Discovery and Characterization of VU0542270, the First Selective Inhibitor of Vascular Kir6.1/SUR2B KATP Channels.

Vascular smooth muscle KATP channels critically regulate blood flow and blood pressure by modulating vascular tone and therefore represent attractive drug targets for treating several cardiovascular disorders. However, the lack of potent inhibitors that can selectively inhibit Kir6.1/SUR2B (vascular KATP) over Kir6.2/SUR1 (pancreatic KATP) has eluded discovery despite decades of intensive research. We therefore screened 47,872 chemically diverse compounds for novel inhibitors of heterologously expressed Kir6.1/SUR2B channels. The most potent inhibitor identified in the screen was an N-aryl-N'-benzyl urea compound termed VU0542270. VU0542270 inhibits Kir6.1/SUR2B with an IC50 of approximately 100 nM but has no apparent activity toward Kir6.2/SUR1 or several other members of the Kir channel family at doses up to 30 µM (>300-fold selectivity). By expressing different combinations of Kir6.1 or Kir6.2 with SUR1, SUR2A, or SUR2B, the VU0542270 binding site was localized to SUR2. Initial structure-activity relationship exploration around VU0542270 revealed basic texture related to structural elements that are required for Kir6.1/SUR2B inhibition. Analysis of the pharmacokinetic properties of VU0542270 showed that it has a short in vivo half-life due to extensive metabolism. In pressure myography experiments on isolated mouse ductus arteriosus vessels, VU0542270 induced ductus arteriosus constriction in a dose-dependent manner similar to that of the nonspecific KATP channel inhibitor glibenclamide. The discovery of VU0542270 provides conceptual proof that SUR2-specific KATP channel inhibitors can be developed using a molecular target-based approach and offers hope for developing cardiovascular therapeutics targeting Kir6.1/SUR2B. SIGNIFICANCE STATEMENT: Small-molecule inhibitors of vascular smooth muscle KATP channels might represent novel therapeutics for patent ductus arteriosus, migraine headache, and sepsis; however, the lack of selective channel inhibitors has slowed progress in these therapeutic areas. Here, this study describes the discovery and characterization of the first vascular-specific KATP channel inhibitor, VU0542270.

Synthesis and SAR of a novel Kir6.2/SUR1 channel opener scaffold identified by HTS.

Kir6.2/SUR1 is an ATP-regulated potassium channel that acts as an intracellular metabolic sensor, controlling insulin and appetite-stimulatory neuropeptides secretion. In this Letter, we present the SAR around a novel Kir6.2/SUR1 channel opener scaffold derived from an HTS screening campaign. New series of compounds with tractable SAR trends and favorable potencies are reported.

Implantable collamer lens implantation (ICL) versus small incision lenticule extraction (SMILE) in low to moderate myopia: study protocol for a randomized, non-inferiority trial.

BACKGROUND: Implantable collamer lens implantation (ICL) is a form of 'foldable' posterior chamber phakic intraocular lens refractive surgery that generally does not impair cornea and natural accommodation. The potential advantages of the ICL over keratorefractive laser procedures include less induction of higher-order aberrations (HOAs) and enhanced retinal image magnification. On the other hand, small incision lenticule extraction (SMILE), currently, one of the most popular refractive surgery procedures, also offers excellent visual outcomes, particularly for eyes with low to moderate amounts of myopia. The aim of this study is to evaluate whether ICL/TICL (toric ICL) is comparable to SMILE for low to moderate myopia in terms of refractive outcomes at 3 and 18 months post-operatively. METHODS/DESIGN: This is a prospective randomized study. A total of 300 participants will be randomized into two groups, the ICL/TICL group and SMILE group. Eligible participants with spherical equivalent (SE) less than - 6.0 diopter (D) will be recruited. Following randomization, participants will be followed at 1, 3, 6, 12, and 18 months. The primary outcome is the refractive predictability at every postoperative point after surgery, which is the proportion of the number of eyes achieving a postoperative SE within ± 0.5 D and ± 1.0 D of the intended target. Secondary outcome parameters include visual acuity, refraction, adverse events, and quality of vision measurements. DISCUSSION: This trial will provide information on whether ICL has comparable, if not superior, refractive outcomes compared to the established SMILE for low to moderate myopia, thus providing evidence for translation into clinical practice. TRIAL REGISTRATION: Chinese clinical trial registry (ChiCTR) 2200055372. Registered on 08 January 2022.

