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_7240892
_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 H29 F3 N3 O2, C2 F3 O2, C4 H10 O'
_chemical_formula_sum            'C29 H39 F6 N3 O5'
_chemical_formula_weight         623.63
_chemical_name_common            40
_chemical_name_systematic
5-((4-((1r,4r)-4-hydroxy-4-(2-(trifluoromethyl)phenyl)cyclohexyl)piperazin-1-yl)methyl)pyridin-2(1H)-one
_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'
_atom_sites_solution_hydrogens   mixed
_audit_creation_date             2019-04-12
_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                 106.097(2)
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   15.6425(3)
_cell_length_b                   12.7231(2)
_cell_length_c                   16.3931(3)
_cell_measurement_reflns_used    6001
_cell_measurement_temperature    172.98(10)
_cell_measurement_theta_max      68.8830
_cell_measurement_theta_min      3.4550
_cell_volume                     3134.66(10)
_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 2014/5 (Sheldrick, 2014)'
_diffrn_ambient_environment      N~2~
_diffrn_ambient_temperature      172.98(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 0.987
_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    -32.00  83.00   0.50    0.05    --    0.00  23.00 152.00  230
  2  \w    -37.00  26.00   0.50    0.16    --   56.14 -23.00 -12.00  126
  3  \w    -32.00 138.00   0.50    0.16    --   56.14  23.00 152.00  340
  4  \w     18.00 174.00   0.50    0.16    --  112.28  23.00 152.00  312
  5  \w    -94.00  26.00   0.50    0.05    --    0.00 -23.00 -12.00  240
  6  \w   -124.00 -76.00   0.50    0.16    --  -29.00 -91.00-150.00   96
  7  \w     32.00 117.00   0.50    0.16    --   56.14-125.00 120.00  170
  8  \w     92.00 138.00   0.50    0.16    --   56.14 125.00  60.00   92
  9  \w     32.00 117.00   0.50    0.16    --   56.14-125.00  60.00  170
 10  \w     92.00 138.00   0.50    0.16    --   56.14 125.00  30.00   92
 11  \w    -27.00  62.00   0.50    0.16    --   56.14 -57.00-180.00  178
 12  \w    -39.00  23.00   0.50    0.16    --   56.14 -19.00-120.00  124
 13  \w     28.00  71.00   0.50    0.16    --  112.28 -63.00  60.00   86
 14  \w    100.00 174.00   0.50    0.16    --  112.28 111.00 150.00  148
 15  \w    100.00 174.00   0.50    0.16    --  112.28 111.00  30.00  148
 16  \w     28.00  71.00   0.50    0.16    --  112.28 -63.00 120.00   86
 17  \w     19.00 102.00   0.50    0.16    --  112.28 -77.00 -90.00  166
 18  \w     28.00  71.00   0.50    0.16    --  112.28 -63.00 150.00   86
 19  \w     28.00  71.00   0.50    0.16    --  112.28 -63.00   0.00   86
 20  \w     73.00 174.00   0.50    0.16    --  112.28  63.00-180.00  202
 21  \w     28.00  71.00   0.50    0.16    --  112.28 -63.00 -60.00   86
 22  \w     28.00  71.00   0.50    0.16    --  112.28 -63.00 -30.00   86
 23  \w     28.00  71.00   0.50    0.16    --  112.28 -63.00  90.00   86
 24  \w     28.00  71.00   0.50    0.16    --  112.28 -63.00  30.00   86
 25  \w     19.00 102.00   0.50    0.16    --  112.28 -77.00-150.00  166
 26  \w     67.00 174.00   0.50    0.16    --  112.28  50.00 -60.00  214
 27  \w     28.00  71.00   0.50    0.16    --  112.28 -63.00-150.00   86
 28  \w   -100.00 -36.00   0.50    0.05    --    0.00 178.00   0.00  128
 29  \w    -47.00  83.00   0.50    0.05    --    0.00  77.00  30.00  260
 30  \w     10.00 134.00   0.50    0.16    --   56.14  77.00 -90.00  248
;
_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      -0.0620808000
_diffrn_orient_matrix_UB_12      -0.0124254000
_diffrn_orient_matrix_UB_13      -0.0906115000
_diffrn_orient_matrix_UB_21      -0.0760014000
_diffrn_orient_matrix_UB_22      -0.0346934000
_diffrn_orient_matrix_UB_23      0.0368830000
