Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor
Cunha, Micael Rodrigues; Bhardwaj, Rajesh; Carrel, Aline Lucie; Lindinger, Sonja; Romanin, Christoph; Parise-Filho, Roberto; Hediger, Matthias A.; Reymond, Jean-Louis; RSC Medicinal Chemistry  (2020) –; doi:10.1039/D0MD00145G

data_7240891
_publ_section_title
;
 Natural product inspired optimization of a selective TRPV6 calcium
 channel inhibitor
;
_journal_name_full               'RSC Medicinal Chemistry'
_journal_paper_doi               10.1039/D0MD00145G
_journal_year                    2020
_chemical_compound_source        Synthesis
_chemical_formula_moiety         'C22 H29 N3'
_chemical_formula_sum            'C22 H29 N3'
_chemical_formula_weight         335.48
_chemical_name_common            cis-22a
_chemical_name_systematic
1-(pyridin-3-yl)-4-((1s,4s)-4-(m-tolyl)cyclohexyl)piperazine
_space_group_crystal_system      triclinic
_space_group_IT_number           2
_space_group_name_Hall           '-P 1'
_space_group_name_H-M_alt        'P -1'
_atom_sites_solution_hydrogens   geom
_atom_sites_solution_primary     dual
_audit_creation_date             2018-04-09
_audit_creation_method
;
Olex2 1.2
(compiled 2018.04.03 svn.r3497 for OlexSys, GUI svn.r5486)
;
_audit_update_record
;
2020-04-15 deposited with the CCDC.	2020-06-25 downloaded from the CCDC.
;
_cell_angle_alpha                96.464(3)
_cell_angle_beta                 95.779(3)
_cell_angle_gamma                99.987(4)
_cell_formula_units_Z            2
_cell_length_a                   7.2232(3)
_cell_length_b                   8.9059(4)
_cell_length_c                   15.2815(6)
_cell_measurement_reflns_used    6144
_cell_measurement_temperature    173.00(10)
_cell_measurement_theta_max      27.7240
_cell_measurement_theta_min      2.3300
_cell_volume                     954.71(7)
_computing_cell_refinement       'CrysAlisPro 1.171.39.43c (Rigaku OD, 2018)'
_computing_data_collection       'CrysAlisPro 1.171.39.43c (Rigaku OD, 2018)'
_computing_data_reduction        'CrysAlisPro 1.171.39.43c (Rigaku OD, 2018)'
_computing_molecular_graphics    'Olex2 (Dolomanov et al., 2009)'
_computing_publication_material  'Olex2 (Dolomanov et al., 2009)'
_computing_structure_refinement  'ShelXL (Sheldrick, 2015)'
_computing_structure_solution    'ShelXT (Sheldrick, 2015)'
_diffrn_ambient_environment      N~2~
_diffrn_ambient_temperature      173.00(10)
_diffrn_detector                 'CCD plate'
_diffrn_detector_area_resol_mean 16.0965
_diffrn_detector_type            Eos
_diffrn_measured_fraction_theta_full 1.000
_diffrn_measured_fraction_theta_max 0.925
_diffrn_measurement_details
;
List of Runs (angles in degrees, time in seconds):

  # Type    Start    End  Width  t~exp~   \w     \q     \k     \f   Frames
  1  \w    -49.00  65.00   1.00    6.50    --   27.42 -57.00 -30.00  114
  2  \w    -54.00  83.00   1.00    6.50    --   27.42 -38.00  90.00  137
  3  \w     35.00 122.00   1.00    6.50    --   27.42 178.00 -60.00   87
  4  \w    -57.00  71.00   1.00    6.50    --   27.42 -77.00  30.00  128
  5  \w    -57.00  71.00   1.00    6.50    --   27.42 -77.00 -90.00  128
  6  \w    -20.00  32.00   1.00    6.50    --  -23.50 -99.00   0.00   52
  7  \w    -20.00  32.00   1.00    6.50    --  -23.50 -99.00-180.00   52
  8  \w    -10.00 103.00   1.00    6.50    --   27.42  57.00 120.00  113
  9  \w    -10.00 103.00   1.00    6.50    --   27.42  57.00-120.00  113
 10  \w    -10.00  72.00   1.00    6.50    --   27.42  57.00  30.00   82
 11  \w    -10.00 103.00   1.00    6.50    --   27.42  57.00 -30.00  113
;
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_type  'SuperNova, Single source at offset/far, Eos'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_type
'CrysAlisPro convention (1999,Acta A55,543-557)'
_diffrn_orient_matrix_UB_11      -0.0638578000
_diffrn_orient_matrix_UB_12      -0.0098142000
_diffrn_orient_matrix_UB_13      0.0321513000
_diffrn_orient_matrix_UB_21      -0.0468843000
_diffrn_orient_matrix_UB_22      0.0567973000
_diffrn_orient_matrix_UB_23      -0.0162645000