Visual outcomes and corneal biomechanics after V4c implantable collamer lens implantation in subclinical keratoconus.

PURPOSE: To quantitatively evaluate the safety, efficacy, stability, predictability, and corneal biomechanical parameters after V4c implantable collamer lens (ICL) implantation in subclinical keratoconus. SETTING: Xi'an AIER Eye Hospital, Xi'an, China. DESIGN: Retrospective case series. METHODS: Patients undergoing V4c ICL/toric ICL implantation were examined. Scheimpflug tomography (Pentacam) was used to measure the Belin-Ambrosio enhanced ectasia total deviation index. Dynamic Scheimpflug biomechanical analysis (CorVis ST) was used to measure the corneal biomechanical parameters and Corvis Biomechanical Index. The Tomographic and Biomechanical Index was measured by combined Pentacam with CorVis ST. Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), refraction, and adverse effects were also investigated. RESULTS: A total of 60 eyes of 60 patients (mean age ± SD, 27.21 ± 7.24 years) were included. The mean preoperative UDVA and CDVA were 1.08 ± 0.25 and 0.12 ± 0.04 logarithm of the minimum angle of resolution (logMAR) (20/230 and 20/28 Snellen VA), respectively. After 2 years, the mean postoperative UDVA and CDVA were 0.01 ± 0.06 and -0.05 ± 0.03 logMAR (20/20 and 20/18 Snellen VA), respectively. The mean difference between the intended and achieved spherical equivalent (SE) was -0.08 ± 0.47 diopter (D), and the SE was within ±1.00 D of the intended correction in 57 eyes (95%), and 58 eyes (97%) had astigmatism less than 0.50 D. The refractive results were stable 2 years postoperatively, and the corneal biomechanical parameters returned to their preoperative levels at 3 months. CONCLUSIONS: The V4c ICL/toric ICL in subclinical keratoconus offered predictable correction of SE refractive error. Refractive results and corneal biomechanics were stable at the 2-year follow-up.

Providing a New Aniline Bioisostere through the Photochemical Production of 1-Aminonorbornanes.

This report describes the photochemical conversion of aminocyclopropanes into 1-aminonorbornanes via formal [3+2] cycloadditions initiated by homolytic fragmentation of amine radical cation intermediates. Aligning with the modern movement toward sp 3 -rich motifs in drug discovery, this strategy provides access to a diverse array of substitution patterns on this saturated carbocyclic framework while offering the robust functional group tolerance (e.g. -OH, -NHBoc) necessary for further derivatization. Evaluating the metabolic stability of selected morpholine-based 1-aminonorbornanes demonstrated a low propensity for oxidative processing and no proclivity toward reactive metabolite formation, suggesting a potential bioisosteric role for 1-aminonorbornanes. Continuous flow processing allowed for efficient operation on gram-scale, providing promise for translation to industrially-relevant scales. This methodology only requires low loadings of a commercially-available, visible light-active photocatalyst and a simple salt, thus it stays true to sustainability goals while readily delivering saturated building blocks that can reduce metabolic susceptibility within drug development programs.

HiPSC-derived retinal ganglion cells grow dendritic arbors and functional axons on a tissue-engineered scaffold.

Numerous therapeutic procedures in modern medical research rely on the use of tissue engineering for the treatment of retinal diseases. However, the cell source and the transplantation method are still a limitation. Previously, it was reported that a self-organizing three-dimensional neural retina can be induced from human-induced pluripotent stem cells (hiPSCs). In this study, we disclose the generation of retinal ganglion cells (RGCs) from the neural retina and their seeding on a biodegradable poly (lactic-co-glycolic acid) (PLGA) scaffold to create an engineered RGC-scaffold biomaterial. Moreover, we explored the dendritic arbor, branching point, functional axon and action potential of the biomaterial. Finally, the cell-scaffold was transplanted into the intraocular environment of rabbits and rhesus monkeys. STATEMENT OF SIGNIFICANCE: As a part of the mammalian central nervous system (CNS), the retinal ganglion cell (RGC) shows little regenerative capacity. With the use of medical biomaterial for cells seeding and deliver, a new domain is now emerging that uses tissue engineering therapy for retinal disease. However, previous studies utilized RGCs from rodent model, which has limitations for human disease treatment. In the present study, we generated RGCs from hiPSCs-3D neural retina and then seeded these RGCs on PLGA scaffold to create an engineered RGC-scaffold biomaterial. Moreover, we assessed the transplantation method for biomaterial in vivo. Our study provides a technique to produce the engineered human RGC-scaffold biomaterial.

