Heart failure causally affects the brain cortical structure: a Mendelian randomization study.

Background: The effects of heart failure (HF) on cortical brain structure remain unclear. Therefore, the present study aimed to investigate the causal effects of heart failure on cortical structures in the brain using Mendelian randomization (MR) analysis. Methods: We conducted a two-sample MR analysis utilizing genetically-predicted HF trait, left ventricular ejection fraction (LVEF), and N-terminal prohormone brain natriuretic peptide (NT-proBNP) levels to examine their effects on the cortical surface area (SA) and thickness (TH) across 34 cortical brain regions. Genome-wide association study summary data were extracted from studies by Rasooly (1,266,315 participants) for HF trait, Schmidt (36,548 participants) for LVEF, the SCALLOP consortium (21,758 participants) for NT-proBNP, and the ENIGMA Consortium (51,665 participants) for cortical SA and TH. A series of MR analyses were employed to exclude heterogeneity and pleiotropy, ensuring the stability of the results. Given the exploratory nature of the study, p-values between 1.22E-04 and 0.05 were considered suggestive of association, and p-values below 1.22E-04 were defined as statistically significant. Results: In this study, we found no significant association between HF and cortical TH or SA (all p > 1.22E-04). We found that the HF trait and elevated NT-proBNP levels were not associated with cortical SA, but were suggested to decrease cortical TH in the pars orbitalis, lateral orbitofrontal cortex, temporal pole, lingual gyrus, precuneus, and supramarginal gyrus. Reduced LVEF was primarily suggested to decrease cortical SA in the isthmus cingulate gyrus, frontal pole, postcentral gyrus, cuneus, and rostral middle frontal gyrus, as well as TH in the postcentral gyrus. However, it was suggested to causally increase in the SA of the posterior cingulate gyrus and medial orbitofrontal cortex and the TH of the entorhinal cortex and superior temporal gyrus. Conclusion: We found 15 brain regions potentially affected by HF, which may lead to impairments in cognition, emotion, perception, memory, language, sensory processing, vision, and executive control in HF patients.

Synthesis and structure based optimization of novel Akt inhibitors.

Based on a high throughput screening hit, pyrrolopyrimidine inhibitors of the Akt kinase are explored. X-ray co-crystal structures of two lead series results in the understanding of key binding interactions, the design of new lead series, and enhanced potency. The syntheses of these series and their biological activities are described. Spiroindoline 13j is found to have an Akt1 kinase IC(50) of 2.4+/-0.6 nM, Akt cell potency of 50+/-19 nM, and provides 68% inhibition of tumor growth in a mouse xenograft model (50 mg/kg, qd, po).

Design, synthesis, and activity of 2-imidazol-1-ylpyrimidine derived inducible nitric oxide synthase dimerization inhibitors.

By the screening of a combinatorial library for inhibitors of nitric oxide (NO) formation by the inducible isoform of nitric oxide synthase (iNOS) using a whole-cell assay, 2-(imidazol-1-yl)pyrimidines were identified. Compounds were found to inhibit the dimerization of iNOS monomers, thus preventing the formation of the dimeric, active form of the enzyme. Optimization led to the selection of the potent, selective, and orally available iNOS dimerization inhibitor, 21b, which significantly ameliorated adjuvant-induced arthritis in a rat model. Analysis of the crystal structure of the 21b--iNOS monomer complex provided a rationalization for both the SAR and the mechanism by which 21b blocks the formation of the protein--protein interaction present in the dimeric form of iNOS.