Synthesis and structure-activity relationships of a series of anxioselective pyrazolopyridine ester and amide anxiolytic agents

Bare, Thomas M.; McLaren, Carolyn; Campbell, J. B.; Firor, Judy W.; Resch, James F.; Walters, Claudia Powers; Salama, Andre I.; Meiners, B.A.; Patel, Jitendra

doi:10.1021/jm00132a011

Cited by 105 publications

(39 citation statements)

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“…Loreclezole (Heeres, 1985;Astleford et al, 1989), tracazolate (Bare et al, 1989), etifoxine (Putman et al, 2007), and ocinaplon (Skolnick and Epstein, 2005) were synthesized in our lab using methods reported in the literature. The enaminones were synthesized as described previously Table 1).…”

Section: Methodsmentioning

confidence: 99%

Limiting Activity at β₁-Subunit-Containing GABA_A Receptor Subtypes Reduces Ataxia

Gee¹,

Tran²,

Hogenkamp³

et al. 2009

J Pharmacol Exp Ther

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GABA A receptor (R) positive allosteric modulators that selectively modulate GABA A Rs containing ␤ 2 -and/or ␤ 3 -over ␤ 1 -subunits have been reported across diverse chemotypes. Examples include loreclezole, mefenamic acid, tracazolate, and etifoxine. In general,"␤ 2/3 -selective" GABA A R positive allosteric modulators are nonbenzodiazepines (nonBZs), do not show ␣-subunit isoform selectivity, yet have anxiolytic efficacy with reduced ataxic/sedative effects in animal models and humans. Here, we report on an enantiomeric pair of nonBZ GABA A R positive allosteric modulators that demonstrate differential ␤-subunit isoform selectivity. We have tested this enantiomeric pair along with a series of other ␤ 2/3 -subunit selective, ␣-subunit isoform-selective, BZ and nonBZ GABA A positive allosteric modulators using electrophysiological, pharmacokinetic, and behavioral assays to test the hypothesis that ataxia may be correlated with the extent of modulation at ␤ 1 -subunit-containing GABA A Rs. Our findings provide an alternative strategy for designing anxioselective allosteric modulators of the GABA A R with BZ-like anxiolytic efficacy by reducing or eliminating activity at ␤ 1 -subunit-containing GABA A Rs.Positive allosteric modulators of the GABA A receptor (R) such as the benzodiazepines (BZs) continue to be used to treat anxiety, despite the well-known side effect of sedation. Diverse drug discovery efforts over two decades have focused on generating "anxioselective" (i.e., reducing anxiety without sedation) GABA A R positive allosteric modulators. Medicinal chemistry efforts have focused primarily on modifications of the BZ template with limited success in reducing sedative liability (Whiting, 2006).One strategy to generate anxioselective positive allosteric modulators involves creation of positive allosteric modulators that selectively modulate individual GABA A R subtypes involved in anxiety, while avoiding those mediating sedation. Several laboratories have focused on ␣-subunit isoform-selective BZ site agonists that evoke positive modulation of ␣ 2 -and ␣ 3 -but not ␣ 1 -subunit-containing GABA A Rs. This "␣ 2/3 -selective" approach is based on pharmacological and genetic data suggesting that ␣ 2 -and ␣ 3 -subunit-containing GABA A Rs mediate the anxiolytic actions of BZs, whereas those with ␣ 1 -subunits, especially the ␣ 1 ␤ 2 ␥ 2 subtype, are thought to mediate their sedative effects (Rudolph et al., 1999;McKernan et al., 2000). Consistent with this general theory, L-838,417 is a ␣ 2,3 -subunit-selective partial agonist BZ receptor ligand reported to be anxioselective in animal models (McKernan et al., 2000). However, recent clinical studies designed to determine whether ␣ 2,3 -subunit selectivity imparts reduced sedative liability has resulted in equivocal results where BZ-like side effects were observed (de Haas et al., 2008(de Haas et al., , 2009. Moreover, the ␣ 3 -subunit-selective BZ site partial agonist adipiplon has potent sedative activity and was in clinical development as a sedative...

