Structure-based discovery of (S)-2-amino-6-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione as low nanomolar, orally bioavailable autotaxin inhibitor.

Inhibition of extracellular secreted enzyme autotaxin (ATX) represents an attractive strategy for the development of new therapeutics to treat various diseases and a few inhibitors entered in clinical trials. We herein describe structure-based design, synthesis, and biological investigations revealing a potent and orally bioavailable ATX inhibitor 1. During the molecular docking and scoring studies within the ATX enzyme (PDB-ID: 4ZGA), the S-enantiomer (Gscore = -13.168 kcal/mol) of the bound ligand PAT-494 scored better than its R-enantiomer (Gscore = -9.562 kcal/mol) which corroborated with the reported observation and analysis of the results suggested the scope of manipulation of the hydantoin substructure in PAT-494. Accordingly, the docking-based screening of a focused library of 10 compounds resulted in compound 1 as a better candidate for pharmacological studies. Compound 1 was synthesized from L-tryptophan and evaluated against ATX enzymatic activities with an IC50 of 7.6 and 24.6 nM in biochemical and functional assays, respectively. Further, ADME-PK studies divulged compound 1 as non-cytotoxic (19.02% cell growth inhibition at 20 µM in human embryonic kidney cells), metabolically stable against human liver microsomes (CLint  = 15.6 µl/min/mg; T1/2  = 113.2 min) with solubility of 4.82 µM and orally bioavailable, demonstrating its potential to be used for in vivo experiments.

Palladium-catalyzed directed synthesis of ortho-deuterated phenylacetic acid and analogues.

The synthesis of deuterium-labeled organic compounds is of increased interest, especially after the approval of deutetrabenazine by the Food and Drug Administration in 2014. The selective incorporation of deuterium in the place of hydrogen not only represents uniqueness in terms of a novel chemical class, but it also can improve the pharmacokinetic profiles of drug molecules while retaining potency and other parameters; thus, hydrogen-deuterium (H/D) exchange methods have been proven to be powerful additions in different areas of chemical science. In that regard, metal-catalyzed deuterium labeling via C-H activation mediated by a unique inbuilt directing group (DG) can play a significant role in the synthesis of novel deuterated chemical entities. In this context, herein, we divulge our results relating to Pd(ii)-catalyzed deuterium incorporation (>97%) at the γ C(sp2)-position of pyridone-containing phenylacetic acid derivatives, where 3-amino-1-methyl-1H-pyridin-2-one (AMP) not only acts as an efficient N,O-directing group, but it also constitutes a part of the target molecules of medicinal importance. Our methodology, which has been optimized based on the effects of temperature, catalyst, time, and substrate scope, shows advantages over existing protocols, with non-selectivity or meager deuteration or the use of an expensive metal (catalytic or super stoichiometric) and a deuterated solvent, reported previously for the deuteration of phenylacetic acid and its derivatives. Moreover, towards our aim of synthesizing deuterium-labeled biologically relevant compounds, the gram scale synthesis of a deuterated analogue of biphenyl acetic acid (3), known to have activity against epileptic seizures, has also been successfully accomplished in high yields and with excellent isotope enrichment via implementing this protocol.

Arterial injuries after penetrating brain injury in civilians: risk factors on admission head computed tomography.

OBJECT: The object of this study was to determine the specific CT findings of the injury profile in penetrating brain injury (PBI) that are risk factors related to intracranial arterial injuries. METHODS: The authors retrospectively evaluated admission head CTs and accompanying digital subtraction angiography (DSA) studies from patients with penetrating trauma to the head in the period between January 2005 and December 2012. Two authors reviewed the CT images to determine the presence or absence of 30 injury profile variables and quantified selected variables. The CT characteristics in patients with and without arterial injuries were compared using univariate analysis, multivariate analysis, and receiver operating characteristic (ROC) curve analysis to determine the respective risk factors, independent predictors, and optimal threshold values for the continuous variables. RESULTS: Fifty-five patients were eligible for study inclusion. The risk factors for an intracranial arterial injury on univariate analysis were an entry wound over the frontobasal-temporal regions, a bihemispheric wound trajectory, a wound trajectory in proximity to the circle of Willis (COW), a subarachnoid hemorrhage (SAH), a higher SAH score, an intraventricular hemorrhage (IVH), and a higher IVH score. A trajectory in proximity to the COW was the best predictor of injury (OR 6.8 and p = 0.005 for all penetrating brain injuries [PBIs]; OR 13.3 and p = 0.001 for gunshot wounds [GSWs]). Significant quantitative variables were higher SAH and IVH scores. An SAH score of 3 (area under the ROC curve [AUC] for all PBIs 0.72; AUC for GSWs 0.71) and an IVH score of 3 (AUC for all PBIs 0.65; AUC for GSWs 0.65) could be used as threshold values to suggest an arterial injury. CONCLUSIONS: The risk factors identified may help radiologists suggest the possibility of arterial injury and prioritize neurointerventional consultation and potential DSA studies.

Vascular complications of penetrating brain injury: comparison of helical CT angiography and conventional angiography.

OBJECT: The authors conducted a study to compare the sensitivity and specificity of helical CT angiography (CTA) and digital subtraction angiography (DSA) in detecting intracranial arterial injuries after penetrating traumatic brain injury (PTBI). METHODS: In a retrospective evaluation of 48 sets of angiograms from 45 consecutive patients with PTBI, 3 readers unaware of the DSA findings reviewed the CTA images to determine the presence or absence of arterial injuries. A fourth reader reviewed all the disagreements and decided among the 3 interpretations. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CTA were calculated on a per-injury basis and in a subpopulation of patients with traumatic intracranial aneurysms (TICAs). RESULTS: Sensitivity of CTA for detecting arterial injuries was 72.7% (95% CI 49.8%-89.3%); specificity, 93.5% (95% CI 78.6%-99.2%); PPV, 88.9% (95% CI 65.3%-98.6%); and NPV, 82.9% (95% CI 66.4%-93.4%). All 7 TICAs were correctly identified by CTA. Sensitivity, specificity, PPV, and NPV of CTA in detecting TICAs were 100%. To compare agreement with DSA, the standard of reference, confidence scores categorized as low, intermediate, and high probability yielded an overall effectiveness of 77.8% (95% CI 71.8%-82.9%). CONCLUSIONS: Computed tomography angiography had limited overall sensitivity in detecting arterial injuries in patients with PTBI. However, it was accurate in identifying TICAs, a subgroup of injuries usually managed by either surgical or endovascular approaches, and non-TICA injuries involving the first-order branches of intracranial arteries.