Simsabrahamsen1792

Perfluorocarbons are versatile compounds with applications in 19F magnetic resonance imaging (MRI) and chemical conjugation to drugs and pH sensors. We present a novel thermoresponsive perfluorocarbon emulsion hydrogel that can be detected by 19F MRI. The developed hydrogel contains perfluoro(polyethylene glycol dimethyl ether) (PFPE) emulsion droplets that are stabilized through ionic cross-linking with polyethylenimine (PEI). Specifically, PFPE ester undergoes hydrolysis upon contact with aqueous PEI solution, resulting in an ionic bond between the PFPE acid and charged PEI amino groups. Due to the ionic nature of the PFPE/PEI bond, potassium buffer is required to preserve the hydrogel's pH and rheological and emulsion droplet stability. The presence of the surface cross-linked PFPE droplets does not affect the hydrogel's rheological behavior, drug loading, or drug release, and the hydrogel is nontoxic. We propose that the presented hydrogel can be adapted to a broad range of biomedical imaging and delivery applications.GPR18 is a rhodopsin-like orphan G-protein-coupled receptor (GPCR) that is activated by the natural cannabinoid (CB) Δ9-tetrahydrocannabinol (THC). It is highly expressed in immune cells and represents a promising new drug target. However, THC is much more potent in activating CB receptors than GPR18, and several other proposed lipidic agonists for GPR18 have not been independently confirmed. Herein we describe the first non-lipid-like agonists for GPR18 based on a tricyclic xanthine-derived scaffold, along with initial structure-activity relationships. PSB-KD107 (5) and PSB-KD477 (16) displayed significantly higher potency and efficacy than THC, determined in a GPR18-dependent β-arrestin recruitment assay, and were found to be selective versus the CB-sensitive receptors CB1, CB2, and GPR55. Structure-activity relationships were steep, and indole substitution was crucial for biological activity. These first selective agonists, which are structurally distinct from the lipidic agonist(s), will allow target validation studies and may eventually contribute to the deorphanization of GPR18.To derive new uricosuric agents, novel phenol derivatives were synthesized to overcome the disadvantages of benzbromarone (BBR), attributed by its structural features. Herein, we report the discovery of new phenol derivatives with a 1,1-dioxo-1,2-dihydro-3H-1,3-benzothiazole scaffold. The selected compound 11 (dotinurad, FYU-981) demonstrated remarkable inhibitory activity on uric acid uptake by primary human renal proximal tubule epithelial cells (RPTECs) and URAT1-mediated uric acid transport, with weak inhibitory activity against mitochondrial respiration. Dotinurad also displayed favorable pharmacokinetic profiles and higher potency in decreasing uric acid than BBR did in Cebus monkeys. Dotinurad has been approved as a new uricosuric medicine in Japan. Our strategy, which focuses on the structural features resulting in unfavorable effects, could be applied to the future developments of other drugs with disadvantages, particularly those having a bis-aryl ketone structure.Metachromatic leukodystrophy (MLD) is a rare, genetic lysosomal storage disorder caused by the deficiency of arylsulfatase A enzyme, which results in the accumulation of sulfatide in the lysosomes of the tissues of central and peripheral nervous systems, leading to progressive demyelination and neurodegeneration. Currently there is no cure for this disease, and the only approved therapy, hematopoietic stem cell transplant, has limitations. We proposed substrate reduction therapy (SRT) as a novel approach to treat this disease, by inhibiting ceramide galactosyltransferase enzyme (UGT8). This resulted in the identification of a thienopyridine scaffold as a starting point to initiate medicinal chemistry. Further optimization of hit compound 1 resulted in the identification of brain penetrable, orally bioavailable compound 19, which showed efficacy in the in vivo pharmacodynamic models, indicating the potential to treat MLD with UGT8 inhibitors.The orexin system consists of two neuropeptides (orexin-A and orexin-B) that exert their mode of action on two receptors (orexin-1 and orexin-2). While the role of the orexin-2 receptor is established as an important modulator of sleep wake states, the role of the orexin-1 receptor is believed to play a role in addiction, panic, or anxiety. In this manuscript, we describe the optimization of a nonselective substituted azabicyclo[2.2.1]heptane dual orexin receptor antagonist (DORA) into orally bioavailable, brain penetrating, selective orexin-1 receptor (OX1R) antagonists. This resulted in the discovery of our first candidate for clinical development, JNJ-54717793.Nonspecific promiscuous compounds can mislead researchers and waste significant resources. This phenomenon, though well-documented for small molecules, has not been widely explored for the peptide modality. Here we demonstrate that two purported peptide-based KRas inhibitors, SAH-SOS1 A and cyclorasin 9A5, exemplify false-positive molecules-in terms of both their binding affinities and cellular activities. Through multiple gold-standard biophysical techniques, we unambiguously show that both peptides lack specific binding to KRas and instead induce protein unfolding. Although these peptides inhibited cellular proliferation, the activities appeared to be off-target on the basis of a counterscreen with KRas-independent cell lines. We further demonstrate that their cellular activities are derived from membrane disruption. Accordingly, we propose that to de-risk false-positive molecules, orthogonal binding assays and cellular counterscreens are indispensable.Photoaffinity labeling (PAL) is one of the upcoming and powerful tools in the field of molecular recognition. It includes the determination of dynamic parameters, such as the identification and localization of the target protein and the site of drug binding. In this study, a photoaffinity-labeled probe for full-length human immunodeficiency virus-1 integrase (HIV-1 IN) capture was designed and synthesized, following the structure of the FDA-approved drug Raltegravir. This photoprobe was found to retain the HIV IN inhibitory potential in comparison with its parent molecule and demonstrates the ability to label the HIV-1 IN protein. DSP-5990 Putative photoprobe/inhibitor binding sites near the catalytic site were then identified after protein digestion coupled to mass and molecular modeling analyses.