Teresa Nguyen, Steve McKerral, Phil Bergeron, Brian Safina, Dan Sutherlin. "United States Patent WO2017058821 Therapeutic Compounds and Methods Use Thereof", Jun 4, 2017
Using structure- and ligand-based design principles, a novel series of piperidyl chromane arylsulfonamide Nav1.7 inhibitors was discovered. Early optimization focused on improvement of potency through refinement of the low energy ligand conformation and mitigation of high in vivo clearance. An in vitro hepatotoxicity hazard was identified and resolved through optimization of lipophilicity and lipophilic ligand efficiency to arrive at GNE-616 (24), a highly potent, metabolically stable, subtype selective inhibitor of Nav1.7. Compound 24 showed a robust PK/PD response in a Nav1.7-dependent mouse model, and site-directed mutagenesis was used to identify residues critical for the isoform selectivity profile of 24.
View details for DOI 10.1021/acs.jmedchem.9b00141
View details for PubMedID 30943032
Currently, Achilles tendon rupture repair is surgically addressed with an open or minimally invasive approach using a heavy, nonabsorbable suture in a locking stitch configuration. However, these sutures have low stiffness and a propensity to stretch, which can result in gapping at the repair site. Our study compares a new multifilament stainless steel cable-crimp repair method to a standard Krackow repair using multistrand, ultra-high molecular weight polyethylene polyester sutures. Eight matched pairs of cadavers were randomly assigned for Achilles tendon repair using either Krackow technique with polyethylene polyester sutures or the multifilament stainless steel cable-crimp technique. Each repair was cyclically loaded from 10 to 50 N for 100 loading cycles, followed by a linear increase in load until complete failure of the repair. During cyclic loading, 4 of the 8 Krackow polyethylene polyester suture repairs failed, whereas none of the multifilament stainless steel cable crimp repairs failed. Load to failure was greater for the multifilament stainless steel cable crimp repairs (321.03 ± 118.71 N) than for the Krackow polyethylene polyester suture repairs (132.47 ± 103.39 N, p?=?.0078). The ultimate tensile strength of the multifilament stainless steel cable crimp repairs was also greater than that of the Krackow polyethylene polyester suture repairs (485.69 ± 47.93 N vs 378.71 ± 107.23 N, respectively, p?=?.12). The mode of failure was by suture breakage at the crimp for all cable-crimp repairs and by suture breakage at the knot, within the tendon, or suture pullout for the polyethylene polyester suture repairs. The multifilament stainless steel cable crimp construct may be a better alternative for Achilles tendon rupture repairs.
View details for DOI 10.1053/j.jfas.2019.01.022
View details for PubMedID 31882153