{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T08:11:27Z","timestamp":1760775087767,"version":"build-2065373602"},"reference-count":39,"publisher":"Elsevier BV","issue":"14","license":[{"start":{"date-parts":[[2019,7,1]],"date-time":"2019-07-01T00:00:00Z","timestamp":1561939200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2019,7,1]],"date-time":"2019-07-01T00:00:00Z","timestamp":1561939200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2020,5,31]],"date-time":"2020-05-31T00:00:00Z","timestamp":1590883200000},"content-version":"am","delay-in-days":335,"URL":"http:\/\/www.elsevier.com\/open-access\/userlicense\/1.0\/"}],"funder":[{"DOI":"10.13039\/501100008982","name":"National Science 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functionalization"],"prefix":"10.1016","volume":"29","author":[{"given":"Kun","family":"Liu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ravi","family":"Kurukulasuriya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"Dykstra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"DiMichelle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinchu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petr","family":"Vachal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3995-0065","authenticated-orcid":false,"given":"Anthony","family":"Ogawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert 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Med"},{"key":"10.1016\/j.bmcl.2019.04.024_b0010","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/164_2016_76","volume":"243","author":"Kolkhof","year":"2017","journal-title":"Handb Exp Pharmacol"},{"issue":"6","key":"10.1016\/j.bmcl.2019.04.024_b0015","doi-asserted-by":"crossref","first-page":"877","DOI":"10.21037\/tau.2016.09.04","article-title":"Hormone therapy for transgender patients","volume":"5","author":"Unger","year":"2016","journal-title":"Transl Androl Urol"},{"key":"10.1016\/j.bmcl.2019.04.024_b0020","doi-asserted-by":"crossref","first-page":"2866","DOI":"10.1016\/j.bmcl.2016.04.052","volume":"26","author":"Ogawa","year":"2016","journal-title":"Bioorg Med Chem Lett"},{"key":"10.1016\/j.bmcl.2019.04.024_b0025","unstructured":"Compound 1 was incubated at a concentration of 10 \u00b5M with cryopreserved rat or human liver microsomes (protein concentration 1\u202fmg\/mL) in 100 mM phosphate buffer (pH 7.4), containing 2 mM magnesium chloride for 1 hour at 37\u202f\u00b0C in a shaking water bath. The incubation was initiated by adding NADPH to a final concentration of 1\u202fmM."},{"key":"10.1016\/j.bmcl.2019.04.024_b0030","unstructured":"The functional activity of most compounds in this series in a cellular assay of GR activity was >10\u202f\u00b5M despite high measured affinity to a truncated GR receptor. This disconnect between a binding affinity assay and a cellular function assay was never fully resolved so we sought to reduce GR binding to mitigate any risk of off-target activity."},{"key":"10.1016\/j.bmcl.2019.04.024_b0035","unstructured":"Putative design structures were modeled based on docking experiments performed starting from the 1.95 \u00c5 MR structure with bound corticosterone (PDB code 2A3I: Li, Y., Suino, K., Daugherty, J., Xu, H. E. Mol. Cell, 2005, 19, 367). Structures were prepared by removal of water molecules, addition of hydrogens, and restrained energy minimization using Macromodel (Macromodel 9.8.107, Schr\u00f6dinger LLC, New York, NY). Molecular docking was performed by employing our in-house docking routine FLOG (Miller, M. D., Kearsley, S. K., Underwood, D. J., Sheridan, R. P. J. Comput. Aided Mol. Des. 1994, 8, 153), which ranked precalculated