共查询到20条相似文献,搜索用时 31 毫秒
1.
《Bioorganic & medicinal chemistry letters》2014,24(24):5572-5575
Osteoarthritis (OA) and the associated joint pain are highly prevalent and a leading cause of disability. We have previously reported the identification of a series of purines as selective CB2 agonists and the identification of compound 1 as a clinical candidate for the treatment of joint pain. In this article we describe the further SAR development of the purine scaffold leading to the discovery of compound 6 as a potent, CNS penetrating CB2 agonist with high selectivity for CB2 over CB1 and oral efficacy in animal models of chronic OA pain. 相似文献
2.
Subasinghe NL Wall MJ Winters MP Qin N Lubin ML Finley MF Brandt MR Neeper MP Schneider CR Colburn RW Flores CM Sui Z 《Bioorganic & medicinal chemistry letters》2012,22(12):4080-4083
Selective blockers of the N-type calcium channel have proven to be effective in animal models of chronic pain. However, even though intrathecally delivered synthetic ω-conotoxin MVIIA from Conus magnus (ziconotide [Prialt®]) has been approved for the treatment of chronic pain in humans, its mode of delivery and narrow therapeutic window have limited its usefulness. Therefore, the identification of orally active, small-molecule N-type calcium channel blockers would represent a significant advancement in the treatment of chronic pain. A novel series of pyrazole-based N-type calcium channel blockers was identified by structural modification of a high-throughput screening hit and further optimized to improve potency and metabolic stability. In vivo efficacy in rat models of inflammatory and neuropathic pain was demonstrated by a representative compound from this series. 相似文献
3.
Augustine T. Osuma Xiangdong Xu Zhi Wang Jennifer A. Van Camp Gail M. Freiberg 《Bioorganic & medicinal chemistry letters》2019,29(19):126603
Effective treatments of neuropathic pain have been a focus of many discovery programs. KCNQ (kv7) are voltage gated potassium channel openers that have the potential for the treatment of CNS disorders including neuropathic pain. Clinical studies have suggested agents such as Retigabine to be a modulator of pain-like effects such as hyperalgesia and allodynia. In this paper, we describe the discovery and evaluation of a series of novel pyrazolopyrimidines and their affinity for potassium channels KCNQ2/3. These pyrazolopyrimidines have also shown good efficacy in the capsaicin-induced acute and secondary mechanical allodynia model and excellent pharmacokinetic properties, which may be superior to Retigabine. 相似文献
4.
McKeown SC Hall A Giblin GM Lorthioir O Blunt R Lewell XQ Wilson RJ Brown SH Chowdhury A Coleman T Watson SP Chessell IP Pipe A Clayton N Goldsmith P 《Bioorganic & medicinal chemistry letters》2006,16(18):4767-4771
The discovery, synthesis and structure-activity relationship (SAR) of a novel series of EP1 receptor antagonists is described. Pyrazole acid 4, identified from a chemical array, had desirable physicochemical properties, an excellent in vitro microsomal inhibition and cytochrome P450 (CYP450) profile and good exposure levels in blood. This compound had an ED50 of 1.3 mg/kg in a rat pain model. A range of more potent analogues in the in vitro assay was identified using efficient array chemistry. These EP1 antagonists have potential as agents in the treatment of PGE2 mediated pain. 相似文献
5.
Sandeep Kadimpati Emily L. Zale Michael W. Hooten Joseph W. Ditre David O. Warner 《PloS one》2015,10(4)
Several cognitive-affective constructs, including pain catastrophizing and pain-related anxiety, have been implicated in the onset and progression of chronic pain, and both constructs have been identified as key targets for multidisciplinary pain treatment. Both neuroticism and depression have been linked to these constructs (and to each other), but how each may contribute to the pain experience is unknown. This study tested associations between neuroticism, depression, and indices of catastrophizing and pain-related anxiety among persons seeking treatment for chronic non-malignant pain. We hypothesized, as a higher-order personality trait, neuroticism would remain uniquely associated with both pain catastrophizing and pain-related anxiety, even after accounting for current symptoms of depression. A retrospective study design assessed depression (as measured by the Centers for Epidemiologic Studies-Depression scale), neuroticism (measured with the Neuroticism-Extraversion-Openness Personality Inventory), the Pain Catastrophizing Scale, and the Pain Anxiety Symptom Score in a consecutive series of patients (n=595) admitted to a 3-week outpatient pain treatment program from March 2009 through January 2011. Hierarchical regression indicated that neuroticism was independently associated with greater pain catastrophizing and pain-related anxiety, above-and-beyond the contributions of sociodemographic characteristics, pain severity, and depression. A depression by neuroticism interaction was not observed, suggesting that associations between neuroticism and cognitive-affective pain constructs remained stable across varying levels of current depression. These findings represent an early but important step towards the clarification of complex associations between trait neuroticism, current depression, and tendencies toward catastrophic and anxiety-provoking appraisals of pain among persons seeking treatment for chronic pain. 相似文献
6.
