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_7240890
_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         'C20 H32 N3 O2, C2 F3 O2, 1.65(H2 O)'
_chemical_formula_sum            'C22 H35.31 F3 N3 O5.65'
_chemical_formula_weight         489.30
_chemical_name_common            19
_chemical_name_systematic
5-(4-((1s,4s)-4-(tert-butyl)cyclohexyl)piperazine-1-carbonyl)pyridin-2(1H)-one
_space_group_crystal_system      monoclinic
_space_group_IT_number           15
_space_group_name_Hall           '-I 2ya'
_space_group_name_H-M_alt        'I 1 2/a 1'
_atom_sites_solution_hydrogens   mixed
_atom_sites_solution_primary     dual
_audit_creation_date             2019-04-30
_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                 90.4130(10)
_cell_angle_gamma                90
_cell_formula_units_Z            8
_cell_length_a                   17.41370(10)
_cell_length_b                   8.14510(10)
_cell_length_c                   33.6364(2)
_cell_measurement_reflns_used    16683
_cell_measurement_temperature    173.01(10)
_cell_measurement_theta_max      76.6160
_cell_measurement_theta_min      2.8610
_cell_volume                     4770.74(7)
_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      173.01(10)
_diffrn_detector                 'CCD plate'
_diffrn_detector_area_resol_mean 10.0000
_diffrn_detector_type            HyPix
_diffrn_measured_fraction_theta_full 0.999
_diffrn_measured_fraction_theta_max 0.972
_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    -56.00   6.00   0.50    0.35    --  -18.75 106.00-149.00  124
  2  \w     17.00  86.00   0.50    0.35    --   47.95-106.00 111.00  138
  3  \w     35.00 111.00   0.50    1.39    --  107.11-106.00 111.00  152
  4  \w    102.00 174.00   0.50    1.39    --  107.11 106.00-149.00  144
  5  \w    -27.00  56.00   0.50    0.35    --  -18.75  15.00 -30.00  166
  6  \w    -66.00  -9.00   0.50    0.35    --  -18.75 125.00  30.00  114
  7  \w    -26.00  23.00   0.50    0.35    --   47.95 -19.00 120.00   98
  8  \w    -26.00  23.00   0.50    0.35    --   47.95 -19.00 -30.00   98
  9  \w    -26.00  23.00   0.50    0.35    --   47.95 -19.00-150.00   98
 10  \w    -26.00  23.00   0.50    0.35    --   47.95 -19.00   0.00   98
 11  \w     35.00  68.00   0.50    1.39    --  107.11 -61.00 120.00   66
 12  \w     35.00  68.00   0.50    1.39    --  107.11 -61.00 -60.00   66
 13  \w     95.00 174.00   0.50    1.39    --  107.11  45.00-180.00  158
 14  \w     35.00 117.00   0.50    1.39    --  107.11-125.00 -60.00  164
 15  \w     35.00  68.00   0.50    1.39    --  107.11 -61.00  90.00   66
 16  \w     95.00 174.00   0.50    1.39    --  107.11  30.00-150.00  158
 17  \w     92.00 174.00   0.50    1.39    --  107.11 125.00 -90.00  164
 18  \w     35.00  68.00   0.50    1.39    --  107.11 -61.00  30.00   66
 19  \w     35.00  68.00   0.50    1.39    --  107.11 -61.00   0.00   66
 20  \w     35.00 117.00   0.50    1.39    --  107.11-125.00-150.00  164
 21  \w     35.00 102.00   0.50    1.39    --  107.11 -77.00-120.00  134
 22  \w     35.00  68.00   0.50    1.39    --  107.11 -61.00-150.00   66
 23  \w     35.00 102.00   0.50    1.39    --  107.11 -77.00 -30.00  134
 24  \w     35.00  68.00   0.50    1.39    --  107.11 -61.00 -30.00   66
 25  \w     26.00  80.00   0.50    0.35    --   47.95  77.00 120.00  108
 26  \w     26.00 120.00   0.50    0.35    --   47.95  77.00 -30.00  188
;
_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      0.0213904000
_diffrn_orient_matrix_UB_12      0.1731522000
_diffrn_orient_matrix_UB_13      -0.0146535000
