- 3-oxoisoindoline-1-carboxamides: Potent, state-dependent blockers of voltage-gated sodium channel nav1.7 with efficacy in rat pain models
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The voltage-gated sodium channel NaV1.7 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 NaV1.7 inhibitors based on the oxoisoindoline core. Extensive studies with focus on optimization of Na V1.7 potency, selectivity over NaV1.5, 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 V1.5 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.
- MacSari, Istvan,Besidski, Yevgeni,Csjernyik, Gabor,Nilsson, Linda I.,Sandberg, Lars,Yngve, Ulrika,?hlin, Kristofer,Bueters, Tjerk,Eriksson, Anders B.,Lund, Per-Eric,Venyike, Elisabet,Oerther, Sandra,Hygge Blakeman, Karin,Luo, Lei,Arvidsson, Per I.
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supporting information; experimental part
p. 6866 - 6880
(2012/09/25)
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- ISOINDOLINE DERIVATIVES COMPRISING PHENYL GROUPS AND THEIR USE IN THE TREATMENT OF PAIN DISORDERS
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Compounds of formula I are claimed, (I) wherein R1 is hydrogen, C1-3alkyl, Ci_3alkoxy, cyano, hydroxy or halo; and wherein said Ci^alkyl is optionally substituted by one or more substituents independently selected from hydroxy, Ci^alkoxy andfluoro; and said Ci^alkoxy is optionally substituted by one or morefluoro; m is 1 or 2; R2 and R3 is each and independently selected from hydrogen, Ci_4haloalkyl, Ci_4haloalkoxy, halo, Ci_4alkoxy, Ci_4alkyl and C3_7cycloalkyloxy; wherein said C3. γcycloalkyloxy is optionally substituted by one or morefluoro; and R2 and R3 may not both be hydrogen; D is C3_7cycloalkyl or C3_7heterocycloalkyl; and wherein said Cs-jcycloalkyl or Cs- γheterocycloalkyl may optionally be substituted by one or more X*; X4 is halo, Ci_3alkyl, Ci_3alkyl0Ci_3alkyl, Ci_3alkoxy, benzyl, Ci_4alkylsulfonyl, oxo, R4O(C=O), R5(C=O), or C5.6 heteroaryl; wherein said Cisalkyl, CisalkylOCisalkyl, Ci^alkoxy and C i^alkylsulfonyl is optionally substituted by one or more fluoro; R4 is Ci_4alkyl, Ci_4alkyl0Ci_4alkyl, C5_6cycloalkyl, or aryl; R5 is Ci_4alkyl, Ci_4fluoroalkyl or Cs_6 heteroaryl; Li is Ci_4alkylene or a bond; L2 is Ci_3alkylene; with the exception of the compound 2-(cyclohexylmethyl)-3-oxo-N-[2-(trifluoromethyl)benzyl]isoindoline-l-carboxamide; as well as a pharmaceutically acceptable salt, or isomer thereof, or a salt of said isomer. The compounds of the invention are useful in therapy such as pain therapy.
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Page/Page column 31
(2009/12/27)
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