Gatekeeper T790M mutation in EGFR is the most prevalent factor underlying acquired resistance. Acrylamide-bearing quinazoline derivatives are powerful irreversible inhibitors for overcoming resistance. Nevertheless, concerns about the risk of non-specific covalent modification have motivated the development of novel cysteine-targeting inhibitors. In this paper, we demonstrate that fluoro-substituted olefins can be tuned to alter Michael addition reactivity. Incorporation of these olefins into the quinazoline templates produced potent EGFR inhibitors with improved safety and pharmacokinetic properties. A lead compound 5a was validated against EGFRWT, EGFR T790M as well as A431 and H1975 cancer cell lines. Additionally, compound 5a displayed a weaker inhibition against the EGFR-independent cancer cell line SW620 when compared withafatinib. Oral administration of 5a at a dose of 30mg/kg induced tumor regression in a murine-EGFRL858R/T790M driven H1975 xenograft model. Also, 5a exhibited improved oral bioavailability and safety, as well as favorable tissue distribution properties and enhanced brain uptake. These findings provide the basis of a promising strategy toward the treatment of NSCLC patients with drug resistance.
R adamantly beats S: 11?-HSD1 is a target for treating metabolic syndrome. The R isomer 5 was selected as a starting point for optimization and SAR studies. Inhibitor 8 w emerged after several rounds of optimization, showing cross-species inhibition of human and mouse 11?-HSD1. It also displays a good DMPK profile in vitro, and was advanced to PK/PD evaluations in vivo. The results confirmed its dose-dependent activity in mice.
The potential roles of 11?-HSD1 inhibitors in metabolic syndrome, T2D and obesity were well established and currently several classes of 11?-HSD1 inhibitors have been developed as promising agents against metabolic diseases. To find potent compounds with good pharmacokinetics, we used the bioisosterism approach, and designed the compound 2 and 3 bearing an 1,2,4-oxadiazole ring to replace the amide group in compound 1. Guided by docking study, we then transformed compound 3 into a potent lead compound 4a by changing sulfonamide group to amide. To elaborate this series of piperidyl-oxadiazole derivatives as human 11?-HSD1 inhibitors, we explored the structure-activity relationship of several parts of the lead compound. Based on their potency toward human 11?-HSD1 two compounds 4h and 4q were advanced to pharmacokinetic study. It was found that 4h and 4q are potent and selective human 11?-HSD1 inhibitors with better pharmacokinetic properties than those of the original piperidine-3-carboxamide compound 1, and suitable for further in vivo preclinical study in primate model.
A new ursane-type triterpenoid, 3?-hydroxy-urs-30-p-Z-hydroxycinnamoyloxy-12-en-28-oic-acid (1), together with three known triterpenoids, 3?-hydroxy-urs-30-p-E-hydroxycinnamoyloxy-12-en-28-oic-acid (2), 2?,3?,19?-trihydroxy-urs-12-en-28-oic-acid (3), and ursolic acid (4), four known lignans, pinoresinol (5), 9?-hydroxypinoresinol (6), (+)-medioresinol (7), and (+)-kobusin (8), and two steroids, ?-sitosterol (9), and daucosterol (10), were isolated from the whole parts of Teucrium viscidum. Their structures were established by a combination of spectroscopic data analysis, besides comparison with literature data. Compounds 1-4 were evaluated for their inhibitory activities against 11?-hydroxysteroid dehydrogenase 1 (11?-HSD1).
Several potent and novel 11?-hydroxysteroid dehydrogenase 1 (11?-HSD1) inhibitors were discovered from in silico screening the commercially available Maybridge database. Among them, seven hit compounds showed good affinity, with IC(50) values lower than 100 nM and the best one 3.7 nM. To select the lead for further optimization, computational ADME/T prediction, the CYP3A4 inhibition and 11?-HSD1 over 11?-HSD2 selectivity test were also performed. Taking all of the above factors into consideration, two promising compounds were selected as lead structures for further development. The employed hierarchical virtual screening protocol not only demonstrates its efficiency, but also provides novel and selective compounds for developing 11?-HSD1 inhibitors to protect against metabolic syndrome.
The title compound, C(24)H(30)N(2)O(4), was obtained by the reaction of (2R,6S)-4-(tert-but-oxy-carbon-yl)-6-methyl-morpho-line-2-carb-oxy-lic acid with diphenyl-methanamine in dimethyl-formamide solution. The morpholine ring is in a chair conformation. In the crystal, weak inter-molecular C-H?O hydrogen bonds link mol-ecules into chains along the b axis.
Several classes of non-steroid 11?-HSD1 inhibitors have been developed as promising treatments for Type 2 Diabetes (T2D). Using a human 11?-HSD1 selective inhibitor as a starting point, we designed and synthesized a new class of derivatives of 1-arylsulfonyl piperidine-3-carboxamides. It was found that the large lipophilic group on the amino moiety may lead to cross-species potency towards human and mouse, allowing drug development by evaluating compounds in rodent model. By exploring structure-activity-relationship, the (R)-(+)-bornylamine derivative is identified as the most potent inhibitor of mouse enzyme 11?-HSD1 with an IC(50) of 18 nM. Docking studies revealed the different possible interaction modes of the S-enantiomer and R-enantiomer bound to h11?-HSD1, and explained why the S-enantiomer is more active than the R-enantiomer. Finally, two potent and isoform-selective compounds, (+)-isopinocampheylamine derivative 8m and (R)-(+)-bornylamine derivative 8l, with suitable in vitro properties, could be selected for future PK/PD evaluation in rodent models. Then, 8l was subjected a pharmacodynamics study in vivo with rodent model. It was shown that 8l have 71% and 63% inhibition in adipose and liver tissue at 1h after administration, but it was a short-acting compound displaying a significant drop in potency in the subsequent 3h. This study not only provides compounds as novel h11?-HSD1 inhibitors, but also presents structure-activity relationships for designing potent human/mouse 11?-HSD1 inhibitors suitable for in vivo evaluation in rodent models.
Related JoVE Video
Journal of Visualized Experiments
What is Visualize?
JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.
How does it work?
We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.
Video X seems to be unrelated to Abstract Y...
In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.