| 1. |
- Macsari, Istvan, et al.
(författare)
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3-Oxoisoindoline-1-carboxamides : Potent, State-Dependent Blockers of Voltage-Gated Sodium Channel Na(V)1.7 with Efficacy in Rat Pain Models
- 2012
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:15, s. 6866-6880
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Tidskriftsartikel (refereegranskat)abstract
- The voltage-gated sodium channel Na(V)1.7 is believed to be a critical mediator of pain sensation based on clinical genetic studies and pharmacological results. Clinical utility of nonselective sodium channel blockers is limited due to serious adverse drug effects. Here, we present the optimization, structure activity relationships, and in vitro and in vivo characterization of a novel series of Na(V)1.7 inhibitors based on the oxoisoindoline core. Extensive studies with focus on optimization of Na(V)1.7 potency, selectivity over Na(V)1.5, and metabolic stability properties produced several interesting oxoisoindoline carboxamides (16A, 26B, 28, 51, 60, and 62) that were further characterized. The oxoisoindoline carboxamides interacted with the local anesthetics binding site. In spite of this, several compounds showed functional selectivity versus Na(V)1.5 of more than 100-fold. This appeared to be a combination of subtype and state-dependent selectivity. Compound 28 showed concentration-dependent inhibition of nerve injury-induced ectopic in an ex vivo DRG preparation from SNL rats. Compounds 16A and 26B demonstrated concentration-dependent efficacy in preclinical behavioral pain models. The oxoisoindoline carboxamides series described here may be valuable for further investigations for pain therapeutics.
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| 2. |
- Macsari, Istvan, et al.
(författare)
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Phenyl isoxazole voltage-gated sodium channel blockers : structure and activity relationship
- 2011
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 21:13, s. 3871-3876
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Tidskriftsartikel (refereegranskat)abstract
- Blocking of certain sodium channels is considered to be an attractive mechanism to treat chronic pain conditions. Phenyl isoxazole carbamate 1 was identified as a potent and selective Na(V)1.7 blocker. Structural analogues of 1, both carbamates, ureas and amides, were proven to be useful in establishing the structure-activity relationship and improving ADME related properties. Amide 24 showed a good overall in vitro profile, that translated well to rat in vivo PK.
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| 3. |
- Nandi, Ganesh C., et al.
(författare)
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Pd-catalyzed C-N coupling of vinylbromides and sulfonimidamides : a facile synthesis of N '-vinylsulfonimidamides
- 2015
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Ingår i: RSC Advances. - : Royal Society of Chemistry (RSC). - 2046-2069. ; 5:76, s. 62084-62090
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Tidskriftsartikel (refereegranskat)abstract
- N'-Vinyl sulfonimidamides have been synthesized through a Pd-catalyzed C-N cross coupling between the N'-(imine nitrogen) of N'-deprotected sulfonimidamides and vinyl bromides. The hitherto unreported products were obtained in moderate to excellent yield, and the C-C double bond geometry of the vinylic substrates were retained during the course of reaction. Single crystal X-ray crystallographic analysis confirmed the product structure. Furthermore, we demonstrate that the formed N'-vinyl sulfonimidamides could undergo hydrogenation with Pd-C/H-2 to provide N'-alkyl sulfonimidamides.
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