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The voltage-gated sodium channel Na

[Image: see text] Cystic fibrosis (CF) is a genetic disorder that affects multiple tissues and organs. CF is caused by mutations in the CFTR gene, resulting in insufficient or impaired cystic fibrosis transmembrane conductance regulator (CFTR) protein. The deletion of phenylalanine at position 508 of the protein (F508del-CFTR) is the most common mutation observed in CF patients. The most effective treatments of these patients employ two CFTR modulator classes, correctors and potentiators. CFTR correctors increase protein levels at the cell surface; CFTR potentiators enable the functional opening of CFTR channels at the cell surface. Triple-combination therapies utilize two distinct corrector molecules (C1 and C2) to further improve the overall efficacy. We identified the need to develop a C2 corrector series that had the potential to be used in conjunction with our existing C1 corrector series and provide robust clinical efficacy for CF patients. The identification of a pyrrolidine series of CFTR C2 correctors and the structure–activity relationship of this series is described. This work resulted in the discovery and selection of (2S,3R,4S,5S)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylic acid (ABBV/GLPG-3221), which was advanced to clinical trials.

Cystic fibrosis (CF) is an autosomal recessive disease resulting from mutations on both copies of the CFTR gene. Phenylalanine deletion at position 508 of the CFTR protein (F508del-CFTR) is the most frequent mutation in CF patients. Currently, the most effective treatments of CF use a dual or triple combination of CFTR correctors and potentiators. In triple therapy, two correctors (C1 and C2) and a potentiator are employed. Herein, we describe the identification and exploration of the SAR of a series of 4-aminopyrrolidine-2-carboxylic acid C2 correctors of CFTR to be used in conjunction with our existing C1 corrector series for the treatment of CF.

A series of 1,2,3,6-tetrahydropyridyl-4-carboxamides, exemplified by 6, have been synthesized and evaluated for in vitro TRPV1 antagonist activity, and in vivo analgesic activity in animal pain models. The tetrahydropyridine 6 is a novel TRPV1 receptor antagonist that potently inhibits receptor-mediated Ca2+ influx in vitro induced by several agonists, including capsaicin, N-arachidonoyldopamine (NADA), and low pH. This compound penetrates the CNS and shows potent anti-nociceptive effects in a broad range of animal pain models upon oral dosing due in part to its ability to antagonize both central and peripheral TRPV1 receptors. The SAR leading to the discovery of 6 is presented in this report.

SAR studies for N-aryl-N′-benzyl urea class of TRPV1 antagonists have been extended to cover α-benzyl alkylation. Alkylated compounds showed weaker in vitro potencies in blocking capsaicin activation of TRPV1 receptor, but possessed improved pharmacokinetic properties. Further structural manipulations that included replacement of isoquinoline core with indazole and isolation of single enantiomer led to TRPV1 antagonists like (R)-16a with superior pharmacokinetic properties and greater potency in animal model of inflammatory pain.

The synthesis and structure-activity relationship of 1-(aryl)-3-(4-(amino)benzyl)urea transient receptor potential vanilloid 1 (TRPV1) antagonists are described. A variety of cyclic amine substituents are well tolerated at the 4-position of the benzyl group on compounds containing either an isoquinoline or indazole heterocyclic core. These compounds are potent antagonists of capsaicin activation of the TRPV1 receptor in vitro. Analogues, such as compound 45, have been identified that have good in vivo activity in animal models of pain. Further optimization of 45 resulted in compound 58 with substantially improved microsome stability and oral bioavailability, as well as in vivo activity.

The stress—strain behavior at room temperature and at 1100° C (2000°F) is measured for two carbon fiber-reinforced silicon carbide (C/SiC) composite materials: a two dimensional (2D) plain-weave quasi-isotropic laminate and a 3D angle interlock woven composite. Previously developed micromechanics-based material models are calibrated by correlating the predicted material property values with the measured values. Four-point beam-bending subelement specimens are fabricated with these two fiber architectures and four-point bending tests are performed at room temperature and at 1100°C. Displacements and strains are measured at the mid-span of the beam and recorded as a function of load magnitude. The calibrated material models are used in concert with a nonlinear finite-element solution using ABAQUS to simulate the structural response of the two materials in the four-point beam bending tests. The structural response predicted by the nonlinear analysis method compared favorably with the measured response for both materials and both test temperatures. Results show that the material models scale-up fairly well from coupons to subcomponent level.

