation and Drug Discovery

Evanston, IL, United States

Center for Molecular Innovation and Drug Discovery

Evanston, IL, United States
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Yu L.,NorthShore University HealthSystem | Derrick M.,NorthShore University HealthSystem | Ji H.,Center for Molecular Innovation and Drug Discovery | Ji H.,Northwestern University | And 6 more authors.
Developmental Neuroscience | Year: 2011

Cerebral palsy and death are serious consequences of perinatal hypoxia-ischemia (HI). Important concepts can now be tested using an animal model of cerebral palsy. We have previously shown that reactive oxygen and nitrogen species are produced in antenatal HI. A novel class of neuronal nitric oxide synthase (nNOS) inhibitors have been designed, and they ameliorate postnatal motor deficits when administered prior to the hypoxic-ischemic insult. This study asks how the new class of inhibitors, using JI-8 (K i for nNOS: 0.014 μM) as a representative, compare with the frequently used nNOS inhibitor 7-nitroindazole (7-NI; K i: 0.09 ± 0.024 μM). A theoretical dose equivalent to 75 K i of JI-8 or equimolar 7-NI was administered to pregnant rabbit dams 30 min prior to and immediately after 40 min of uterine ischemia at 22 days gestation (70% term). JI-8 treatment resulted in a significant decrease in NOS activity (39%) in fetal brain homogenates acutely after HI, without affecting maternal blood pressure and heart rate. JI-8 treatment resulted in 33 normal kits, 2 moderately and 13 severely affected kits and 5 stillbirths, compared with 8 normal, 3 moderately affected and 5 severely affected kits and 10 stillbirths in the 7-NI group. In terms of neurobehavioral outcome, 7-NI was not different from saline treatment, while JI-8 was superior to saline and 7-NI in its protective effect (p < 0.05). In the surviving kits, JI-8 significantly improved the locomotion score over both saline and 7-NI scores. JI-8 was also significantly superior to saline in preserving smell, muscle tone and righting reflex function, but 7-NI did not show significant improvement. Furthermore, a 100-fold increase in the dose (15.75 μmol/kg) of 7-NI significantly decreased systolic blood pressure in the dam, while JI-8 did not. The new class of inhibitors such as JI-8 shows promise in the prevention of cerebral palsy and is superior to the previously more commonly used nNOS inhibitor. © 2011 S. Karger AG, Basel.

Roberts J.M.,Northwestern University | Farha O.K.,Center for Molecular Innovation and Drug Discovery | Hupp J.T.,Northwestern University | Hupp J.T.,Center for Molecular Innovation and Drug Discovery | And 2 more authors.
Crystal Growth and Design | Year: 2011

Four new azolium-containing metal - organic frameworks (MOFs) have been synthesized, where the azoliums are potential organocatalyst precursors. Modifying the number of azoliums on a standard biphenyl dicarboxylate strut affects the morphology or the degree of interpenetration in two representative types of MOFs: NbO-type Cu-paddlewheel 2D sheets and cubic IRMOFs. © 2011 American Chemical Society.

Kudoh T.,Center for Molecular Innovation and Drug Discovery | Park C.S.,Center for Molecular Innovation and Drug Discovery | Lefurgy S.T.,Yeshiva University | Sun M.,Yeshiva University | And 3 more authors.
Bioorganic and Medicinal Chemistry | Year: 2010

Survival of the human pathogen Streptococcus pneumoniae requires a functional mevalonate pathway, which produces isopentenyl diphosphate, the essential building block of isoprenoids. Flux through this pathway appears to be regulated at the mevalonate kinase (MK) step, which is strongly feedback-inhibited by diphosphomevalonate (DPM), the penultimate compound in the pathway. The human mevalonate pathway is not regulated by DPM, making the bacterial pathway an attractive antibiotic target. Since DPM has poor drug characteristics, being highly charged, we propose to use unphosphorylated, cell-permeable prodrugs based on mevalonate that will be phosphorylated in turn by MK and phosphomevalonate kinase (PMK) to generate the active compound in situ. To test the limits of this approach, we synthesized a series of C3-substituted mevalonate analogues to probe the steric and electronic requirements of the MK and PMK active sites. MK and PMK accepted substrates with up to two additional carbons, showing a preference for small substituents. This result establishes the feasibility of using a prodrug strategy for DPM-based antibiotics in S. pneumoniae and identified several analogues to be tested as inhibitors of MK. Among the substrates accepted by both enzymes were cyclopropyl, vinyl, and ethynyl mevalonate analogues that, when diphosphorylated, might be mechanism-based inactivators of the next enzyme in the pathway, diphosphomevalonate decarboxylase. © 2009 Elsevier Ltd. All rights reserved.

