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_7240893
_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         'C24 H34 N2 O2, 2(C2 F3 O2)'
_chemical_formula_sum            'C28 H34 F6 N2 O6'
_chemical_formula_weight         608.57
_chemical_name_common            9
_chemical_name_systematic
2-methoxy-4-((4-((1s,4s)-4-phenylcyclohexyl)piperazin-1-yl)methyl)phenol
_space_group_crystal_system      monoclinic
_space_group_IT_number           14
_space_group_name_Hall           '-P 2ybc'
_space_group_name_H-M_alt        'P 1 21/c 1'
_atom_sites_solution_hydrogens   mixed
_atom_sites_solution_primary     dual
_audit_creation_date             2019-06-27
_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                90
_cell_angle_beta                 93.2560(10)
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   12.18020(10)
_cell_length_b                   16.45030(10)
_cell_length_c                   14.08290(10)
_cell_measurement_reflns_used    17811
_cell_measurement_temperature    173.00(10)
_cell_measurement_theta_max      75.9770
_cell_measurement_theta_min      3.1370
_cell_volume                     2817.21(4)
_computing_cell_refinement       'CrysAlisPro 1.171.40.45a (Rigaku OD, 2019)'
_computing_data_collection       'CrysAlisPro 1.171.40.45a (Rigaku OD, 2019)'
_computing_data_reduction        'CrysAlisPro 1.171.40.45a (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 0.977
_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    -39.00  55.00   0.50    0.25    --  -18.75  71.00 -90.00  188
  2  \w     28.00 120.00   0.50    0.25    --   47.95  71.00 -90.00  184
  3  \w    -23.00  69.00   0.50    0.25    --   47.95 -71.00 138.00  184
  4  \w     35.00  86.00   0.50    1.00    --  107.11 -71.00 138.00  102
  5  \w     87.00 174.00   0.50    1.00    --  107.11  71.00 -90.00  174
  6  \w    -90.00   2.00   0.50    0.25    --  -18.75 -71.00 138.00  184
  7  \w    -66.00  -9.00   0.50    0.25    --  -18.75 125.00-180.00  114
  8  \w    -26.00  23.00   0.50    0.25    --   47.95 -19.00 120.00   98
  9  \w    -26.00  23.00   0.50    0.25    --   47.95 -19.00 150.00   98
 10  \w    -26.00  23.00   0.50    0.25    --   47.95 -19.00 -30.00   98
 11  \w     35.00 102.00   0.50    1.00    --  107.11 -77.00-180.00  134
 12  \w     35.00  68.00   0.50    1.00    --  107.11 -61.00  60.00   66
 13  \w     35.00  68.00   0.50    1.00    --  107.11 -61.00-150.00   66
 14  \w     35.00 102.00   0.50    1.00    --  107.11 -77.00 -30.00  134
 15  \w     35.00  68.00   0.50    1.00    --  107.11 -61.00-180.00   66
 16  \w     95.00 174.00   0.50    1.00    --  107.11  45.00-150.00  158
 17  \w     95.00 174.00   0.50    1.00    --  107.11  45.00 -30.00  158
 18  \w     35.00  68.00   0.50    1.00    --  107.11 -61.00 -90.00   66
 19  \w     35.00 109.00   0.50    1.00    --  107.11 -94.00  30.00  148
 20  \w     35.00  68.00   0.50    1.00    --  107.11 -61.00-120.00   66
 21  \w     35.00  68.00   0.50    1.00    --  107.11 -61.00  30.00   66
 22  \w     95.00 174.00   0.50    1.00    --  107.11  45.00 -90.00  158
 23  \w     95.00 174.00   0.50    1.00    --  107.11  45.00-180.00  158
 24  \w     33.00 120.00   0.50    0.25    --   47.95  57.00  90.00  174
;
_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      -0.0115388000
_diffrn_orient_matrix_UB_12      -0.0679679000
_diffrn_orient_matrix_UB_13      0.0740485000
_diffrn_orient_matrix_UB_21      -0.1052620000
_diffrn_orient_matrix_UB_22      -0.0301314000
_diffrn_orient_matrix_UB_23      -0.0547988000
_diffrn_orient_matrix_UB_31      0.0695402000
_diffrn_orient_matrix_UB_32      -0.0569737000
