ABSTRACT
The Na(V)1.7 ion channel is an attractive target for development of potential analgesic drugs based on strong genetic links between mutations in the gene coding for the channel protein and inheritable pain conditions. The (S)-N-chroman-3-ylcarboxamide series, exemplified by 1, was used as a starting point for development of new channel blockers, resulting in the phenethyl nicotinamide series. The structure and activity relationship for this series was established and the metabolic issues of early analogues were addressed by appropriate substitutions. Compound 33 displayed acceptable overall in vitro properties and in vivo rat PK profile.
Subject(s)
NAV1.7 Voltage-Gated Sodium Channel/metabolism , Niacinamide/analogs & derivatives , Niacinamide/pharmacology , Sodium Channel Blockers/pharmacology , Animals , Dose-Response Relationship, Drug , Humans , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Niacinamide/chemical synthesis , Niacinamide/chemistry , Rats , Sodium Channel Blockers/chemical synthesis , Sodium Channel Blockers/chemistry , Solubility , Stereoisomerism , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Amides/chemical synthesis , Analgesics/chemical synthesis , Isoindoles/chemical synthesis , Pain/drug therapy , Sodium Channel Blockers/chemical synthesis , Sodium Channels/physiology , Amides/pharmacokinetics , Amides/pharmacology , Analgesics/pharmacokinetics , Analgesics/pharmacology , Animals , Arthritis, Experimental/drug therapy , Arthritis, Experimental/etiology , CHO Cells , Carrageenan , Chronic Pain/drug therapy , Chronic Pain/etiology , Cricetinae , Cricetulus , HEK293 Cells , Humans , Isoindoles/pharmacokinetics , Isoindoles/pharmacology , Male , Microsomes, Liver/metabolism , NAV1.7 Voltage-Gated Sodium Channel , Pain/etiology , Patch-Clamp Techniques , Rats , Rats, Sprague-Dawley , Sodium Channel Blockers/pharmacokinetics , Sodium Channel Blockers/pharmacology , Solubility , Spinal Nerves/injuries , Structure-Activity RelationshipABSTRACT
Recent findings showing a relation between mutations in the Na(V)1.7 channel in humans and altered pain sensation has contributed to increase the attractiveness of this ion channel as target for development of potential analgesics. Amido chromanes 1 and 2 were identified as blockers of the Na(V)1.7 channel and analogues with modifications of the 5-substituent and the carboxamide part of the molecule were prepared to establish the structure-activity relationship. Compounds 13 and 29 with good overall in vitro and in vivo rat PK profile were identified. Furthermore, 29 showed in vivo efficacy in a nociceptive pain model.
Subject(s)
Chromans/chemistry , Chromans/therapeutic use , NAV1.7 Voltage-Gated Sodium Channel/metabolism , Nociceptive Pain/drug therapy , Voltage-Gated Sodium Channel Blockers/pharmacology , Voltage-Gated Sodium Channel Blockers/therapeutic use , Analgesics/chemistry , Analgesics/pharmacokinetics , Analgesics/pharmacology , Analgesics/therapeutic use , Animals , Chromans/pharmacokinetics , Chromans/pharmacology , Formaldehyde , Humans , Nociceptive Pain/chemically induced , Rats , Structure-Activity Relationship , Voltage-Gated Sodium Channel Blockers/chemistry , Voltage-Gated Sodium Channel Blockers/pharmacokineticsABSTRACT
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.