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Section: Methodsmentioning

confidence: 99%

Limiting Activity at β₁-Subunit-Containing GABA_A Receptor Subtypes Reduces Ataxia

Gee¹,

Tran²,

Hogenkamp³

et al. 2009

J Pharmacol Exp Ther

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“…[8][9][10][11] Compounds 27a, d-e, g-i, p, x, and z were commercially available. The other 1-methylpyrazoles, 27c and 27f, were prepared by condensation of methylhydrazine to the corresponding Michael acceptors 33 and 34, respectively.…”

Section: Chemistrymentioning

confidence: 99%

“…Male Hartley guinea pigs aged 7 weeks (nϭ5) were actively sensitized by intraperitoneal administration of 1 mg of ovalbumin (OVA) containing 5ϫ10 9 killed Bordetella pertussis organisms on day 0. On day 14, the bronchoconstrictor response was measured using a modified version of the method of Konzett and Rüssler.…”

Section: Srs-a Mediated Bronchoconstriction In Guinea Pigsmentioning

confidence: 99%

Discovery of New Orally Active Phosphodiesterase (PDE4) Inhibitors

Ochiai

Ishida

Ohtani

et al. 2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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Phosphodiesterase 4 (PDE4) is an enzyme that is responsible for the inactivation of cyclic adenosine monophosphate (cAMP).1,2) The anti-inflammatory effects of PDE4 inhibitors have been well established in a variety of animal models. 3)However, clinical use of these inhibitors has not been achieved yet because of dose-limiting side effects such as nausea and vomiting that restrict therapeutic application. 4)In previous reports, we have described the design and synthesis of bicyclo[3 · 3 · 0]octane derivatives 5) and piperidine derivatives, 6) which are interesting new classes of PDE4 inhibitors with therapeutic potential. Structure activity relationship (SAR) studies of PDE4 inhibitors based on the structural features of Ariflo 1 7) have revealed that its further modification yields a series of PDE4 inhibitors with an improved therapeutic index relative to the classical inhibitor, rolipram 2 (Fig. 1). To create efficient new PDE4 inhibitors with a higher therapeutic potential, discovery and evaluation of a new chemical lead with a completely different structure was considered to provide another approach to chemical modification. Here we report on the discovery of two new orally active pyrazolopyridines 5 and 9 (Fig. 2). SAR data are also presented. ChemistryThe synthesis of the test compounds listed in Tables 1-3 is outlined in Chart 1. [8][9][10][11] Compounds 27a, d-e, g-i, p, x, and z were commercially available. The other 1-methylpyrazoles, 27c and 27f, were prepared by condensation of methylhydrazine to the corresponding Michael acceptors 33 and 34, respectively. 3-Methylpyrazoles, 27j-o, q-w, and y were prepared from 35 and the corresponding hydrazine derivatives. Michael addition of 27a-z to diethyl ethoxymethylenemalonate gave 28a-z, respectively, after which ring closure was accomplished with phosphorus oxychloride under reflux to afford chlorides 29a-z, respectively. Alkaline hydrolysis of 29a-z gave carboxylic acids 30a-z, respectively. Heating of 30a-z with thionyl chloride, followed by treatment with aqueous ammonia, resulted in production of the amides 31a-z, respectively. Replacement of the chloro moiety of 31a-z with appropriate anilines led to the test compounds 5 and 8-26. N-Methylation of the 3-methoxyaniline moiety afforded 7. Compounds 3, 4, and 6 were prepared from 31a according to the procedure described for preparation of 5 from 31a. Results and DiscussionA series of pyrazolopyridine derivatives were synthesized and evaluated for inhibition of phosphodiesterase type 4 prepared from U937 cells, 12) which were derived from human monocytes. The results of the assays are expressed as IC 50 values, i.e., the test compound concentration that achieved 50% inhibition relative to the vehicle. Test compounds were also evaluated for inhibition of LPS-induced production of tumor necrosis factor-a (TNF-a) in rats.13) The results are expressed as ID 50 values, i.e., the dose that showed 50% inhibition relative to the vehicle.During the course of screening of PDE4 inhibitors, compound 3 showed moderate ...

