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_7240889
_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         'C23 H30 F3 N3 O, 2(C2 F3 O2)'
_chemical_formula_sum            'C27 H30 F9 N3 O5'
_chemical_formula_weight         647.54
_chemical_name_common            31
_chemical_name_systematic
5-((4-((1s,4s)-4-(3-(trifluoromethyl)phenyl)cyclohexyl)piperazin-1-yl)methyl)pyridin-2(1H)-one
_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   mixed
_atom_sites_solution_primary     dual
_audit_creation_date             2019-03-20
_audit_creation_method
;
Olex2 1.2
(compiled 2018.05.29 svn.r3508 for OlexSys, GUI svn.r5506)
;
_audit_update_record
;
2020-04-15 deposited with the CCDC.	2020-06-25 downloaded from the CCDC.
;
_cell_angle_alpha                98.1817(9)
_cell_angle_beta                 92.5946(8)
_cell_angle_gamma                103.5389(8)
_cell_formula_units_Z            2
_cell_length_a                   8.23301(6)
_cell_length_b                   13.02347(14)
_cell_length_c                   13.57687(16)
_cell_measurement_reflns_used    23345
_cell_measurement_temperature    173.00(10)
_cell_measurement_theta_max      76.8250
_cell_measurement_theta_min      3.2950
_cell_volume                     1396.21(3)
_computing_cell_refinement       'CrysAlisPro 1.171.40.39a (Rigaku OD, 2019)'
_computing_data_collection       'CrysAlisPro 1.171.40.39a (Rigaku OD, 2019)'
_computing_data_reduction        'CrysAlisPro 1.171.40.39a (Rigaku OD, 2019)'
_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 10.0000
_diffrn_detector_type            HyPix
_diffrn_measured_fraction_theta_full 1.000
_diffrn_measured_fraction_theta_max 0.976
_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    -66.00  -9.00   0.50    0.44    --  -18.75 125.00-127.00  114
  2  \w     26.00 120.00   0.50    0.44    --   47.95  77.00 -30.00  188
  3  \w     78.00 174.00   0.50    1.76    --  107.11 146.00  39.00  192
  4  \w     92.00 174.00   0.50    1.76    --  107.11 125.00-127.00  164
  5  \w     94.00 174.00   0.50    1.76    --  107.11  15.00   0.00  160
  6  \w     95.00 174.00   0.50    1.76    --  107.11  45.00  90.00  158
  7  \w     94.00 174.00   0.50    1.76    --  107.11  15.00 -30.00  160
  8  \w     95.00 174.00   0.50    1.76    --  107.11  45.00-150.00  158
  9  \w     95.00 174.00   0.50    1.76    --  107.11  30.00-120.00  158
 10  \w     95.00 174.00   0.50    1.76    --  107.11  45.00 -90.00  158
 11  \w     95.00 133.00   0.50    1.76    --  107.11  45.00  60.00   76
 12  \w     94.00 174.00   0.50    1.76    --  107.11  15.00  60.00  160
 13  \w     95.00 174.00   0.50    1.76    --  107.11  30.00 150.00  158
 14  \w     85.00 174.00   0.50    1.76    --  107.11  77.00 150.00  178
 15  \w     32.00  96.00   0.50    0.44    --   47.95-125.00 155.00  128
 16  \w     35.00 117.00   0.50    1.76    --  107.11-125.00 155.00  164
 17  \w     43.00 109.00   0.50    0.44    --   47.95-146.00 -11.00  132
 18  \w     43.00 132.00   0.50    1.76    --  107.11-146.00 -11.00  178
 19  \w     35.00  68.00   0.50    1.76    --  107.11 -61.00 120.00   66
 20  \w     35.00  68.00   0.50    1.76    --  107.11 -61.00  60.00   66
 21  \w     35.00 109.00   0.50    1.76    --  107.11 -94.00   0.00  148
 22  \w     35.00 102.00   0.50    1.76    --  107.11 -77.00 -60.00  134
 23  \w     35.00  68.00   0.50    1.76    --  107.11 -61.00 -60.00   66
 24  \w     35.00  68.00   0.50    1.76    --  107.11 -61.00-120.00   66
 25  \w     35.00  68.00   0.50    1.76    --  107.11 -61.00-150.00   66
 26  \w     35.00  68.00   0.50    1.76    --  107.11 -61.00-180.00   66
 27  \w     35.00 102.00   0.50    1.76    --  107.11 -77.00-180.00  134
 28  \w     35.00 102.00   0.50    1.76    --  107.11 -77.00-150.00  134
 29  \w     35.00  68.00   0.50    1.76    --  107.11 -61.00 -30.00   66
 30  \w     35.00 109.00   0.50    1.76    --  107.11 -94.00  30.00  148
 31  \w     35.00 102.00   0.50    1.76    --  107.11 -77.00 120.00  134
 32  \w     35.00  68.00   0.50    1.76    --  107.11 -61.00  30.00   66
 33  \w     35.00 102.00   0.50    1.76    --  107.11 -77.00  30.00  134
 34  \w     33.00 120.00   0.50    0.44    --   47.95  57.00 -90.00  174
 35  \w     26.00 120.00   0.50    0.44    --   47.95  77.00 -90.00  188
 36  \w     26.00 120.00   0.50    0.44    --   47.95  77.00-180.00  188
 37  \w     26.00 120.00   0.50    0.44    --   47.95  77.00-150.00  188
 38  \w     26.00 120.00   0.50    0.44    --   47.95  77.00  30.00  188
 39  \w     26.00 120.00   0.50    0.44    --   47.95  77.00 120.00  188
 40  \w     26.00 120.00   0.50    0.44    --   47.95  77.00 150.00  188
 41  \w     26.00 120.00   0.50    0.44    --   47.95  77.00  60.00  188
 42  \w     26.00 120.00   0.50    0.44    --   47.95  77.00  90.00  188