_diffrn_orient_matrix_UB_31      -0.0617854000
_diffrn_orient_matrix_UB_32      -0.0577471000
_diffrn_orient_matrix_UB_33      -0.0302867000
_diffrn_radiation_monochromator  mirror
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           MoK\a
_diffrn_radiation_wavelength     0.71073
_diffrn_reflns_av_R_equivalents  0.0378
_diffrn_reflns_av_unetI/netI     0.0329
_diffrn_reflns_Laue_measured_fraction_full 1.000
_diffrn_reflns_Laue_measured_fraction_max 0.925
_diffrn_reflns_limit_h_max       9
_diffrn_reflns_limit_h_min       -9
_diffrn_reflns_limit_k_max       11
_diffrn_reflns_limit_k_min       -11
_diffrn_reflns_limit_l_max       19
_diffrn_reflns_limit_l_min       -19
_diffrn_reflns_number            16139
_diffrn_reflns_point_group_measured_fraction_full 1.000
_diffrn_reflns_point_group_measured_fraction_max 0.925
_diffrn_reflns_theta_full        25.242
_diffrn_reflns_theta_max         28.104
_diffrn_reflns_theta_min         2.343
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_type              'SuperNova (Mo) X-ray Source'
_exptl_absorpt_coefficient_mu    0.069
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.68722
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.39.43c (Rigaku Oxford Diffraction, 2018)
Empirical absorption correction using spherical harmonics,
 implemented in SCALE3 ABSPACK scaling algorithm.
;
_exptl_crystal_colour            'clear light colourless'
_exptl_crystal_colour_lustre     clear
_exptl_crystal_colour_modifier   light
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.167
_exptl_crystal_description       block
_exptl_crystal_F_000             364
_exptl_crystal_recrystallization_method
'Re-crystallisation from solvent: EtOAc:Hexanes'
_exptl_crystal_size_max          0.25
_exptl_crystal_size_mid          0.25
_exptl_crystal_size_min          0.2
_refine_diff_density_max         0.254
_refine_diff_density_min         -0.273
_refine_diff_density_rms         0.043
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.041
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     227
_refine_ls_number_reflns         4310
_refine_ls_number_restraints     3
_refine_ls_restrained_S_all      1.051
_refine_ls_R_factor_all          0.0656
_refine_ls_R_factor_gt           0.0504
_refine_ls_shift/su_max          0.000
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0590P)^2^+0.2372P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1229
_refine_ls_wR_factor_ref         0.1388
_reflns_Friedel_coverage         0.000
_reflns_number_gt                3364
_reflns_number_total             4310
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d0md00145g2.cif
_cod_data_source_block           18jlr007
_cod_database_code               7240891
_shelx_shelxl_version_number     2014/7
_chemical_oxdiff_formula         C22H29N3
_shelx_estimated_absorpt_t_max   0.986
_shelx_estimated_absorpt_t_min   0.983
_reflns_odcompleteness_completeness 99.97
_reflns_odcompleteness_iscentric 1
_reflns_odcompleteness_theta     26.32
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups
 At 1.5 times of:
  All C(H,H,H) groups
2. Restrained distances
 H14A-H9A
 2.01 with sigma of 0.001
 H12B-H6
 2.01 with sigma of 0.001
 H8A-H4
 2.01 with sigma of 0.001
3.a Ternary CH refined with riding coordinates:
 C16(H16), C13(H13)
3.b Secondary CH2 refined with riding coordinates:
 C15(H15A,H15B), C17(H17A,H17B), C18(H18A,H18B), C14(H14A,H14B), C8(H8A,H8B),
 C9(H9A,H9B), C11(H11A,H11B), C12(H12A,H12B)
3.c Aromatic/amide H refined with riding coordinates:
 C24(H24), C20(H20), C22(H22), C23(H23), C4(H4), C6(H6), C2(H2), C3(H3)
3.d Idealised Me refined as rotating group:
 C25(H25A,H25B,H25C)
;
_shelx_res_checksum              70326
_olex2_date_sample_data_collection 2018-04-07
_olex2_submission_special_instructions 'No special instructions were received'
_oxdiff_exptl_absorpt_empirical_details
;
Empirical correction (ABSPACK) includes:
- Absorption correction using spherical harmonics
- Frame scaling
;
_oxdiff_exptl_absorpt_empirical_full_max 1.603
_oxdiff_exptl_absorpt_empirical_full_min 0.671