Xue F.,Center for Molecular Innovation and Drug Discovery | Silverman R.B.,Center for Molecular Innovation and Drug Discovery
Tetrahedron Letters | Year: 2010

We report a fast N→O tert-butyloxycarbonyl (Boc) migration of the imide (3R,4R)-tert-butyl 3-((6-(bis(tert-butoxycarbonyl)amino)-4-methylpyridin-2-yl)methyl)-4-hyd roxypyrrolidine-1-carboxylate (2) via a base-generated alkoxide. The mechanism of the migration is intramolecular, involving an unusual nine-membered cyclic transition state. © 2010 Elsevier Ltd. All rights reserved.

Chang C.-C.,Center for Molecular Innovation and Drug Discovery | Cao S.,Center for Molecular Innovation and Drug Discovery | Cao S.,East China University of Science and Technology | Kang S.,Center for Molecular Innovation and Drug Discovery | And 7 more authors.
Bioorganic and Medicinal Chemistry | Year: 2010

L-type Ca2+ channels in mammalian brain neurons have either a CaV1.2 or CaV1.3 pore-forming subunit. Recently, it was shown that CaV1.3 Ca2+ channels underlie autonomous pacemaking in adult dopaminergic neurons in the substantia nigra pars compacta, and this reliance renders them sensitive to toxins used to create animal models of Parkinson's disease. Antagonism of these channels with the dihydropyridine antihypertensive drug isradipine diminishes the reliance on Ca2+ and the sensitivity of these neurons to toxins, pointing to a potential neuroprotective strategy. However, for neuroprotection without an antihypertensive side effect, selective CaV1.3 channel antagonists are required. In an attempt to identify potent and selective antagonists of CaV1.3 channels, 124 dihydropyridines (4-substituted-1,4-dihydropyridine-3,5-dicarboxylic diesters) were synthesized. The antagonism of heterologously expressed CaV1.2 and CaV1.3 channels was then tested using electrophysiological approaches and the FLIPR Calcium 4 assay. Despite the large diversity in substitution on the dihydropyridine scaffold, the most CaV1.3 selectivity was only about twofold. These results support a highly similar dihydropyridine binding site at both CaV1.2 and CaV1.3 channels and suggests that other classes of compounds need to be identified for CaV1.3 selectivity. © 2010 Elsevier Ltd. All rights reserved.

Lukas T.J.,Northwestern University | Schiltz G.E.,Center for Molecular Innovation and Drug Discovery | Arrat H.,Northwestern University | Scheidt K.,Center for Molecular Innovation and Drug Discovery | Siddique T.,Northwestern University
Bioorganic and Medicinal Chemistry Letters | Year: 2014

The treatment of neurodegenerative diseases is difficult because of multiple etiologies and the interplay of genetics and environment as precipitating factors. In the case of amyotrophic lateral sclerosis (ALS), we have knowledge of a handful of genes that cause disease when mutated. However, drugs to counteract the effect of genetic mutations have not yet been found. One of the causative genes, Cu, Zn-superoxide dismutase (SOD1) is responsible for about 10-15% of the genetically linked autosomal dominant disease. Our rationale was that compounds that reduce expression of the mutant protein would be beneficial to slow onset and/or disease progression. We screened candidate compounds using a cell-based in vitro assay for those that reduce mutant SOD1 (G93A) protein expression. This led to the discovery of 2-[3-iodophenyl) methylsulfanyl]-5pyridin-4-yl-1,3,4-oxadiazole, a known protein kinase inhibitor that decreases G93A-SOD1 expression in vitro and in the brain and spinal cord in vivo. However, this compound has a biphasic dose response curve and a likely toxophore which limit its therapeutic window for chronic disease such as ALS. Therefore, we designed and tested a focused library of analogs for their ability to decrease SOD1 expression in vitro. This exercise resulted in the identification of a lead compound with improved drug-like characteristics and activity. Development of small molecules that reduce the expression of etiologically relevant toxic proteins is a strategy that may also be extended to familial ALS linked to gain of function mutations in other genes. © 2014 Elsevier Ltd. All rights reserved.

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