Cu-Catalyzed Amination of Base-Sensitive Aryl Bromides and the Chemoselective N- and O-Arylation of Amino Alcohols.

We report a general and functional-group-tolerant method for the Cu-catalyzed amination of base-sensitive aryl bromides including substrates possessing acidic functional groups and small five-membered heteroarenes. The results presented herein substantially expand the scope of Cu-catalyzed C-N coupling reactions. The combination of L8, an anionic N1,N2-diarylbenzene-1,2-diamine ligand, along with the mild base NaOTMS leads to the formation of a stable yet reactive catalyst that resists deactivation from coordination to heterocycles or charged intermediates. This system enables the use of low catalyst and ligand loadings. Exploiting the differences in nucleophile deprotonation in C-O and C-N coupling reactions catalyzed by Cu·L8 we developed a method to chemoselectively N- and O-arylate a variety of amino alcohol substrates. Employing NaOt-Bu as the base resulted exclusively in C-O coupling when the amino alcohols featured primary alcohols and more hindered amines or aniline groups. Utilizing NaOTMS enabled the ability to override the steric-based selectivity of these reactions completely and exclusively promoted C-N coupling regardless of the structure of the amino alcohol. The ability to invert the observed chemoselectivity is distinct from previously described methods that require protecting group manipulations or rely entirely on steric effects to control reactivity. These results substantially improve the scope of Cu-catalyzed C-N coupling reactions using N1,N2-diarylbenzene-1,2-diamine ligands and introduce a new chemoselective method to arylate amino alcohols.

Cortisol synergizing with endoplasmic reticulum stress induces regulatory T-cell dysfunction.

The dysfunction of regulatory T cell (Treg) is associated with the pathogenesis of many immune diseases. The regiments used to re-establish Treg's function are currently unsatisfactory and need to be improved. The purpose of this study is to elucidate the synergistic effects of cortisol and endoplasmic reticulum (ER) stress on impairing regulatory T cell functions. In this study, blood samples were collected from patients with food allergy (FA). Immune cells were purified from blood specimens by flow cytometry. A mouse model of FA was established with ovalbumin as a specific antigen. We observed that serum cortisol levels of FA patients were negatively correlated with peripheral Treg counts. Overwhelmed ER stress status was detected in Tregs of FA patients. The antigen-specific immune response induced ER stress in Tregs, which was exacerbated by concurrent cortisol exposure. ER stress mediated the effects of cortisol on impairing the immune suppressive ability of Tregs. The expression of Rnf20 was observed in Tregs upon exposure to cortisol. Rnf20 reduced the expression of Foxp3 and transforming growth factor (TGF)-ß in Tregs. Rnf20 inhibition re-established the immunosuppressive functions of Tregs obtained in patients with FA. The experimental FA in mice was attenuated by inhibition of Rnf20 in Tregs. In summary, specific immune response in synergy with cortisol to induce the expression of Rnf20 in Tregs. Rnf20 reduces the levels of Foxp3 and TGF-ß to impair the immune suppressive function. Inhibition of Rnf20 can restore the immune suppressive ability of Tregs obtained from FA patients.

Endoplasmic reticulum stress impairs the immune regulation property of macrophages in asthmatic patients.

The current study aims to characterize the counteraction of M2 cells in response to Endoplasmic reticulum (ER) stress. ER stress was detected in bronchoalveolar lavage fluids (BALF) Mϕs, which was at unresolved state in asthma patients. A positive correlation was detected between ER stress in Mϕs and lung functions/allergic mediators/Th2 cytokines in BALF or specific IgE in the serum. Levels of immune regulatory mediator in the BALF were negatively correlated to ER stress in BALF Mϕs. The ER stress state influenced the immune regulatory property of BALF Mϕ. Exposure to environmental pollutant, 3-metheyl-4-nitrophenol, exacerbated ER stress in Mϕ, which affected the Mϕ phenotyping. Exacerbation of ER stress suppressed the expression of IL-10 and programmed cell death protein-1 (PD-1) in Mϕs by increasing the expression of the ring finger protein 20 (Rnf20). Conditional inhibition of Rnf20 in Mϕs attenuated experimental airway allergy.

5-Bromo-2-chloro-4-fluoro-3-iodopyridine as a Halogen-rich Intermediate for the Synthesis of Pentasubstituted Pyridines.

The 60 individual halopyridine isomers that contain one bromine, chlorine, fluorine, iodine, and H are valuable potential building blocks in medicinal chemistry research, but surprisingly, there has been only one report on the synthesis of just two of them. Herein, we describe simple syntheses of the unique 5-bromo-2-chloro-4-fluoro-3-iodopyridine (10) and 3-bromo-6-chloro-4-fluoro-2-iodopyridine (32) using halogen dance reactions. C6 magnesiation of 10 and its 3-phenyl analogue 22 followed by trapping with electrophiles generated a variety of pentasubstituted pyridines with desired functionalities for further chemical manipulations.

