title: 3-Oxoisoindoline-1-carboxamides: potent, state-dependent blockers of voltage-gated sodium channel Na(V)1.7 with efficacy in rat pain models.
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.
authors: Medicinal Chemistry, CNSP iMed, AstraZeneca R&D Södertälje , SE-151 85 Södertälje, Sweden. istvan.macsari@astrazeneca.com
authors: Istvan
authors: I
authors: Macsari
authors: Yevgeni
authors: Y
authors: Besidski
authors: Gabor
authors: G
authors: Csjernyik
authors: Linda I
authors: LI
authors: Nilsson
authors: Lars
authors: L
authors: Sandberg
authors: Ulrika
authors: U
authors: Yngve
authors: Kristofer
authors: K
authors: Ahlin
authors: Tjerk
authors: T
authors: Bueters
authors: Anders B
authors: AB
authors: Eriksson
authors: Per-Eric
authors: PE
authors: Lund
authors: Elisabet
authors: E
authors: Venyike
authors: Sandra
authors: S
authors: Oerther
authors: Karin
authors: K
authors: Hygge Blakeman
authors: Lei
authors: L
authors: Luo
authors: Per I
authors: PI
authors: Arvidsson
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000209:etiology; D016466:CHO Cells; D002351:Carrageenan; D059350:Chronic Pain / Q000188:drug therapy / Q000209:etiology; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D054833:Isoindoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D062556:NAV1.7 Voltage-Gated Sodium Channel; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015222:Sodium Channels / Q000502:physiology*; D012995:Solubility; D013127:Spinal Nerves / Q000293:injuries; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000700:Analgesics; D054833:Isoindoles; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D002351:Carrageenan