_diffrn_orient_matrix_UB_21      -0.0066406000
_diffrn_orient_matrix_UB_22      -0.0591697000
_diffrn_orient_matrix_UB_23      -0.0433942000
_diffrn_orient_matrix_UB_31      -0.0855817000
_diffrn_orient_matrix_UB_32      0.0478522000
_diffrn_orient_matrix_UB_33      -0.0006366000
_diffrn_radiation_monochromator  mirror
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0225
_diffrn_reflns_av_unetI/netI     0.0167
_diffrn_reflns_Laue_measured_fraction_full 0.999
_diffrn_reflns_Laue_measured_fraction_max 0.972
_diffrn_reflns_limit_h_max       17
_diffrn_reflns_limit_h_min       -22
_diffrn_reflns_limit_k_max       10
_diffrn_reflns_limit_k_min       -10
_diffrn_reflns_limit_l_max       42
_diffrn_reflns_limit_l_min       -42
_diffrn_reflns_number            23932
_diffrn_reflns_point_group_measured_fraction_full 0.999
_diffrn_reflns_point_group_measured_fraction_max 0.972
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         77.093
_diffrn_reflns_theta_min         2.627
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_type              'PhotonJet (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    0.961
_exptl_absorpt_correction_T_max  1.000
_exptl_absorpt_correction_T_min  0.643
_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    1.362
_exptl_crystal_description       prism
_exptl_crystal_F_000             2084
_exptl_crystal_recrystallization_method 'Vapour deposition'
_exptl_crystal_size_max          0.204
_exptl_crystal_size_mid          0.127
_exptl_crystal_size_min          0.066
_refine_diff_density_max         0.288
_refine_diff_density_min         -0.238
_refine_diff_density_rms         0.040
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.049
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     354
_refine_ls_number_reflns         4918
_refine_ls_number_restraints     4
_refine_ls_restrained_S_all      1.057
_refine_ls_R_factor_all          0.0391
_refine_ls_R_factor_gt           0.0362
_refine_ls_shift/su_max          0.002
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0478P)^2^+2.9531P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.0950
_refine_ls_wR_factor_ref         0.0974
_reflns_Friedel_coverage         0.000
_reflns_number_gt                4477
_reflns_number_total             4918
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d0md00145g2.cif
_cod_data_source_block           19jlr004
_cod_database_code               7240890
_shelx_shelxl_version_number     2018/1
_chemical_oxdiff_formula         'C22 H35 F3 N3 O5.5'
_chemical_oxdiff_usercomment     MRC92F1TFA
_shelx_estimated_absorpt_t_max   0.939
_shelx_estimated_absorpt_t_min   0.828
_reflns_odcompleteness_completeness 99.89
_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, All N(H) groups
 At 1.5 times of:
  All C(H,H,H) groups, All O(H,H) groups
2. Others
 Sof(O6A)=Sof(H6AA)=Sof(H6AB)=FVAR(1)
 Sof(O6B)=Sof(H6BA)=Sof(H6BB)=FVAR(2)
 Sof(F2A)=Sof(F1A)=Sof(F3A)=1-FVAR(3)
 Sof(F1)=Sof(F2)=Sof(F3)=FVAR(3)
3.a Free rotating group:
 O6A(H6AA,H6AB), O6B(H6BA,H6BB), O5(H5A,H5B)
3.b Ternary CH refined with riding coordinates:
 N3(H3), C11(H11), C14(H14)
3.c Secondary CH2 refined with riding coordinates:
 C7(H7A,H7B), C8(H8A,H8B), C9(H9A,H9B), C10(H10A,H10B), C12(H12A,H12B),
 C13(H13A,H13B), C15(H15A,H15B), C16(H16A,H16B)
3.d Aromatic/amide H refined with riding coordinates:
 N1(H1), C2(H2), C3(H3A), C5(H5)
3.e Idealised Me refined as rotating group:
 C18(H18A,H18B,H18C), C19(H19A,H19B,H19C), C20(H20A,H20B,H20C)
;
_shelx_res_checksum              97807
_olex2_submission_special_instructions 'No special instructions were received'