Synthesis of functionalized derivatives of the gamma-secretase modulator BMS-932481 and identification of its major metabolite.

In an effort to improve physical properties by introducing polar functionality into the bicyclic pyrimidine gamma-secretase modulator (GSM) clinical candidate BMS-932481, we prepared several oxidative products of BMS-932481. Among the analogs that were prepared, the C-5 alcohol 3 was identified as the predominant metabolite of BMS-932481 found in rat and human liver microsomes. Alcohol 3 was determined to be chemically unstable, leading to the hypothesis that 3 may lead to the production of reactive species both in vitro and in vivo.

Discovery of new indole-based acylsulfonamide Nav1.7 inhibitors.

Screening of 100 acylsulfonamides from the Bristol-Myers Squibb compound collection identified the C3-cyclohexyl indole 6 as a potent Nav1.7 inhibitor. Replacement of the C2 furanyl ring of 6 with a heteroaryl moiety or truncation of this group led to the identification of 4 analogs with hNav1.7 IC50 values under 50 nM. Fluorine substitution of the truncated compound 12 led to 34 with improved potency and isoform selectivity. The inverted indole 36 also maintained good activity. Both 34 and 36 exhibited favorable CYP inhibition profiles, good membrane permeability and a low efflux ratio and, therefore, represent new leads in the search for potent and selective Nav1.7 inhibitors to treat pain.

The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu4 PAM development candidate.

This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu4 positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).

Bcl2L12 mediates effects of protease-activated receptor-2 on the pathogenesis of Th2-dominated responses of patients with ulcerative colitis.

The immune dysregulation plays an important role in the pathogenesis of ulcerative colitis (UC). Bcl2 like protein-12 (Bcl2L12) and mast cells are involved in immune dysregulation of UC. This study aims to elucidate the role of Bcl2L12 in the contribution to the pathogenesis of T helper (Th)2-biased inflammation in UC patients. The results showed that Bcl2L12 was expressed by peripheral CD4+ T cells that was associated with Th2 polarization in UC patients. Bcl2L12 mediated the protease-activated receptor-2 (PAR2)-induced IL-4 expression in CD4+ cells. Activation of PAR2 increased expression of Bcl2L12 in CD4+ T cells. Bcl2L12 mRNA decayed spontaneously in CD4+ T cells after separated from UC patients which was prevented by activating PAR2. Bcl2L12 mediated the binding between GATA3 and the Il4 promoter in CD4+ T cells. Mice with Bcl2L12 deficiency failed to induce Th2-biased inflammation in the colon mucosa. We conclude that CD4+ T cells from UC patients expressed high levels of Bcl2L12; the latter plays an important role in the development of Th2-biased inflammation in the intestine. Bcl2L12 may be a novel therapeutic target in the treatment of Th2-biased inflammation.

Discovery of morpholine-based aryl sulfonamides as Nav1.7 inhibitors.

Replacement of the piperidine ring in the lead benzenesulfonamide Nav1.7 inhibitor 1 with a weakly basic morpholine core resulted in a significant reduction in Nav1.7 inhibitory activity, but the activity was restored by shortening the linkage from methyleneoxy to oxygen. These efforts led to a series of morpholine-based aryl sulfonamides as isoform-selective Nav1.7 inhibitors. This report describes the synthesis and SAR of these analogs.

Discovery and characterization of N-(1,3-dialkyl-1H-indazol-6-yl)-1H-pyrazolo[4,3-b]pyridin-3-amine scaffold as mGlu4 positive allosteric modulators that mitigate CYP1A2 induction liability.

Previous reports from our laboratory disclosed the structure and activity of a novel 1H-pyrazolo[4,3-b]pyridine-3-amine scaffold (VU8506) which showed excellent potency, selectivity and in vivo efficacy in preclinical rodent models of Parkinson's disease. Unfortunately, this compound suffered from significant CYP1A2 induction as measured through upstream AhR activation (125-fold) and thus was precluded from further advancement in chronic studies. Herein, we report a new scaffold developed recently which was systematically studied in order to mitigate the CYP1A2 liabilities presented in the earlier scaffolds. We have identified a novel structure that maintains the potency and selectivity of other mGlu4 PAMs, leading to 9i (hmGlu4 EC50 = 43 nM; AhR activation = 2.3-fold).

Wearable Sweatband Sensor Platform Based on Gold Nanodendrite Array as Efficient Solid Contact of Ion-Selective Electrode.