Knutsen LJ Hobbs CJ Earnshaw CG Fiumana A Gilbert J Mellor SL Radford F Smith NJ Birch PJ Russell Burley J Ward SD James IF 《Bioorganic & medicinal chemistry letters》2007,17(3):662-667
A series of new N-type (Ca(v)2.2) calcium channel blockers derived from the 'hit' structures 2-(3-bromo-4-fluorophenyl)-3-(2-pyridin-2-ylethyl)thiazolidin-4-one 9 and its 2-[4-(4-bromophenyl)pyridin-3-yl]-3-isobutyl analogue 10 is described. Extensive SAR studies using a range of synthetic approaches resulted in novel, patented compounds with IC50 values of up to 0.2 microM in an in vitro IMR32 assay, and selectivities for N/L of up to 30-fold. The new compounds described have potential in treatment of neuropathic pain. 相似文献
7.
Scott D. Kuduk Ronald K. Chang Jenny M.-C. Wai Christina N. Di Marco Victoria Cofre Robert M. DiPardo Sean P. Cook Matthew J. Cato Aneta Jovanovska Mark O. Urban Michael Leitl Robert H. Spencer Stefanie A. Kane George D. Hartman Mark T. Bilodeau 《Bioorganic & medicinal chemistry letters》2009,19(15):4059-4063
A series of indole amidines modified at the 2-position of the indole ring were evaluated as inhibitors of Acid-Sensing Ion Channel-3 (ASIC3), a novel target for the treatment of chronic pain. 相似文献
8.
R M Schelkun P Yuen T C Malone D M Rock S Stoehr B Szoke K Tarczy-Hornoch 《Bioorganic & medicinal chemistry letters》1999,9(16):2447-2452
Voltage activated calcium channel (VACC) blockers have been demonstrated to have utility in the treatment of stroke and pain. A series of aminomethyl substituted phenol derivatives has been identified with good functional activity and selectivity for N-type VACC's over sodium and potassium channels. The methods of synthesis and preliminary pharmacology are discussed herein. 相似文献
9.
Mark P. Healy Amanda C. Allan Kristin Bailey Andy Billinton Iain P. Chessell Nicholas M. Clayton Gerard M.P. Giblin Melanie A. Kay Tarik Khaznadar Anton D. Michel Alan Naylor Helen Price David J. Spalding David A. Stevens Martin E. Swarbrick Alexander W. Wilson 《Bioorganic & medicinal chemistry letters》2018,28(10):1892-1896
A novel series of EP4 agonists and antagonists have been identified, and then used to validate their potential in the treatment of inflammatory pain. This paper describes these novel ligands and their activity within a number of pre-clinical models of pain, ultimately leading to the identification of the EP4 partial agonist GSK726701A. 相似文献
10.
Rawson DJ Brugier D Harrison A Hough J Newman J Otterburn J Maw GN Price J Thompson LR Turnpenny P Warren AN 《Bioorganic & medicinal chemistry letters》2011,21(12):3771-3773
A potent series of substituted (2S,4S)-benzylproline α2δ ligands have been designed from the readily available starting material (2S,4R)-hydroxy-l-proline. The ligands have improved pharmacokinetic profile over the (4S)-phenoxyproline derivatives described previously and have potential for development as oral agents for the treatment of neuropathic pain. Compound 16 has been progressed to clinical development. 相似文献
11.
London C Hoyt SB Parsons WH Williams BS Warren VA Tschirret-Guth R Smith MM Priest BT McGowan E Martin WJ Lyons KA Li X Karanam BV Jochnowitz N Garcia ML Felix JP Dean B Abbadie C Kaczorowski GJ Duffy JL 《Bioorganic & medicinal chemistry letters》2008,18(5):1696-1701
A series of imidazopyridines were evaluated as potential sodium channel blockers for the treatment of neuropathic pain. Several members were identified with good hNa(v)1.7 potency and excellent rat pharmacokinetic profiles. Compound 4 had good efficacy (52% and 41% reversal of allodynia at 2 and 4h post-dose, respectively) in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain when dosed orally at 10mg/kg. 相似文献
12.