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“…Currently, the widespread selective pressure and the efficient dissemination channels for multidrug-resistant organisms are major factors that may have contributed to the rapid emergence of the resistant organisms [21][22][23][24][25]. Fused heterocyclic containing pyrazolopyridine systems have been described associated with several biological and medicinal activities including anxiolytic [26], antiviral [27,28], antileishmanial [29] and anti-inflammatory [30] profiles [31]. However, pyrazolo [3,4-b] pyridine derivatives have been studied as antiviral [32], potential antimalarial agents [33], compounds inhibiting cholesterol formation [34], for the treatment of Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, drug and alcohol withdrawal symptoms, drug addiction and infertility [35].…”

Section: Introductionmentioning

confidence: 99%

Substituted Pyrazolo[3,4-B]Pyridin-3-Ones and Pyrazolo[3,4-B]Pyridine-5- Carbaldehyde, New One-Pot Synthesis Strategy Amelioration Using Vinamidinium Salts, Antibacterial and Antifungal Activities Promising Environmental Protection

Chtiba¹,

Amri²,

Tazarki³

et al. 2017

J Bacteriol Parasitol

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This review summarizes the current knowledge about the syntheses and biological behavior of some pyrazolo [5,4-b]pyridines. So, an expedient method for the synthesis of 2-phenyl-5-aryl-1,6-dihydropyrazolo [3,4-b]pyridin-3-ones and 2-phenyl-3-oxo-1,6-dihydropyrazolo[3,4-b]pyridine-5-carbaldehyde in a single-step via condensation of vinamidinium salts with 3-amino-1-phenyl-2-pyrazolin-5-one is described according to our recent study with synthesis strategy amelioration. Five derivatives (PYR 1-5 ) were prepared and characterized by spectral data (NMR and MS spectral studies). All the derivatives were studied for their antimicrobial activities. So, we screened for antibacterial effects at 1:2, and 1:4 dilutions by the paper disc diffusion method against respectively Bacteria (Escherichia coli CIP 53126 and Bacillus subtilis CIP 5262) and Fungi (Candida albicans ATCC 10231). Then, we screened for Fungi (Aspergillus niger ATCC 16404) by the dilution method (agar and liquid broth). The agar diffusion method (paper disc and well) and the dilution method (agar and liquid broth) are described.

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Synthesis and structure-activity relationships of a series of anxioselective pyrazolopyridine ester and amide anxiolytic agents

Cited by 105 publications

References 0 publications

Limiting Activity at β₁-Subunit-Containing GABA_A Receptor Subtypes Reduces Ataxia

Limiting Activity at β₁-Subunit-Containing GABA_A Receptor Subtypes Reduces Ataxia

Discovery of New Orally Active Phosphodiesterase (PDE4) Inhibitors

Substituted Pyrazolo[3,4-B]Pyridin-3-Ones and Pyrazolo[3,4-B]Pyridine-5- Carbaldehyde, New One-Pot Synthesis Strategy Amelioration Using Vinamidinium Salts, Antibacterial and Antifungal Activities Promising Environmental Protection

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Synthesis and structure-activity relationships of a series of anxioselective pyrazolopyridine ester and amide anxiolytic agents

Cited by 105 publications

References 0 publications

Limiting Activity at β1-Subunit-Containing GABAA Receptor Subtypes Reduces Ataxia

Limiting Activity at β1-Subunit-Containing GABAA Receptor Subtypes Reduces Ataxia

Discovery of New Orally Active Phosphodiesterase (PDE4) Inhibitors

Substituted Pyrazolo[3,4-B]Pyridin-3-Ones and Pyrazolo[3,4-B]Pyridine-5- Carbaldehyde, New One-Pot Synthesis Strategy Amelioration Using Vinamidinium Salts, Antibacterial and Antifungal Activities Promising Environmental Protection

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Limiting Activity at β₁-Subunit-Containing GABA_A Receptor Subtypes Reduces Ataxia

Limiting Activity at β₁-Subunit-Containing GABA_A Receptor Subtypes Reduces Ataxia