Identification of second-generation P2X3 antagonists for treatment of pain.

A second-generation small molecule P2X3 receptor antagonist has been developed. The lead optimization strategy to address shortcomings of the first-generation preclinical lead compound is described herein. These studies were directed towards the identification and amelioration of preclinical hepatobiliary findings, reducing potential for drug-drug interactions, and decreasing the projected human dose of the first-generation lead.

Benzoxazolinone aryl sulfonamides as potent, selective Nav1.7 inhibitors with in vivo efficacy in a preclinical pain model.

Studies on human genetics have suggested that inhibitors of the Nav1.7 voltage-gated sodium channel hold considerable promise as therapies for the treatment of chronic pain syndromes. Herein, we report novel, peripherally-restricted benzoxazolinone aryl sulfonamides as potent Nav1.7 inhibitors with excellent selectivity against the Nav1.5 isoform, which is expressed in the heart muscle. Elaboration of initial lead compound 3d afforded exemplar 13, which featured attractive physicochemical properties, outstanding lipophilic ligand efficiency and pharmacological selectivity against Nav1.5 exceeding 1000-fold. Key structure-activity relationships associated with oral bioavailability were leveraged to discover compound 17, which exhibited a comparable potency/selectivity profile as well as full efficacy following oral administration in a preclinical model indicative of antinociceptive behavior.

Discovery of selective, orally bioavailable, N-linked arylsulfonamide Nav1.7 inhibitors with pain efficacy in mice.

The voltage-gated sodium channel Nav1.7 is a genetically validated target for the treatment of pain with gain-of-function mutations in man eliciting a variety of painful disorders and loss-of-function mutations affording insensitivity to pain. Unfortunately, drugs thought to garner efficacy via Nav1 inhibition have undesirable side effect profiles due to their lack of selectivity over channel isoforms. Herein we report the discovery of a novel series of orally bioavailable arylsulfonamide Nav1.7 inhibitors with high levels of selectivity over Nav1.5, the Nav isoform responsible for cardiovascular side effects, through judicious use of parallel medicinal chemistry and physicochemical property optimization. This effort produced inhibitors such as compound 5 with excellent potency, selectivity, behavioral efficacy in a rodent pain model, and efficacy in a mouse itch model suggestive of target modulation.

A point mutation at F1737 of the human Nav1.7 sodium channel decreases inhibition by local anesthetics.

Voltage-gated sodium channels (VGSC) contribute to the initiation and propagation of action potentials within the nervous system. These channels are important targets for inhibition by several classes of drugs, including antiarrhythmics and local anesthetics. Structural and pharmacological studies have localized the binding of these drugs to a common site near the channel's intracellular pore region. Point mutations within this region disrupt local anesthetic inhibition of cardiac, CNS, and skeletal muscle VGSC subtypes. This study was designed to test whether a similar structural requirement for drug binding exists on the peripheral neuronal VGSC subtype; Na(v)1.7. In support of this hypothesis, an alanine substitution for phenylalanine at position 1737 (F1737A) in the pore lining S6 segment of domain IV in human Na(v)1.7 reduced both use- and state- dependent inhibition of the local anesthetics, lidocaine and tetracaine, by 8-21-fold. We also saw a 2-3-fold reduction in tonic inhibition with the F1737A mutant. The voltage dependence of both activation and inactivation were unaffected by the F1737A mutation, however, fast inactivation kinetics were impaired, such that a significant portion of inward current remained at the end of a 20-ms depolarization. These data suggest that F1737 forms a part of the high affinity binding of local anesthetics as well as mediating inactivation processes of neuronal Na(v)1.7 channels.

High concentration electrophysiology-based fragment screen: discovery of novel acid-sensing ion channel 3 (ASIC3) inhibitors.

The Merck Fragment Library was screened versus acid-sensing ion channel 3 (ASIC3), a novel target for the treatment of pain. Fragment hits were optimized using two strategies, and potency was improved from 0.7 mM to 3 µM with retention of good ligand efficiency and incorporation of reasonable physical properties, off-target profile, and rat pharmacokinetics.