Discovery of 4-((2S,4S)-4-Ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic Acid (LNP023), a Factor B Inhibitor Specifically Designed To Be Applicable to Treating a Diverse Array of Complement Mediated Diseases.

The alternative pathway (AP) of the complement system is a key contributor to the pathogenesis of several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. The serine protease factor B (FB) is a key node in the AP and is integral to the formation of C3 and C5 convertase. Despite the prominent role of FB in the AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we describe in more detail our efforts to identify FB inhibitors by high-throughput screening (HTS) and leveraging insights from several X-ray cocrystal structures during optimization efforts. This work culminated in the discovery of LNP023 (41), which is currently being evaluated clinically in several diverse AP mediated indications.

Modeling Biological Oscillations: Integration of Short Reaction Pauses into a Stationary Model of a Negative Feedback Loop Generates Sustained Long Oscillations.

Sustained oscillations are frequently observed in biological systems consisting of a negative feedback loop, but a mathematical model with two ordinary differential equations (ODE) that has a negative feedback loop structure fails to produce sustained oscillations. Only when a time delay is introduced into the system by expanding to a three-ODE model, transforming to a two-delay differential equations (DDE) model, or introducing a bistable trigger do stable oscillations present themselves. In this study, we propose another mechanism for producing sustained oscillations based on periodic reaction pauses of chemical reactions in a negative feedback system. We model the oscillatory system behavior by allowing the coefficients in the two-ODE model to be periodic functions of time-called pulsate functions-to account for reactions with go-stop pulses. We find that replacing coefficients in the two-ODE system with pulsate functions with microscale (several seconds) pauses can produce stable system-wide oscillations that have periods of approximately 1 to several hours long. We also compare our two-ODE and three-ODE models with the two-DDE, three-ODE, and three-DDE models without the pulsate functions. Our numerical experiments suggest that sustained long oscillations in biological systems with a negative feedback loop may be an intrinsic property arising from the slow diffusion-based pulsate behavior of biochemical reactions.

A Novel Selective Soluble Guanylate Cyclase Activator, MGV354, Lowers Intraocular Pressure in Preclinical Models, Following Topical Ocular Dosing.

Purpose: The nitric oxide/soluble guanylate cyclase/protein kinase G (NO/sGC/PKG) is known to be involved in the regulation of intraocular pressure (IOP) and may be dysregulated in glaucoma. The purpose is to demonstrate that the sGC activator MGV354 lowers IOP in a monkey model of glaucoma and could be considered as a possible new clinical drug candidate. Methods: Changes to cGMP were assessed in primary human trabecular meshwork (hNTM) cells and binding studies were conducted using human sGC full-length protein. Ocular safety tolerability, exposure, and efficacy studies were conducted in rabbit and monkey models following topical ocular dosing of MGV354. Results: sGC was highly expressed in the human and cynomolgus monkey outflow pathways. MGV354 had a 7-fold greater Bmax to oxidized sGC compared to that of reduced sGC and generated an 8- to 10-fold greater cGMP compared to that of a reduced condition in hTM cells. A single topical ocular dose with MGV354 caused a significant dose-dependent reduction of 20% to 40% (versus vehicle), lasting up to 6 hours in pigmented rabbits and 24 hours postdose in a cynomolgus monkey model of glaucoma. The MGV354-induced IOP lowering was sustained up to 7 days following once-daily dosing in a monkey model of glaucoma and was greater in magnitude compared to Travatan (travoprost)-induced IOP reduction. Mild to moderate ocular hyperemia was the main adverse effect noted. Conclusions: MGV354 represents a novel class of sGC activators that can lower IOP in preclinical models of glaucoma. The potential for sGC activators to be used as effective IOP-lowering drugs in glaucoma patients could be further determined in clinical studies.

The Discovery of ( S)-1-(6-(3-((4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-dihydro-1 H-inden-4-yl)pyridin-2-yl)-5-methyl-1 H-pyrazole-4-carboxylic Acid, a Soluble Guanylate Cyclase Activator Specifically Designed for Topical Ocular Delivery as a Therapy for Glaucoma.

Soluble guanylate cyclase (sGC), the endogenous receptor for nitric oxide (NO), has been implicated in several diseases associated with oxidative stress. In a pathological oxidative environment, the heme group of sGC can be oxidized becoming unresponsive to NO leading to a loss in the ability to catalyze the production of cGMP. Recently a dysfunctional sGC/NO/cGMP pathway has been implicated in contributing to elevated intraocular pressure associated with glaucoma. Herein we describe the discovery of molecules specifically designed for topical ocular administration, which can activate oxidized sGC restoring the ability to catalyze the production of cGMP. These efforts culminated in the identification of compound (+)-23, which robustly lowers intraocular pressure in a cynomolgus model of elevated intraocular pressure over 24 h after a single topical ocular drop and has been selected for clinical evaluation.

Highly curved image sensors: a practical approach for improved optical performance.

