Inhibition of mixed lineage kinase 3 (MLK3) is a potential strategy for treatment of Parkinson’s disease and HIV-1 associated neurocognitive disorders (HAND), requiring an inhibitor that can achieve ...significant brain concentration levels. We report here URMC-099 (1) an orally bioavailable (F = 41%), potent (IC50 = 14 nM) MLK3 inhibitor with excellent brain exposure in mouse PK models and minimal interference with key human CYP450 enzymes or hERG channels. The compound inhibits LPS-induced TNFα release in microglial cells, HIV-1 Tat-induced release of cytokines in human monocytes and up-regulation of phospho-JNK in Tat-injected brains of mice. Compound 1 likely functions in HAND preclinical models by inhibiting multiple kinase pathways, including MLK3 and LRRK2 (IC50 = 11 nM). We compare the kinase specificity and BBB penetration of 1 with CEP-1347 (2). Compound 1 is well tolerated, with excellent in vivo activity in HAND models, and is under investigation for further development.
Oligosaccharide synthesis is hindered by the need for multiple steps as well as numerous selective protections and deprotections. Herein we report a highly efficient de novo route to various ...oligosaccharide motifs, of use for biological and medicinal structure activity studies. The key to the overall efficiency is the judicious use of asymmetric catalysis and synthetic design. These green principles include the bidirectional use of highly stereoselective catalysis (Pd(0)-catalyzed glycosylation/post-glycosylation). In addition, the chemoselective use of C–C and C–O π-bond functionality, as atom-less protecting groups as well as an anomeric directing group (via a Pd-π-allyl), highlights the atom-economical aspects of the route to a divergent set of natural and unnatural oligosaccharides (i.e., various d-/l-diastereomers of oligosaccharides as well as deoxysugars which lack C-2 anomeric directing groups). For example, in only 12 steps, the construction of a highly branched heptasaccharide with 35 stereocenters was accomplished from an achiral acylfuran.
Highlights • TAK-242 prevents LPS evoked TNF release from RAW267.4 cells and male and female macrophages. • IV, IT, and IP TAK-242 administration prevents LPS-induced allodynia in males. • TLR4 ...deficiency and TAK-242 treatment prevents the delayed onset of formalin-induced tactile allodynia in both sexes. • TAK-242 does not reverse established tactile allodynia in the current experiments.
Drug-eluting embolic transarterial chemoembolization (DEE-TACE) improves the overall survival of hepatocellular carcinoma (HCC), but the agents used are not tailored to HCC. Our patented liposomal ...formulation enables the loading and elution of targeted therapies onto DEEs. This study aimed to establish the safety, feasibility, and pharmacokinetics of sorafenib or regorafenib DEE-TACE in a VX2 model. DEE-TACE was performed in VX2 hepatic tumors in a selective manner until stasis using liposomal sorafenib- or regorafenib-loaded DEEs. The animals were euthanized at 1, 24, and 72 h timepoints post embolization. Blood samples were taken for pharmacokinetics at 5 and 20 min and at 1, 24, and 72 h. Measurements of sorafenib or regorafenib were performed in all tissue samples on explanted hepatic tissue using the same mass spectrometry method. Histopathological examinations were carried out on tumor tissues and non-embolized hepatic specimens. DEE-TACE was performed on 23 rabbits. The plasma concentrations of sorafenib and regorafenib were statistically significantly several folds lower than the embolized liver at all examined timepoints. This study demonstrates the feasibility of loading sorafenib or regorafenib onto commercially available DEEs for use in TACE. The drugs eluted locally without release into systemic circulation.
A highly stereoselective and sterospecific palladium-catalyzed glycosylation reaction of a variety of alcohols is reported. The reaction selectively converts α-2-substituted ...6-carboxy-2H-pyran-3(6H)-ones into α-2-substituted 6-alkoxy-2H-pyran-3(6H)-ones with complete retention of configuration and similarly converts the pyranones with β-carboxy groups into pyranones with β-alkoxy groups. The reaction works equally well with both amino acid- and carbohydrate-based alcohols. To demonstrate the utility of this process for carbohydrate chemistry several of the products were selectively converted into α-manno-pyranosides in two additional steps. Because the 2-substituted 6-carboxy-2H-pyran-3(6H)-ones are prepared by asymmetric synthesis, this reaction can be used for the preparation of either d- or l-pyranones.
NASH causes a tremendous health care burden in the United States. A glucagon-like peptide-1 agonist, semaglutide (Sema), treatment resulted in hepatic steatosis reduction in clinical trials of NASH. ...Lysophosphatidic acid receptor 1 antagonists are known to have antifibrotic effects in several organs. We tested Sema and a novel lysophosphatidic acid receptor 1 antagonist, EPGN2154, individually and in combination to evaluate their efficacy for NASH remission in preclinical models.
In the present study, we used (1) C57Bl6/J wild-type mice fed on a high-fat, high-carbohydrate (HFHC) diet for 16 weeks and (2) leptin-deficient mice (ob/ob) fed on an Amylin liver NASH diet for 16 weeks. After 16 weeks, the mice were randomly distributed in equal numbers in (1) no-drug, (2) EPGN2154, (3) Sema, and (4) EPGN2154+Sema treatment groups for 8 additional weeks at a dosage of 10 mg/kg body weight for EPGN2154 (oral gavage, 5 days a week) and 6.17 μg/kg body weight of Sema (subcutaneous injection every alternate day, 3 days a week).
In the wild-type-high-fat, high-carbohydrate model, we observed the most body weight loss in the EPGN2154+Sema combination group compared to the other treatment groups. All groups led to a significant reduction in alanine transaminase levels when compared to high-fat, high-carbohydrate-fed wild type. However, no significant difference in alanine transaminase levels was observed among the treatment groups. In the ob/ob mice study, Sema did not cause body weight loss. Moreover, the EPGN2154 and the combination groups had a lower NAFLD Activity Score and incidence of advanced-stage hepatic fibrosis than the Sema group.
EPGN2154 demonstrated a hepato-protective effect independent of body weight loss in preclinical NASH models.
The natural all d- and/or unnatural all l-1,4- and 1,6-oligosaccharides were synthesized from furan alcohols using a palladium-catalyzed glycosylation reaction. The 1,4- and 1,6-α-manno-disaccharides ...were achieved in seven total steps starting from chiral furan alcohols. Similarly, 1,4- and 1,6-α-manno-trisaccharides were also synthesized in nine total steps. Key to the overall efficiency of this process was the use of highly diastereoselective palladium-catalyzed glycosylations, reductions, and dihydroxylations.
A series of 2-(3-aminopiperidine)-benzimidazoles were identified as selective H(1)-antihistamines for evaluation as potential sedative hypnotics. Representative compounds showed improved hERG ...selectivity over a previously identified 2-aminobenzimidazole series. While hERG activity could be modulated via manipulation of the benzimidazole N1 substituent, this approach led to a reduction in CNS exposure for the more selective compounds. One example, 9q, retained a suitable selectivity profile with CNS exposure equivalent to known centrally active H(1)-antihistamines.
PDF