Stage-specific differentiation of iPSCs toward retinal ganglion cell lineage.

PURPOSE: As an alternative and desirable approach for regenerative medicine, human induced pluripotent stem cell (hiPSC) technology raises the possibility of developing patient-tailored cell therapies to treat intractable degenerative diseases in the future. This study was undertaken to guide human Tenon's capsule fibroblasts-derived iPSCs (TiPSCs) to differentiate along the retinal ganglion cell (RGC) lineage, aiming at producing appropriate cellular material for RGC regeneration. METHODS: By mimicking RGC genesis, we deliberately administered the whole differentiation process and directed the stage-specific differentiation of human TiPSCs toward an RGC fate via manipulation of the retinal inducers (DKK1+Noggin+Lefty A) alongside master gene (Atoh7) sequentially. Throughout this stepwise differentiation process, changes in primitive neuroectodermal, eye field, and RGC marker expression were monitored with quantitative real-time PCR (qRT-PCR), immunocytochemistry, and/or flow cytometry. RESULTS: Upon retinal differentiation, a large fraction of the cells developed characteristics of retinal progenitor cells (RPCs) in response to simulated environment signaling (DKK1+Noggin+Lefty A), which was selectively recovered with manual isolation approaches and then maintained in the presence of mitogen for multiple passages. Thereafter, overexpression of ATOH7 further promoted RGC specification in TiPSC-derived RPCs. A subset of transfected cells displayed RGC-specific expression patterns, including Brn3b, iSlet1, calretinin, and Tuj, and approximately 23% of Brn3b-positive RGC-like cells were obtained finally. CONCLUSIONS: Our DKK1+Noggin+Lefty A/Atoh7-based RGC-induction regime could efficiently direct TiPSCs to differentiate along RGC lineage in a stage-specific manner, which may provide a benefit to develop possible cell therapies to treat retinal degenerative diseases such as glaucoma.

4-[(2'-Cyano-biphen-yl-4-yl)meth-yl]morpholin-4-ium tetra-fluoridoborate.

In the crystal structure of the title compound, C(18)H(19)N(2)O(+)·BF(4) (-), bifurcated N-H⋯(F,F) hydrogen bonds link the protonated 4'-morpholine-methyl-biphenyl-2-carbonitrile cations and slightly distorted tetra-fluoro-borate anions. π-π inter-actions [centroid-centroid distance = 3.805 (3) Å] help to consolidate the packing. The dihedral angle between the benzene rings in the cation is 57.24 (11)°.

Tear menisci and ocular discomfort during daily contact lens wear in symptomatic wearers.

PURPOSE: To investigate the relationship between tear meniscus volumes and ocular discomfort during daily soft contact lens wear in symptomatic and asymptomatic wearers. METHODS: Three groups of subjects (n = 20 each) were enrolled. Group 1: symptomatic lens wearers; group 2: asymptomatic lens wearers; group 3: asymptomatic non-lens wearers. Lenses were worn on both eyes and imaged at 2, 4, 6, 8, and 10 hours by optical coherence tomography (OCT). Afterward, a re-wetting drop was instilled onto a randomly selected eye of each subject and re-imaged immediately and at 5, 10, 20, and 30 minutes. Tear meniscus volumes were calculated based on meniscus areas and eyelid lengths. Ocular comfort was also ranked at each time point. RESULTS: Upper and lower meniscus volumes in group 1 were the lowest among the three groups at each time point (P < 0.05). For each group, meniscus volumes decreased gradually during the 10-hour study period (P < 0.05). Among the individuals in each group, the comfort ratings were linearly correlated with the tear meniscus volumes during the 10 hours of lens wear (r = 0.21-0.47, all P < 0.05).Tear volume increased after re-wetting, but lasted only 10 - 20 minutes. Ocular comfort in groups 1 and 2 increased after instillation, but lasted only 10 and 20 minutes, respectively. Ocular comfort in group 3 did not improve. CONCLUSIONS: Tear volume decreased gradually during lens wear and contributed to the ocular comfort in both symptomatic and asymptomatic wearers. The efficacy of re-wetting was brief.