Identification of CNS-Penetrant Aryl Sulfonamides as Isoform-Selective Na<sub>V</sub>1.6 Inhibitors with Efficacy in Mouse Models of Epilepsy.
Focken, Thilo; Burford, Kristen; Grimwood, Michael E.; Zenova, Alla; Andrez, Jean-Christophe; Gong, Wei; Wilson, Michael; Taron, Matt; Decker, Shannon; Lofstrand, Verner; Chowdhury, Sultan; Shuart, Noah; Lin, Sophia; Goodchild, Samuel J.; Young, Clint; Soriano, Maegan; Tari, Parisa K.; Waldbrook, Matthew; Nelkenbrecher, Karen; Kwan, Rainbow; Lindgren, Andrea; de Boer, Gina; Lee, Stephanie; Sojo, Luis; DeVita, Robert J.; Cohen, Charles J.; Wesolowski, Steven S.; Johnson, Jr, J P; Dehnhardt, Christoph M.; Empfield, James R.; Journal of medicinal chemistry  (2019) –; doi:10.1021/acs.jmedchem.9b01032

data_1552487
_publ_section_title
;
 Identification of CNS-Penetrant Aryl Sulfonamides as Isoform-Selective
 Na<sub>V</sub>1.6 Inhibitors with Efficacy in Mouse Models of Epilepsy.
;
_journal_name_full               'Journal of medicinal chemistry'
_journal_paper_doi               10.1021/acs.jmedchem.9b01032
_journal_year                    2019
_chemical_formula_moiety         'C21 H23 F3 N4 O2 S2'
_chemical_formula_sum            'C21 H23 F3 N4 O2 S2'
_chemical_formula_weight         484.55
_chemical_name_systematic
;
 2,6-difluoro-4-({2-fluoro-6-({methyl(isopropyl)amino}methyl)benzyl}amino)-
N-(1,3-thiazol-4-yl)benzenesulfonamide
;
_space_group_crystal_system      monoclinic
_space_group_IT_number           14
_space_group_name_Hall           '-P 2yn'
_space_group_name_H-M_alt        'P 1 21/n 1'
_symmetry_space_group_name_Hall  '-P 2yn'
_symmetry_space_group_name_H-M   'P 1 21/n 1'
_atom_sites_solution_hydrogens   mixed
_audit_creation_method           SHELXL-2016/6
_cell_angle_alpha                90
_cell_angle_beta                 97.3465(7)
_cell_angle_gamma                90
_cell_formula_units_Z            8
_cell_length_a                   17.1470(3)
_cell_length_b                   12.1241(2)
_cell_length_c                   21.6325(4)
_cell_measurement_reflns_used    9801
_cell_measurement_temperature    173(2)
_cell_measurement_theta_max      73.63
_cell_measurement_theta_min      3.10
_cell_volume                     4460.30(14)
_computing_cell_refinement       'Bruker SAINT'
_computing_data_collection       'Bruker APEX2'
_computing_data_reduction        'Bruker SAINT'
_computing_molecular_graphics    'Bruker SHELXTL'
_computing_publication_material  'Bruker SHELXTL'
_computing_structure_refinement  'SHELXL-2016/6 (Sheldrick, 2016)'
_computing_structure_solution    'SHELXD (Schneider & Sheldrick, 2002)'
_diffrn_ambient_temperature      173(2)
_diffrn_measured_fraction_theta_full 0.999
_diffrn_measured_fraction_theta_max 0.996
_diffrn_measurement_device_type  'Bruker APEX-II CCD'
_diffrn_measurement_method       '\f and \w scans'
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54178
_diffrn_reflns_av_R_equivalents  0.0178
_diffrn_reflns_av_unetI/netI     0.0151
_diffrn_reflns_Laue_measured_fraction_full 0.999
_diffrn_reflns_Laue_measured_fraction_max 0.996
_diffrn_reflns_limit_h_max       19
_diffrn_reflns_limit_h_min       -21
_diffrn_reflns_limit_k_max       15
_diffrn_reflns_limit_k_min       -15
_diffrn_reflns_limit_l_max       26
_diffrn_reflns_limit_l_min       -26
_diffrn_reflns_number            30998
_diffrn_reflns_point_group_measured_fraction_full 0.999
_diffrn_reflns_point_group_measured_fraction_max 0.996
_diffrn_reflns_theta_full        67.679
_diffrn_reflns_theta_max         73.913
_diffrn_reflns_theta_min         3.103
_exptl_absorpt_coefficient_mu    2.625
_exptl_absorpt_correction_T_max  0.6600
_exptl_absorpt_correction_T_min  0.5004
_exptl_absorpt_correction_type   numerical
_exptl_absorpt_process_details   'SADABS 2016/2 (Krause et al., 2015)'
_exptl_crystal_colour            colourless
_exptl_crystal_density_diffrn    1.443
_exptl_crystal_description       fragment
_exptl_crystal_F_000             2016
_exptl_crystal_size_max          0.371
_exptl_crystal_size_mid          0.320
_exptl_crystal_size_min          0.255
_refine_diff_density_max         0.309
_refine_diff_density_min         -0.403
_refine_diff_density_rms         0.036
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.023
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     605
_refine_ls_number_reflns         9011
_refine_ls_number_restraints     0
_refine_ls_restrained_S_all      1.023
_refine_ls_R_factor_all          0.0324
_refine_ls_R_factor_gt           0.0306
_refine_ls_shift/su_max          0.001
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0418P)^2^+1.5458P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.0826
_refine_ls_wR_factor_ref         0.0845
_reflns_Friedel_coverage         0.000
_reflns_number_gt                8445
_reflns_number_total             9011
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm9b01032_si_002.cif
_cod_data_source_block           ext1702
_cod_original_cell_volume        4460.31(14)
_cod_database_code               1552487
_shelx_shelxl_version_number     2016/6
_shelx_estimated_absorpt_t_min   0.443
_shelx_estimated_absorpt_t_max   0.554
_shelx_res_checksum              23979
_shelx_hkl_checksum              20662