Novel 5,6-fused heteroaromatic ureas were synthesized and evaluated for their activity as TRPV1 antagonists. It was found that 4-aminoindoles and indazoles are the preferential cores for the attachment of ureas. Bulky electron-withdrawing groups in the para-position of the aromatic ring of the urea substituents imparted the best in vitro potency at TRPV1. The most potent derivatives were assessed in in vivo inflammatory and neuropathic pain models. Compound 46, containing the indazole core and a 3,4-dichlorophenyl group appended to it via a urea linker, demonstrated in vivo analgesic activity upon oral administration. This derivative also showed selectivity versus other receptors in the CEREP screen and exhibited acceptable cardiovascular safety at levels exceeding the therapeutic dose.

We have discovered that polar 7-substituents of pyridopyrimidine derivatives affect not only whole cell AK inhibitory potency, but also selectivity in causing locomotor side effects in vivo animal models. We have identified compound, 1o, which has potent whole cell AK inhibitory potency, analgesic activity and minimal reduction of locomotor activity.

A new, low cost process for hot-melt impregnation of continuous reinforcing fibers with thermoplastic polymers is described. This technique can be used to fabricate various product forms including discontinuous, long-fiber products for compression molded parts, continuous fiber products for pultrusion, filament winding, and woven fabric applications. Mechanical data are presented for composites with various fiber and polymer combinations. Effects of fiber orientation and length on mechanical properties are discussed, and the effect of fiber–polymer bonding on impact strength and microstructure are shown. It is shown that the low cost and high performance achieved with this approach has the potential to expand applications of thermoplastic composite materials.

Novel chroman and tetrahydroquinoline ureas were synthesized and evaluated for their activity as TRPV1 antagonists. It was found that aryl substituents on the 7- or 8-position of both bicyclic scaffolds imparted the best in vitro potency at TRPV1. The most potent chroman ureas were assessed in chronic and acute pain models, and compounds with the ability to cross the blood-brain barrier were shown to be highly efficacious. The tetrahydroquinoline ureas were found to be potent CYP3A4 inhibitors, but replacement of bulky substituents at the nitrogen atom of the tetrahydroisoquinoline moiety with small groups such as methyl can minimize the inhibition.

The synthesis and structure-activity relationships of a series of 5-monosubstituted and 4,5-disubstituted 2-arylaminooxazoles as novel antagonists of the transient receptor potential vanilloid 1 (TRPV1) receptor are described. The 7-hydroxy group of the tetrahydronaphthyl moiety on the 2-amino substituent of the oxazole ring was important for obtaining excellent in vitro potency at the human TRPV1 receptor, while a variety of alkyl and phenyl substituents at the 4- and 5-positions of the oxazole ring were well tolerated and yielded potent TRPV1 antagonists. Despite excellent in vitro potency, the 5-monosubstituted compounds suffered from poor pharmacokinetics. It was found that 4,5-disubstitution on the oxazole ring was critical to the improvement of the overall pharmacokinetic profile of these analogues, which led to the discovery of compound (R)-27, a novel TRPV1 antagonist with good oral activity in preclinical animal models of pain.

The synthesis and SAR of a series of indazole TRPV1 antagonists leading to the discovery of 21 (ABT-116) is described. Biological studies demonstrated potent in vitro and in vivo activity for 21, as well as suitable physicochemical and pharmacokinetic properties for advancement to clinical development for pain management.

Three novel series of histamine H(4) receptor (H(4)R) antagonists containing the 2-aminopyrimidine motif are reported. The best of these compounds display good in vitro potency in both functional and binding assays. In addition, representative compounds are able to completely block itch responses when dosed ip in a mouse model of H(4)-agonist induced scratching, thus demonstrating their activities as H(4)R antagonists.

The TRPV1 antagonist A-995662 demonstrates analgesic efficacy in monoiodoacetate-induced osteoarthritic (OA) pain in rat, and repeated dosing results in increased in vivo potency and a prolonged duration of action. To identify possible mechanism(s) underlying these observations, release of neuropeptides and the neurotransmitter glutamate from isolated spinal cord was measured. In OA rats, basal release of glutamate, bradykinin and calcitonin gene-related peptide (CGRP) was significantly elevated compared to naive levels, whereas substance P (SP) levels were not changed. In vitro studies showed that capsaicin-evoked TRPV1-dependent CGRP release was 54.7+/-7.7% higher in OA, relative to levels measured for naive rats, suggesting that TRPV1 activity was higher under OA conditions. The efficacy of A-995662 in OA corresponded with its ability to inhibit glutamate and CGRP release from the spinal cord. A single, fully efficacious dose of A-995662, 100 micromol/kg, reduced spinal glutamate and CGRP release, while a single sub-efficacious dose of A-995662 (25 micromol/kg) was ineffective. Multiple dosing with A-995662 increased the potency and duration of efficacy in OA rats. Changes in efficacy did not correlate with plasma concentrations of A-995662, but were accompanied with reductions in spinal glutamate release. These findings suggest that repeated dosing of TRPV1 antagonists enhances therapeutic potency and duration of action against OA pain, at least in part, by the sustained reduction in release of glutamate and CGRP from the spinal cord.