《Bioorganic & medicinal chemistry》2020,28(1):115195
N-acylethanolamine acid amidase (NAAA) inhibition represents an exciting novel approach to treat inflammation and pain. NAAA is a cysteine amidase which preferentially hydrolyzes the endogenous biolipids palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). PEA is an endogenous agonist of the nuclear peroxisome proliferator-activated receptor-α (PPAR-α), which is a key regulator of inflammation and pain. Thus, blocking the degradation of PEA with NAAA inhibitors results in augmentation of the PEA/PPAR-α signaling pathway and regulation of inflammatory and pain processes. We have prepared a new series of NAAA inhibitors exploring the azetidine-nitrile (cyanamide) pharmacophore that led to the discovery of highly potent and selective compounds. Key analogs demonstrated single-digit nanomolar potency for hNAAA and showed >100-fold selectivity against serine hydrolases FAAH, MGL and ABHD6, and cysteine protease cathepsin K. Additionally, we have identified potent and selective dual NAAA-FAAH inhibitors to investigate a potential synergism between two distinct anti-inflammatory molecular pathways, the PEA/PPAR-α anti-inflammatory signaling pathway,1–4 and the cannabinoid receptors CB1 and CB2 pathways which are known for their antiinflammatory and antinociceptive properties.5–8 Our ligand design strategy followed a traditional structure–activity relationship (SAR) approach and was supported by molecular modeling studies of reported X-ray structures of hNAAA. Several inhibitors were evaluated in stability assays and demonstrated very good plasma stability (t1/2 > 2 h; human and rodents). The disclosed cyanamides represent promising new pharmacological tools to investigate the potential role of NAAA inhibitors and dual NAAA-FAAH inhibitors as therapeutic agents for the treatment of inflammation and pain. 相似文献
13.
《Bioorganic & medicinal chemistry letters》2014,24(5):1280-1284
A series of 1-aryl-2-(((6-aryl)pyrimidin-4-yl)amino)ethanols have been found to be competitive inhibitors of fatty acid amide hydrolase (FAAH). One member of this class, JNJ-40413269, was found to have excellent pharmacokinetic properties, demonstrated robust central target engagement, and was efficacious in a rat model of neuropathic pain. 相似文献
14.
Tyagarajan S Chakravarty PK Zhou B Taylor B Eid R Fisher MH Parsons WH Wyvratt MJ Lyons KA Klatt T Li X Kumar S Williams B Felix J Priest BT Brochu RM Warren V Smith M Garcia M Kaczorowski GJ Martin WJ Abbadie C McGowan E Jochnowitz N Weber A Duffy JL 《Bioorganic & medicinal chemistry letters》2010,20(24):7479-7482
A series of novel biphenyl pyrazole dicarboxamides were identified as potential sodium channel blockers for treatment of neuropathic pain. Compound 20 had outstanding efficacy in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain. 相似文献
15.
Tyagarajan S Chakravarty PK Park M Zhou B Herrington JB Ratliff K Bugianesi RM Williams B Haedo RJ Swensen AM Warren VA Smith M Garcia M Kaczorowski GJ McManus OB Lyons KA Li X Madeira M Karanam B Green M Forrest MJ Abbadie C McGowan E Mistry S Jochnowitz N Duffy JL 《Bioorganic & medicinal chemistry letters》2011,21(2):869-873
N-type calcium channels (Cav2.2) have been shown to play a critical role in pain. A series of low molecular weight 2-aryl indoles were identified as potent Cav2.2 blockers with good in vitro and in vivo potency. 相似文献
16.
Malan TP Ibrahim MM Vanderah TW Makriyannis A Porreca F 《Chemistry and physics of lipids》2002,121(1-2):191-200
Cannabinoid receptor agonists diminish responses to painful stimuli. Extensive evidence demonstrates that CB(1) cannabinoid receptor activation inhibits pain responses. Recently, the synthesis of CB(2) cannabinoid receptor-selective agonists has allowed testing whether CB(2) receptor activation inhibits pain. CB(2) receptor activation is sufficient to inhibit acute nociception, inflammatory hyperalgesia, and the allodynia and hyperalgesia produced in a neuropathic pain model. Studies using site-specific administration of agonist and antagonist have suggested that CB(2) receptor agonists inhibit pain responses by acting at peripheral sites. CB(2) receptor activation also inhibits edema and plasma extravasation produced by inflammation. CB(2) receptor-selective agonists do not produce central nervous system (CNS) effects typical of cannabinoids retaining agonist activity at the CB(1) receptor. Peripheral antinociception without CNS effects is consistent with the peripheral distribution of CB(2) receptors. CB(2) receptor agonists may have promise for the treatment of pain and inflammation without CNS side effects. 相似文献
17.
