Structure−Activity Relationships of a Series of Pyrrolo[3,2-<i>d</i>]pyrimidine Derivatives and Related Compounds as Neuropeptide Y5 Receptor Antagonists

Norman, Mark H.; Chen, Ning; Chen, Zhidong; Fotsch, Christopher; Hale, Clarence; Han, Nianhe; Hurt, Ray; Jenkins, Tracy J.; Kincaid, John; Liu, Longbin; Lu, Yuelie; Moreno, Ofir A.; Santora, Vincent J.; Sonnenberg, Jennifer D.; Karbon, William

doi:10.1021/jm000269t

Cited by 92 publications

(65 citation statements)

References 45 publications

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“…NVP was kindly supplied by Boehringer-Ingelheim GmbH. 12-OH-NVP (Grozinger et al, 1995), 12-Cl-NVP (Kelly et al, 1995), and 4-Cl-NVP (Hargrave et al, 1991;Norman et al, 2000) were synthesized as described previously. Phosphate-buffered saline (pH 7.4, fetal bovine serum (FBS), 1640 RPMI-HEPES modified, Eagle's minimal essential medium nonessential amino acids solution, and penicillin-streptomycin liquid were purchased from Invitrogen Canada, Inc. (Burlington, ON, Canada).…”

Section: Methodsmentioning

confidence: 99%

A Study of the Specificity of Lymphocytes in Nevirapine-Induced Skin Rash

Chen

Tharmanathan²,

Mannargudi³

et al. 2009

J Pharmacol Exp Ther

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Nevirapine treatment can cause a skin rash. We developed an animal model of this rash and determined that the 12-hydroxylation metabolic pathway is responsible for the rash, and treatment of animals with 12-OH-nevirapine also leads to a rash. In the present study, we investigated the specificity of lymphocytes in nevirapine-induced skin rash. Brown Norway rats were treated with nevirapine or 12-OH-nevirapine to induce a rash. Lymph nodes were removed, and the response of lymphocytes to nevirapine and its metabolites/analogs was determined by cytokine production (enzyme-linked immunosorbent assay, enzyme-linked immunosorbent spot assay, and Luminex) and proliferation (alamar blue assay). Subsets of lymphocytes were depleted to determine which cells were responsible for cytokine production. Lymphocytes from animals rechallenged with nevirapine proliferated to nevirapine, but not to 12-OH-nevirapine or 4-chloro-nevirapine. They also produced interferon-␥ (IFN-␥) when exposed to nevirapine, significantly less when exposed to 4-chloro-nevirapine, and very little when exposed to 12-OHnevirapine, even though oxidation to 12-OH-nevirapine is required to induce the rash. Moreover, the specificity of lymphocytes from 12-OH-nevirapine-treated rats was the same, i.e., responding to nevirapine more than to 12-OH-nevirapine, even though these animals had never been exposed to nevirapine. A Luminex immunoassay showed that a variety of other cytokines/chemokines were also produced by nevirapine-stimulated lymphocytes. CD4 ϩ cells were the major source of IFN-␥. The specificity of lymphocytes in activation assays cannot be used to determine what initiated an immune response. This has significant implications for understanding the evolution of an immune response and the basis of the pharmacological interaction hypothesis.Nevirapine (NVP), marketed under the trade name Viramune (Boehringer Ingelheim GmbH, Ingelheim, Germany), is a non-nucleoside reverse transcriptase inhibitor used in the treatment of human immunodeficiency virus infections. Although effective, its use has been limited because of its propensity to cause skin rash and liver toxicity. In patients, skin rashes vary from mild erythematous, maculopapular rashes to more severe Stevens-Johnson syndrome or toxic epidermal necrolysis (Warren et al., 1998;Fagot et al., 2001). Our group discovered a novel animal model of NVPinduced skin rash in rats. The characteristics of NVP-induced skin rash in Brown Norway rats are very similar to the milder rashes that occur in humans, which suggests that the mechanisms are very similar. Specifically, in both humans and rats there is a 2-to 3-week delay between starting the drug and the onset of rash, and on re-exposure, symptoms are more severe and accelerated (Shenton et al., 2003;Taiwo, 2006). Females are more susceptible to developing rash than males in both Brown Norway rats and humans. Furthermore, the sensitivity to NVP-induced skin rash can be transferred with CD4 ϩ T cells from NVP-rechallenged rats to naive recipients ...

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Section: Methodsmentioning

confidence: 99%

A Study of the Specificity of Lymphocytes in Nevirapine-Induced Skin Rash

Chen

Tharmanathan²,

Mannargudi³

et al. 2009

J Pharmacol Exp Ther

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“…In short, reaction of pyridine 1 with a mixture of phosphoryl chloride and phosphorous pentachloride rendered the known 2 [11] in high yield. Displacement of the chloro group of 2 with a methoxy group, using sodium methoxide in methanol finished intermediate 3 which was in turn transformed to the desired 4 by the action of treatment with a base followed by condensation of the resultant carbanion with diethyl oxalate.…”

Section: Resultsmentioning

confidence: 99%

“…The resulting solution was allowed to react, with stirring, for 20 at 0°C and then allowed to warm to room temperature and stirred for an additional one hour. The resulting slurry was filtered and the solids collected by vacuum filtration to afford the title compound 6-Chloro-2-methyl-3-nitropyridine 2 as a brown solid solid [11].…”

Section: Experimental Workmentioning

confidence: 99%

Synthesis of Functionalized Polythiophene as a Potenial Organic Semi-Conductor

Siddiqui

Ullah

Al‐Betar

et al. 2016

MATEC Web of Conferences

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Abstract. The synthesis Poly [1,5-naphthyridine-(3-hexylthiophene)] (PN3HTh) semi-conducting polymer has been accomplished by adopting both conventional and microwave-assisted Suzuki-Miyaura cross-coupling reaction between 3-hexylthiophene-2,5-diboronic ester and 2,6-dibromo-1,5-naphthyridine. The electrochemical and transport properties of PN3HTh were investigated both in the bulk as well as in thin film form. These properties can be further tuned by changing the solvent and the nature of the electrode used. Consequently, cyclic voltammetry (CV) measurements were conducted using a potentiostat coupled with an electrochemical cell. The CV results of PN3HTh as a bulk form in H2SO4 solution indicated that the concentration of the polymer in the solution is not well defined because of polymer poor solubility in aqueous solutions. On the other hand, the sulfur group which works as electron donating makes the system more electron-rich. This can explain by the absence of the reduction peak. For the thin film, two single oxidation peaks were obtained at around 0 V and 0.3 V for both cases. Different solvents can tune the transport properties of the polymer as can be seen from the two CVs where BF3 exhibited enhanced transport properties over ACN. The synthesized polymers were characterized by modern spectroscopic methods including IR and NMR.

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“…Two original methods of preparing 6-substituted pyrrolo[3,2-d]pyrimidines 27 are described in [31]. The authors showed that 4-chloro-5-nitropyrimidines 23 could act as arylating agents toward enamines.…”

Section: Abmentioning

confidence: 99%