As chemical sensors are in great demand for portable and wearable analytical applications, it is highly desirable to develop an all-solid-state ion-selective electrode (ISE) and reference electrode (RE) platform with simplicity and stability. Here we propose a wearable sensor platform with a new type of all-solid-state ISE based on a gold nanodendrite (AuND) array electrode as the solid contact and a poly(vinyl acetate)/inorganic salt (PVA/KCl) membrane-coated all-solid-state RE. A simple and controllable method was developed to fabricate the AuNDs on a microwell array patterned chip by one-step electrodeposition without additional processing. For the first time, the AuND electrodes with different real surface area and double layer capacitance were developed as solid contact of the Na+-ISE to investigate the relationship between performance of the ISE and surface area. As-prepared AuND-ISE with larger surface area (∼7.23 cm2) exhibited enhanced potential stability compared to those with smaller surface area (∼1.85 cm2) and to bare Au ISE. Important as the ISE, the PVA/KCl membrane-coated Ag/AgCl RE exhibited highly stable potential even after 3 months' storage. Finally, a wearable sweatband sensor platform was developed for efficient sweat collection and real-time analysis of sweat sodium during indoor exercise. This all-solid-state ISE and RE integrated sensor platform provided a very simple and reliable way to construct diverse portable and wearable devices for healthcare, sports, clinical diagnosis, and environmental analysis applications.

Discovery of non-zwitterionic aryl sulfonamides as Nav1.7 inhibitors with efficacy in preclinical behavioral models and translational measures of nociceptive neuron activation.

Since zwitterionic benzenesulfonamide Nav1.7 inhibitors suffer from poor membrane permeability, we sought to eliminate this characteristic by replacing the basic moiety with non-basic bicyclic acetals and monocyclic ethers. These efforts led to the discovery of the non-zwitterionic aryl sulfonamide 49 as a selective Nav1.7 inhibitor with improved membrane permeability. Despite its moderate cellular activity, 49 exhibited robust efficacy in mouse models of neuropathic and inflammatory pain and modulated translational electromyogram measures associated with activation of nociceptive neurons.

Expedient Synthesis of Furo[2,3-d][1,3]thiazinamines and Pyrano[2,3-d][1,3]thiazinamines from Enones and Thiourea.

Michael addition of thiourea to enones with subsequent intramolecular aminal ether formation provided easy access to furo[2,3-d]thiazinamines and pyrano[2,3-d][1,3]thiazin-2-amines. These amines served as versatile intermediates to a variety of beta-amyloid cleaving enzyme-1 (BACE1) inhibitors.

Synthesis of pyrimido[4,5-c]azepine- and pyrimido[4,5-c]oxepine-based γ-secretase modulators.

This Letter describes an efficient ring-closing metathesis approach to 2-chloro-4-amino-pyrimido[4,5-c]azepines and 2-chloro-4-amino-pyrimido[4,5-c]oxepines. These chlorides were applied to the synthesis of several potent γ-secretase modulators (GSMs).

Discovery of furo[2,3-d][1,3]thiazinamines as beta amyloid cleaving enzyme-1 (BACE1) inhibitors.

This Letter describes the synthesis and structure-activity relationships of a series of furo[2,3-d][1,3]thiazinamine BACE1 inhibitors. The co-crystal structure of a representative thiazinamine 2e bound with the BACE1 active site displayed a binding mode driven by interactions with the catalytic aspartate dyad and engagement of the biaryl amide toward the S1 and S3 pockets. This work indicates that furo[2,3-d]thiazine can serve as a viable bioisostere of the known furo[3,4-d]thiazine.

2D Confined-Space Assisted Growth of Molecular-Level-Thick Polypyrrole Sheets with High Conductivity and Transparency.

Herein, the use of a 2D soft template system composed of hundred-nanometer-thick water/ethanol mixed layers sandwiched by lamellar bilayer membranes of a self-assembled amphiphilic molecule to produce ultrathin polyprrole (PPy) with a uniform thickness as thin as 3.8 nm and with large dimensions (>2 µm(2)) is presented. The obtained PPy nanosheets exhibit regioregularity with ordered chain alignment where the polymer chains in the nanosheets produced are well aligned with a clear interchain spacing as confirmed by small-angle X-ray scattering measurement. The molecular-level-thick PPy nanosheets exhibit extremely high conductivity up to 1330 S m(-1), thanks to the ordered alignment of polymer chains in the nanosheets, and a high transparency in both the visible region (transmittance >99%) and near-infrared region (transmittance >93%).

Macrocyclic prolinyl acyl guanidines as inhibitors of ß-secretase (BACE).

The synthesis, evaluation, and structure-activity relationships of a class of acyl guanidines which inhibit the BACE-1 enzyme are presented. The prolinyl acyl guanidine chemotype (7c), unlike compounds of the parent isothiazole chemotype (1), yielded compounds with good agreement between their enzymatic and cellular potency as well as a reduced susceptibility to P-gp efflux. Further improvements in potency and P-gp ratio were realized via a macrocyclization strategy. The in vivo profile in wild-type mice and P-gp effects for the macrocyclic analog 21c is presented.

Discovery of a cyclopentylamine as an orally active dual NK1 receptor antagonist-serotonin reuptake transporter inhibitor.

Cyclopentylamine 4 was identified as a potent dual NK1R antagonist-SERT inhibitor. This compound demonstrated significant oral activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists-SERT inhibitors may be useful in treating depression disorders.