Bini Mathew Timothy S. Snowden Michele C. Connelly R. Kiplin Guy Robert C. Reynolds 《Bioorganic & medicinal chemistry letters》2018,28(12):2136-2142
Non-steroidal anti-inflammatory drugs (NSAIDs) have a variety of potential indications that include management of pain and inflammation as well as chemoprevention and/or treatment of cancer. Furthermore, a specific form of ibuprofen, dexibuprofen or the S-(+) form, shows interesting neurological activities and has been proposed for the treatment of Alzheimer’s disease. In a continuation of our work probing the anticancer activity of small sulindac libraries, we have prepared and screened a small diversity library of α-methyl substituted sulindac amides in the profen class. Several compounds of this series displayed promising activity compared with a lead sulindac analog. 相似文献
18.
Williams BS Felix JP Priest BT Brochu RM Dai K Hoyt SB London C Tang YS Duffy JL Parsons WH Kaczorowski GJ Garcia ML 《Biochemistry》2007,46(50):14693-14703
Voltage-gated sodium channels (Nav1) transmit pain signals from peripheral nociceptive neurons, and blockers of these channels have been shown to ameliorate a number of pain conditions. Because these drugs can have adverse effects that limit their efficacy, more potent and selective Nav1 inhibitors are being pursued. Recent human genetic data have provided strong evidence for the involvement of the peripheral nerve sodium channel subtype, Nav1.7, in the signaling of nociceptive information, highlighting the importance of identifying selective Nav1.7 blockers for the treatment of chronic pain. Using a high-throughput functional assay, novel Nav1.7 blockers, namely, the 1-benzazepin-2-one series, have recently been identified. Further characterization of these agents indicates that, in addition to high-affinity inhibition of Nav1.7 channels, selectivity against the Nav1.5 and Nav1.8 subtypes can also be achieved within this structural class. The most potent, nonselective member of this class of Nav1.7 blockers has been radiolabeled with tritium. [3H]BNZA binds with high affinity to rat brain synaptosomal membranes (Kd = 1.5 nM) and to membranes prepared from HEK293 cells stably transfected with hNav1.5 (Kd = 0.97 nM). In addition, and for the first time, high-affinity binding of a radioligand to hNav1.7 channels (Kd = 1.6 nM) was achieved with [3H]BNZA, providing an additional means for identifying selective Nav1.7 channel inhibitors. Taken together, these data suggest that members of the novel 1-benzazepin-2-one structural class of Nav1 blockers can display selectivity toward the peripheral nerve Nav1.7 channel subtype, and with appropriate pharmacokinetic and drug metabolism properties, these compounds could be developed as analgesic agents. 相似文献
19.
Ten female infants were referred for symptomatic hemangiomas in the anogenital area. (One had had steroid treatment prior to consultation.) The natural history of these lesions is well known. Virtually all will spontaneously involute over a period of years. However, the lesions reported were particularly troublesome because of repeated ulcerations and subsequent pain. Prior treatment had been local wound care with antibiotic ointment and Telfa-type dressings. After referral from a family practitioner or pediatrician, argon laser treatment was performed in an outpatient setting. Eight of the 10 patients were treated with local anesthesia, and 2 had general anesthesia. All lesions healed in 1 to 5 weeks. No patients referred during this period were excluded from this series. All who received treatment were included. All the lesions involuted following treatment. In our estimation, the final result is identical to what may be expected after spontaneous involution of an ulcerated or infected hemangioma. The major difference is that involution occurred in a few weeks in laser-treated patients rather than a period of months or years. Ulcerated hemangiomas of the anogenital area have significant morbidity that can be efficiently avoided with the use of argon laser therapy. Lesions of the anogenital area have a strong predilection for females. 相似文献
20.
《Bioorganic & medicinal chemistry》2014,22(4):1468-1478
A series of piperazine ureas were designed, synthesized, and evaluated for their potential as novel orally efficacious fatty acid amide hydrolase (FAAH) inhibitors for the treatment of neuropathic and inflammatory pain. We carried out an optimization study of compound 5 to improve its in vitro FAAH inhibitory activity, and identified the 2-pyrimidinylpiperazine derivative 21d with potent inhibitory activity, favorable DMPK profile and brain permeability. Compound 21d showed robust and dose-dependent analgesic efficacy in animal models of both neuropathic and inflammatory pain. 相似文献