_diffrn_orient_matrix_UB_33      -0.0592881000
_diffrn_radiation_monochromator  mirror
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0247
_diffrn_reflns_av_unetI/netI     0.0142
_diffrn_reflns_Laue_measured_fraction_full 1.000
_diffrn_reflns_Laue_measured_fraction_max 0.977
_diffrn_reflns_limit_h_max       15
_diffrn_reflns_limit_h_min       -15
_diffrn_reflns_limit_k_max       16
_diffrn_reflns_limit_k_min       -20
_diffrn_reflns_limit_l_max       17
_diffrn_reflns_limit_l_min       -17
_diffrn_reflns_number            27224
_diffrn_reflns_point_group_measured_fraction_full 1.000
_diffrn_reflns_point_group_measured_fraction_max 0.977
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         77.140
_diffrn_reflns_theta_min         3.635
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_type              'PhotonJet (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    1.093
_exptl_absorpt_correction_T_max  1.000
_exptl_absorpt_correction_T_min  0.327
_exptl_absorpt_correction_type   gaussian
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.40.45a (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    1.435
_exptl_crystal_description       prism
_exptl_crystal_F_000             1272
_exptl_crystal_recrystallization_method 'Vapour deposition'
_exptl_crystal_size_max          0.293
_exptl_crystal_size_mid          0.203
_exptl_crystal_size_min          0.192
_refine_diff_density_max         0.517
_refine_diff_density_min         -0.383
_refine_diff_density_rms         0.040
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.044
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     447
_refine_ls_number_reflns         5836
_refine_ls_number_restraints     258
_refine_ls_restrained_S_all      1.023
_refine_ls_R_factor_all          0.0448
_refine_ls_R_factor_gt           0.0424
_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^)+(0.0615P)^2^+0.9881P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1173
_refine_ls_wR_factor_ref         0.1192
_reflns_Friedel_coverage         0.000
_reflns_number_gt                5395
_reflns_number_total             5836
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d0md00145g2.cif
_cod_data_source_block           19jlr007_mrc65
_cod_database_code               7240893
_shelx_shelxl_version_number     2018/1
_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. Uiso/Uaniso restraints and constraints
C19A \\sim C19 \\sim C20 \\sim C20A \\sim C21A \\sim C21 \\sim C22 \\sim C22A
\\sim C23A \\sim C23 \\sim C24 \\sim C24A: within 2A with sigma of 0.04 and
sigma for terminal atoms of 0.08
3. Rigid body (RIGU) restrains
 C19A, C19, C20, C20A, C21A, C21, C22, C22A, C23A, C23, C24, C24A
 with sigma for 1-2 distances of 0.004 and sigma for 1-3 distances of 0.004
4. Others
 Sof(H16A)=Sof(C19A)=Sof(C20A)=Sof(H20A)=Sof(C21A)=Sof(H21A)=Sof(C22A)=
 Sof(H22A)=Sof(C23A)=Sof(H23A)=Sof(C24A)=Sof(H24A)=1-FVAR(1)
 Sof(H16)=Sof(C19)=Sof(C20)=Sof(H20)=Sof(C21)=Sof(H21)=Sof(C22)=Sof(H22)=
 Sof(C23)=Sof(H23)=Sof(C24)=Sof(H24)=FVAR(1)
5.a Ternary CH refined with riding coordinates:
 C13(H13), C16(H16), C16(H16A)
5.b Secondary CH2 refined with riding coordinates:
 C8(H8A,H8B), C9(H9A,H9B), C10(H10A,H10B), C11(H11A,H11B), C12(H12A,H12B),
 C14(H14A,H14B), C15(H15A,H15B), C17(H17A,H17B), C18(H18A,H18B)
5.c Aromatic/amide H refined with riding coordinates:
 C3(H3), C5(H5), C6(H6), C20(H20), C20A(H20A), C21A(H21A), C21(H21), C22(H22),
 C22A(H22A), C23A(H23A), C23(H23), C24(H24), C24A(H24A)
5.d Idealised Me refined as rotating group:
 C7(H7A,H7B,H7C)
;
_shelx_res_checksum              31722
_olex2_submission_special_instructions 'No special instructions were received'