_diffrn_orient_matrix_UB_31      -0.0296009000
_diffrn_orient_matrix_UB_32      0.1153214000
_diffrn_orient_matrix_UB_33      0.0012841000
_diffrn_radiation_monochromator  mirror
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0411
_diffrn_reflns_av_unetI/netI     0.0339
_diffrn_reflns_Laue_measured_fraction_full 1.000
_diffrn_reflns_Laue_measured_fraction_max 0.987
_diffrn_reflns_limit_h_max       19
_diffrn_reflns_limit_h_min       -19
_diffrn_reflns_limit_k_max       15
_diffrn_reflns_limit_k_min       -14
_diffrn_reflns_limit_l_max       20
_diffrn_reflns_limit_l_min       -20
_diffrn_reflns_number            24071
_diffrn_reflns_point_group_measured_fraction_full 1.000
_diffrn_reflns_point_group_measured_fraction_max 0.987
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         71.606
_diffrn_reflns_theta_min         3.456
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_type              'PhotonJet (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    0.977
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.45522
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.40.45a (Rigaku Oxford Diffraction, 2019)
Empirical absorption correction using spherical harmonics,
 implemented in SCALE3 ABSPACK scaling algorithm.
;
_exptl_crystal_colour            'clear colourless'
_exptl_crystal_colour_lustre     clear
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.321
_exptl_crystal_description       needle
_exptl_crystal_F_000             1312
_exptl_crystal_recrystallization_method 'Vapour deposition'
_exptl_crystal_size_max          0.2
_exptl_crystal_size_mid          0.075
_exptl_crystal_size_min          0.075
_refine_diff_density_max         1.147
_refine_diff_density_min         -0.549
_refine_diff_density_rms         0.101
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.051
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     402
_refine_ls_number_reflns         6049
_refine_ls_number_restraints     1
_refine_ls_restrained_S_all      1.051
_refine_ls_R_factor_all          0.0897
_refine_ls_R_factor_gt           0.0759
_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^)+(0.1712P)^2^+1.1095P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.2374
_refine_ls_wR_factor_ref         0.2551
_reflns_Friedel_coverage         0.000
_reflns_number_gt                4771
_reflns_number_total             6049
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d0md00145g2.cif
_cod_data_source_block           19JLR003_MRC129
_cod_database_code               7240892
_shelx_shelxl_version_number     2014/7
_chemical_oxdiff_formula         C25H29F6N3O5
_chemical_oxdiff_usercomment     MRC129
_shelx_estimated_absorpt_t_max   0.930
_shelx_estimated_absorpt_t_min   0.829
_diffrn_oxdiff_digest_frames
;
014a6373326fb853a8b999829a08516ffe02404a98a
;
_diffrn_oxdiff_digest_hkl
;
017bf7c1840531a5c78d01b8d4ef5c6b3d5aed
;
_reflns_odcompleteness_completeness 99.95
_reflns_odcompleteness_iscentric 1
_reflns_odcompleteness_theta     66.97
_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
 O21-H21
 0.98 with sigma of 0.02
3.a Ternary CH refined with riding coordinates:
 C15(H15)
3.b Secondary CH2 refined with riding coordinates:
 C17(H17A,H17B), C20(H20A,H20B), C10(H10A,H10B), C19(H19A,H19B), C11(H11A,
 H11B), C13(H13A,H13B), C14(H14A,H14B), C16(H16A,H16B), C8(H8A,H8B), C34(H34A,
 H34B), C36(H36A,H36B)
3.c Aromatic/amide H refined with riding coordinates:
 C4(H4), C23(H23), C6(H6), C24(H24), C7(H7), C26(H26), C25(H25)
3.d Idealised Me refined as rotating group:
 C33(H33A,H33B,H33C), C37(H37A,H37B,H37C)
;
_shelx_res_checksum              43110
_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 1.416
_oxdiff_exptl_absorpt_empirical_full_min 0.431