 43  \w    -25.00  40.00   0.50    0.44    --   47.95 -38.00-180.00  130
 44  \w    -26.00  23.00   0.50    0.44    --   47.95 -19.00 -90.00   98
 45  \w    -25.00  40.00   0.50    0.44    --   47.95 -38.00  30.00  130
 46  \w    -26.00  23.00   0.50    0.44    --   47.95 -19.00  60.00   98
 47  \w    -78.00 -20.00   0.50    0.44    --  -18.75 146.00  39.00  116
 48  \w    -90.00  -5.00   0.50    0.44    --  -18.75 -45.00 -60.00  170
 49  \w    -90.00   5.00   0.50    0.44    --  -18.75 -77.00 150.00  190
;
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_type  'XtaLAB Synergy, Dualflex, HyPix'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_type
'CrysAlisPro convention (1999,Acta A55,543-557)'
_diffrn_orient_matrix_UB_11      0.0127393000
_diffrn_orient_matrix_UB_12      0.0483501000
_diffrn_orient_matrix_UB_13      0.1112606000
_diffrn_orient_matrix_UB_21      -0.0418193000
_diffrn_orient_matrix_UB_22      -0.1133022000
_diffrn_orient_matrix_UB_23      0.0279558000
_diffrn_orient_matrix_UB_31      0.1881003000
_diffrn_orient_matrix_UB_32      0.0023076000
_diffrn_orient_matrix_UB_33      0.0083231000
_diffrn_radiation_monochromator  mirror
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0285
_diffrn_reflns_av_unetI/netI     0.0149
_diffrn_reflns_Laue_measured_fraction_full 1.000
_diffrn_reflns_Laue_measured_fraction_max 0.976
_diffrn_reflns_limit_h_max       10
_diffrn_reflns_limit_h_min       -8
_diffrn_reflns_limit_k_max       16
_diffrn_reflns_limit_k_min       -16
_diffrn_reflns_limit_l_max       16
_diffrn_reflns_limit_l_min       -17
_diffrn_reflns_number            32559
_diffrn_reflns_point_group_measured_fraction_full 1.000
_diffrn_reflns_point_group_measured_fraction_max 0.976
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         77.165
_diffrn_reflns_theta_min         3.300
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_type              'PhotonJet (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    1.285
_exptl_absorpt_correction_T_max  1.000
_exptl_absorpt_correction_T_min  0.548
_exptl_absorpt_correction_type   gaussian
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.40.39a (Rigaku Oxford Diffraction, 2019)
Numerical absorption correction based on gaussian integration over
			a multifaceted crystal model
Empirical absorption correction using spherical harmonics,
 implemented in SCALE3 ABSPACK scaling algorithm.
;
_exptl_crystal_colour            colourless
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.540
_exptl_crystal_description       prism
_exptl_crystal_F_000             668
_exptl_crystal_recrystallization_method 'Vapour deposition'
_exptl_crystal_size_max          0.26
_exptl_crystal_size_mid          0.092
_exptl_crystal_size_min          0.043
_refine_diff_density_max         0.684
_refine_diff_density_min         -0.555
_refine_diff_density_rms         0.052
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.056
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     434
_refine_ls_number_reflns         5783
_refine_ls_number_restraints     108
_refine_ls_restrained_S_all      1.054
_refine_ls_R_factor_all          0.0544
_refine_ls_R_factor_gt           0.0516
_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^)+(0.0661P)^2^+1.0041P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1368
_refine_ls_wR_factor_ref         0.1392
_reflns_Friedel_coverage         0.000
_reflns_number_gt                5341
_reflns_number_total             5783
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d0md00145g2.cif
_cod_data_source_block           19jlr002b
_cod_original_cell_volume        1396.21(2)
_cod_database_code               7240889
_shelx_shelxl_version_number     2018/1
_shelx_estimated_absorpt_t_max   0.947
_shelx_estimated_absorpt_t_min   0.731
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups, All C(H,H,H,H) groups
2. Uiso/Uaniso restraints and constraints
F1 \\sim F2 \\sim F3 \\sim C23 \\sim F2A \\sim F3A \\sim F1A: within 2A with
sigma of 0.04 and sigma for terminal atoms of 0.08
3. Rigid body (RIGU) restrains
 F3A, F3, C23, F2, F2A, F1, F1A
 with sigma for 1-2 distances of 0.004 and sigma for 1-3 distances of 0.004
4. Others
 Sof(F2A)=Sof(F3A)=Sof(F1A)=1-FVAR(1)
 Sof(F1)=Sof(F2)=Sof(F3)=FVAR(1)
5.a Ternary CH refined with riding coordinates:
 C11(H11), C14(H14)
5.b Secondary CH2 refined with riding coordinates:
 C6(H6A,H6B), C7(H7A,H7B), C8(H8A,H8B), C9(H9A,H9B), C10(H10A,H10B), C12(H12A,
 H12B), C13(H13A,H13B), C15(H15A,H15B), C16(H16A,H16B)
5.c Aromatic/amide H refined with riding coordinates:
 C2(H2A), C3(H3A), C5(H5), C18(H18), C20(H20), C21(H21), C22(H22)
;
_shelx_res_checksum              13768
_olex2_submission_special_instructions 'No special instructions were received'