The significant optical and size benefits of using a curved focal surface for imaging systems have been well studied yet never brought to market for lack of a high-quality, mass-producible, curved image sensor. In this work we demonstrate that commercial silicon CMOS image sensors can be thinned and formed into accurate, highly curved optical surfaces with undiminished functionality. Our key development is a pneumatic forming process that avoids rigid mechanical constraints and suppresses wrinkling instabilities. A combination of forming-mold design, pressure membrane elastic properties, and controlled friction forces enables us to gradually contact the die at the corners and smoothly press the sensor into a spherical shape. Allowing the die to slide into the concave target shape enables a threefold increase in the spherical curvature over prior approaches having mechanical constraints that resist deformation, and create a high-stress, stretch-dominated state. Our process creates a bridge between the high precision and low-cost but planar CMOS process, and ideal non-planar component shapes such as spherical imagers for improved optical systems. We demonstrate these curved sensors in prototype cameras with custom lenses, measuring exceptional resolution of 3220 line-widths per picture height at an aperture of f/1.2 and nearly 100% relative illumination across the field. Though we use a 1/2.3" format image sensor in this report, we also show this process is generally compatible with many state of the art imaging sensor formats. By example, we report photogrammetry test data for an APS-C sized silicon die formed to a 30° subtended spherical angle. These gains in sharpness and relative illumination enable a new generation of ultra-high performance, manufacturable, digital imaging systems for scientific, industrial, and artistic use.

Discovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in Vivo.

The highly specific S1 serine protease factor D (FD) plays a central role in the amplification of the complement alternative pathway (AP) of the innate immune system. Genetic associations in humans have implicated AP activation in age-related macular degeneration (AMD), and AP dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The combination of structure-based hit identification and subsequent optimization of the center (S)-proline-based lead 7 has led to the discovery of noncovalent reversible and selective human factor D (FD) inhibitors with drug-like properties. The orally bioavailable compound 2 exerted excellent potency in 50% human whole blood in vitro and blocked AP activity ex vivo after oral administration to monkeys as demonstrated by inhibition of membrane attack complex (MAC) formation. Inhibitor 2 demonstrated sustained oral and ocular efficacy in a model of lipopolysaccharide (LPS)-induced systemic AP activation in mice expressing human FD.

Postinflationary Higgs relaxation and the origin of matter-antimatter asymmetry.

The recent measurement of the Higgs boson mass implies a relatively slow rise of the standard model Higgs potential at large scales, and a possible second minimum at even larger scales. Consequently, the Higgs field may develop a large vacuum expectation value during inflation. The relaxation of the Higgs field from its large postinflationary value to the minimum of the effective potential represents an important stage in the evolution of the Universe. During this epoch, the time-dependent Higgs condensate can create an effective chemical potential for the lepton number, leading to a generation of the lepton asymmetry in the presence of some large right-handed Majorana neutrino masses. The electroweak sphalerons redistribute this asymmetry between leptons and baryons. This Higgs relaxation leptogenesis can explain the observed matter-antimatter asymmetry of the Universe even if the standard model is valid up to the scale of inflation, and any new physics is suppressed by that high scale.

Oral fluoroquinolones and risk of glaucoma.

OBJECTIVE: To evaluate the risk of developing glaucoma in patients taking systemic fluoroquinolones. METHODS: A case-control study was carried out among a cohort of subjects who had visited an ophthalmologist in the Province of British Columbia, Canada from 2000 to 2007. Cases were identified as those newly diagnosed with glaucoma (ICD-9 360). For each case, 5 controls were selected and matched to the cases by age and calendar time. Crude and adjusted rate ratios (RRs) for current, recent, past, and distant use of fluoroquinolones were calculated. RESULTS: From the cohort of 989,591 subjects, 178,264 subjects were diagnosed with glaucoma and 891,320 were corresponding controls. The 2 groups had same average age of 65 and comparable systemic comorbidities including hypertension, coronary artery disease, and diabetes. There was no statistically significant association between the use of systemic fluoroquinolones and the development of glaucoma for current use [RR=1.01 (95% confidence interval (CI), 0.95-1.07)], recent use [RR=1.00 (95% CI, 0.92-1.08)], or past use [RR=0.94 (95% CI, 0.90-1.00)]. Distant use of systemic fluoroquinolones had a small statistically significant increased risk of developing glaucoma [RR=1.12 (95% CI, 1.09-1.14)]. CONCLUSIONS: There was no detected increased association of the development of glaucoma with current, recent, or past use of systemic fluoroquinolone but a minimal statistically significant increased risk was associated with distant use. Future studies should further examine a potential delayed response with fluoroquinolones and glaucoma.

VarioWatch: providing large-scale and comprehensive annotations on human genomic variants in the next generation sequencing era.

VarioWatch (http://genepipe.ncgm.sinica.edu.tw/variowatch/) has been vastly improved since its former publication GenoWatch in the 2008 Web Server Issue. It is now at least 10 000-times faster in annotating a variant. Drastic speed increase, through complete re-design of its working mechanism, makes VarioWatch capable of annotating millions of human genomic variants generated from next generation sequencing in minutes, if not seconds. While using MegaQuery of VarioWatch to quickly annotate variants, users can apply various filters to retrieve a subgroup of variants according to the risk levels, interested regions, etc. that satisfy users' requirements. In addition to performance leap, many new features have also been added, such as annotation on novel variants, functional analyses on splice sites and in/dels, detailed variant information in tabulated form, plus a risk level decision tree regarding the analyzed variant. Up to 1000 target variants can be visualized with our carefully designed Genome View, Gene View, Transcript View and Variation View. Two commonly used reference versions, NCBI build 36.3 and NCBI build 37.2, are supported. VarioWatch is unique in its ability to annotate comprehensively and efficiently millions of variants online, immediately delivering the results in real time, plus visualizes up to 1000 annotated variants.