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.
The first example of a transition metal-catalyzed hetero-5 + 2 cycloaddition reaction is described. Use of cyclopropyl imines as five-atom components, an alkyne as a two-carbon component, and a Rh(I) ...catalyst enables a new route to dihydroazepines. This new hetero-5 + 2 cycloaddition works well with aldimines, ketimines, and with substituted cyclopropanes and affords the desired dihydroazepines in excellent yields as single regioisomers. Use of serial imine formation/aza-5 + 2 cycloaddition generates the desired dihydroazepines in one operation from three commercially available starting materials. The reaction has been scaled to give gram quantities of dihydroazepine.
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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.
Nav1.8 (also known as PN3) is a tetrodotoxin-resistant (TTx-r) voltage-gated sodium channel (VGSC) that is highly expressed on small diameter sensory neurons and has been implicated in the ...pathophysiology of inflammatory and neuropathic pain. Recent studies using an Nav1.8 antisense oligonucleotide in an animal model of chronic pain indicated that selective blockade of Nav1.8 was analgesic and could provide effective analgesia with a reduction in the adverse events associated with nonselective VGSC blocking therapeutic agents. Herein, we describe the preparation and characterization of a series of 5-substituted 2-furfuramides, which are potent, voltage-dependent blockers (IC50 < 10 nM) of the human Nav1.8 channel. Selected derivatives, such as 7 and 27, also blocked TTx-r sodium currents in rat dorsal root ganglia (DRG) neurons with comparable potency and displayed >100-fold selectivity versus human sodium (Nav1.2, Nav1.5, Nav1.7) and human ether-a-go-go (hERG) channels. Following systemic administration, compounds 7 and 27 dose-dependently reduced neuropathic and inflammatory pain in experimental rodent models.
The voltage-gated sodium channels are a family of proteins that control the flow of sodium ions across cell membranes. Considerable data support the hypothesis that hyperexcitability and spontaneous ...action potential firing in peripheral sensory neurons mediated by voltage-gated sodium channels contribute to the pathophysiology of chronic pain. Sodium channel blockers are, therefore, appealing entities for therapeutic intervention in painful human neuropathies. This review will focus on the latest advances in the development of small molecule sodium channel blockers and their application to the treatment of chronic pain.
We have recently reported that systemic delivery of A-803467 5-(4-chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide, a selective Na(v)1.8 sodium channel blocker, reduces behavioral measures of ...chronic pain. In the current study, the effects of A-803467 on evoked and spontaneous firing of wide dynamic range (WDR) neurons were measured in uninjured and rats with spinal nerve ligations (SNLs). Administration of A-803467 (10-30 mg/kg i.v.) reduced mechanically evoked (10-g von Frey hair) and spontaneous WDR neuronal activity in SNL rats. In uninjured rats, A-803467 (20 mg/kg i.v.) transiently reduced evoked but not spontaneous firing of WDR neurons. The systemic effects of A-803467 in SNL rats were not altered by spinal transection or by systemic pretreatment with the transient receptor potential vanilloid type 1 (TRPV1) receptor agonist, resiniferatoxin, at doses that impair the function of TRPV1-expressing fibers. To determine sites of action, A-803467 was administered into spinal tissue, into the uninjured L4 dorsal root ganglion (DRG), or into the neuronal receptive field. Injections of A-803467 into the L4 DRG (30-100 nmol/1 mul) or into the hindpaw receptive field (300 nmol/50 mul) reduced evoked but not spontaneous WDR firing. In contrast, intraspinal (50-150 nmol/0.5 mul) injection of A-803467 decreased both evoked and spontaneous discharges of WDR neurons. Thus, Na(v)1.8 sodium channels on the cell bodies/axons within the L4 DRG as well as on peripheral and central terminals of primary afferent neurons regulate the inflow of low-intensity mechanical signals to spinal WDR neurons. However, Na(v)1.8 sodium channels on central terminals seem to be key to the modulation of spontaneous firing in SNL rats.
Studies in our laboratory are directed at the advancement of synthesis, biology, and medicine. This lecture will focus on new transition metal-catalyzed reactions that have been inspired by ...biologically potent targets such as phorbol and Taxol® and by the more general interest in producing syntheses that are concise, efficient, cost- and resource-effective, environmentally benign, quick, and simple to conductin essence, ideal. A special emphasis in our program is placed on new transition metal-catalyzed reactions that, in the absence of catalyst, would be forbidden or difficult to achieve. We have thus far reported the first examples of intramolecular metal-catalyzed 4+2, 5+2, and 4+4 cycloadditions, reactions that produce 6-, 7-, and 8-membered rings, respectively. Recent advances in our 5+2 cycloaddition studies will be presented, including new catalysts for relative and absolute stereochemical control. We will also describe recyclable catalysts that can be used in water, thereby minimizing cost and environmental concerns about solvent waste streams. New multicomponent reactions will also be presented. Finally, we will report a new 6+2 cycloaddition that produces an 8-membered ring.
A series of diazabicyclo3.3.0octane substituted pyridines and pyrazines was synthesized and characterized at the α4β2 neuronal nicotinic acetylcholine receptor (nAChR). The compounds were designed to ...mimic the profile of ABT-089, high affinity binding ligand for the α4β2 nAChR, with limited agonist activity. Carboxamide derivatives of 3-(diazabicyclo3.3.0octane)-substituted pyridines or 2-(diazabicyclo3.3.0octane)-substituted pyrazines were found to have the desired binding and activity profile. The structure–activity relationship of these compounds is presented.
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The voltage-gated sodium channel Nav1.7 is an attractive target for the treatment of pain based on the high level of target validation with genetic evidence linking Nav1.7 to pain in ...humans. Our effort to identify selective, CNS-penetrant Nav1.7 blockers with oral activity, improved selectivity, good drug-like properties, and safety led to the discovery of 2-substituted quinolines and quinolones as potent small molecule Nav1.7 blockers. The design of these molecules focused on maintaining potency at Nav1.7, improving selectivity over the hERG channel, and overcoming phospholipidosis observed with the initial leads. The structure-activity relationship (SAR) studies leading to the discovery of (R)-(3-fluoropyrrolidin-1-yl)(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinolin-2-yl)methanone (ABBV-318) are described herein. ABBV-318 displayed robust in vivo efficacy in both inflammatory and neuropathic rodent models of pain. ABBV-318 also inhibited Nav1.8, another sodium channel isoform that is an active target for the development of new pain treatments.
Described herein is an efficient preparative scale synthesis of 1-(2-methyoxyethoxy)-1-vinylcyclopropane and the investigation of the utility of this reagent as a new five-carbon component in ...metal-catalyzed 5 + 2 cycloadditions. A new cycloaddition procedure is also described that proceeds up to 12-fold faster and with 10-fold less catalyst than previously described, providing cycloheptenones in many cases in minutes and in isolated yields of 75−97%. The procedure is readily conducted on a small or large scale (up to 100 mmol thus far).
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