A variable high temperature / low pressure facility has been developed to characterize the thermal response of candidate thermal protection materials in reentry environments. Transient, non-linear finite element models were developed to optimize the design of the test facility. All models used temperature dependent material properties and time dependent boundary conditions based on thermocouple data obtained during checkout runs. These experimental runs were based on simulated reentry profiles. A one-dimensional model was developed considering only the axial heat flow through the thickness of the test stack. It was used as a benchmark when considering multi-dimensional heating effects. Axisymmetric and three-dimensional models were developed to minimize transverse heating and edge effects through a unique combination of material selection and geometry. The final, optimized configuration is capable of temperatures as high as 4500 °F with pressures as low as 100 mTorr in inert atmosphere. Heating rates that produce surface temperature changes of 300 °F / min are attainable. Pyrometers are used to measure the element temperature and the specimen hot face temperature. Up to thirty-five thermocouples are used to measure internal specimen, cold-face, and insulation temperatures within the stack. A PID algorithm is used to control the furnace, while a data acquisition system is used to log all data.Copyright © 2006 by ASME

Novel transient receptor potential vanilloid 1 (TRPV1) receptor antagonists with various bicyclic heteroaromatic pharmacophores were synthesized, and their in vitro activity in blocking capsaicin activation of TRPV1 was assessed. On the basis of the contribution of these pharmacophores to the in vitro potency, they were ranked in the order of 5-isoquinoline > 8-quinoline = 8-quinazoline > 8-isoquinoline > or = cinnoline approximately phthalazine approximately quinoxaline approximately 5-quinoline. The 5-isoquinoline-containing compound 14a (hTRPV1 IC50 = 4 nM) exhibited 46% oral bioavailability and in vivo activity in animal models of visceral and inflammatory pain. Pharmacokinetic and pharmacological properties of 14a are substantial improvements over the profile of the high-throughput screening hit 1 (hTRPV1 IC50 = 22 nM), which was not efficacious in animal pain models and was not orally bioavailable.

To fulfill President George W. Bush’s “Vision for Space Exploration” (NASA, 2004) — successful human and robotic missions to and from other solar system bodies in order to explore their atmospheres and surfaces — the National Aeronautics and Space Administration (NASA) must reduce the trip time, cost, and vehicle weight so that the payload and scientific experiments’ capabilities can be maximized. The new project described in this paper will generate thermal protection system (TPS) products that will enable greater fidelity in mission/vehicle design trade studies, support risk reduction for material selections, assist in the optimization of vehicle weights, and provide materials and processes templates for use in the development of human‐rated TPS qualification and certification plans.

In this report we demonstrate the use of the scanning acoustic microscope (SAM) for non-destructive characterization of fatigue damage in SiC fiber composites. Four continuous fiber ceramic composites (CFCC) samples, subjected to fatigue damage, were studied by scanning acoustic microscopy. The damaged samples were inspected by the high-frequency Ernst Leitz Scanning Acoustic Microscope (ELSAM) and the lowfrequency time-resolved acoustic microscope developed at the Institute of Biochemical Physics (IBCP), Moscow. It has been demonstrated that the high-frequency microscope provides a powerful means of detecting subsurface cracks in composite matrix. In a previously published paper (Manghnani et al. 2000), the low-frequency acoustic microscope was chosen to study the internal fatigue damage in samples without any preparation for SAM investigation. The surface of the fiber sample was rough because of the thick fiber bundles breaking at the surface. It was shown that internal cracks (several millimeters in length) propagated parallel to the sample surface and could be detected by the time-resolved acoustic microscope (Manghnani et al. 2000). In this report we show that a small subsurface crack of several millimeters in length becomes visible after polishing the sample surface. Most of the observed cracks run perpendicularly to the bundles of fibers. Samples with different fatigue loading cycles were thus investigated with SAM, and findings are presented here.

A novel series of pyridopyrimidine analogues 9 was identified as potent adenosine kinase inhibitors based on the SAR and computational studies. Substitution of the C7 position of the pyridopyrimidino core with C2' substituted pyridino moiety increased the in vivo potency and enhanced oral bioavailability of these adenosine kinase inhibitors.

Carbon-carbon materials are being developed for high temperature use in gas turbine engines and other applications. They have high specific strength and stiffness at elevated temperature, as well as thermal shock resistance. Silicon carbide based coatings are commonly used to protect the material from oxidation.