conformations of the target molecules in a 6 \u00c5 grid centered on the crystallographic ligand. Conformations were generated using our in-house metric matrix distance geometry algorithm JG (Kearsley, S. K. Merck & Co., Inc., unpublished). The conformations were subjected to energy minimization with Macromodel using the MMFFs force field (Halgren, T. A. J. Comput. Chem. 1999, 20, 720). A representative docking pose (data not shown) was selected by visual inspection and was subjected to restrained energy minimization (using Macromodel) to produce a putative model."},{"key":"10.1016\/j.bmcl.2019.04.024_b0040","unstructured":"Synthetic procedures for most compounds presented herein appear in: T. A. Cernak, K. D. Dykstra, D.-M. Shen, K. Liu, A. Stamford, J. Qiang Tan. \u201cPreparation of indazole derivatives as mineralocorticoid receptor antagonists for the treatment of aldosterone-mediated diseases\u201d, PCT International Application, 2014, WO2014014794."},{"key":"10.1016\/j.bmcl.2019.04.024_b0045","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1039\/C5CS00628G","volume":"45","author":"Cernak","year":"2016","journal-title":"Chem Soc Rev"},{"key":"10.1016\/j.bmcl.2019.04.024_h0050","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1021\/cr900206p","volume":"110","author":"Mkhalid","year":"2010","journal-title":"Chem Rev"},{"key":"10.1016\/j.bmcl.2019.04.024_h0055","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0022-328X(03)00176-1","volume":"680","author":"Ishiyama","year":"2003","journal-title":"Organomet Chem"},{"key":"10.1016\/j.bmcl.2019.04.024_h0060","first-page":"40","volume":"2011","author":"Hartwig","year":"1992","journal-title":"Chem Soc Rev"},{"key":"10.1016\/j.bmcl.2019.04.024_h0065","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1351\/pac200678071369","volume":"78","author":"Ishiyama","year":"2006","journal-title":"Pure Appl Chem"},{"key":"10.1016\/j.bmcl.2019.04.024_h0070","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1021\/ar200206a","volume":"45","author":"Hartwig","year":"2011","journal-title":"Acc Chem Res"},{"key":"10.1016\/j.bmcl.2019.04.024_h0075","doi-asserted-by":"crossref","first-page":"5649","DOI":"10.1016\/S0040-4039(02)01135-8","volume":"43","author":"Takagi","year":"2002","journal-title":"Tetrahedron Lett"},{"key":"10.1016\/j.bmcl.2019.04.024_h0080","doi-asserted-by":"crossref","first-page":"11389","DOI":"10.1021\/ja104442v","volume":"132","author":"Liskey","year":"2010","journal-title":"J Am Chem Soc"},{"key":"10.1016\/j.bmcl.2019.04.024_h0085","doi-asserted-by":"crossref","first-page":"2604","DOI":"10.1039\/C5SC04751J","volume":"7","author":"Kutchukian","year":"2016","journal-title":"Chem Sci"},{"key":"10.1016\/j.bmcl.2019.04.024_b0060","doi-asserted-by":"crossref","first-page":"15434","DOI":"10.1021\/ja076498n","volume":"129","author":"Murphy","year":"2007","journal-title":"J Am Chem Soc"},{"key":"10.1016\/j.bmcl.2019.04.024_h0095","doi-asserted-by":"crossref","first-page":"14012","DOI":"10.1021\/ja405919z","volume":"135","author":"Mazzotti","year":"2013","journal-title":"J Am Chem Soc"},{"key":"10.1016\/j.bmcl.2019.04.024_h0100","doi-asserted-by":"crossref","first-page":"5993","DOI":"10.1002\/anie.200802164","volume":"47","author":"Furuya","year":"2008","journal-title":"Angew Chem Int Ed"},{"key":"10.1016\/j.bmcl.2019.04.024_h0105","doi-asserted-by":"crossref","first-page":"2552","DOI":"10.1021\/ja310909q","volume":"135","author":"Fier","year":"2013","journal-title":"J Am Chem Soc"},{"key":"10.1016\/j.bmcl.2019.04.024_h0110","doi-asserted-by":"crossref","first-page":"4648","DOI":"10.1021\/ja400300g","volume":"135","author":"Ye","year":"2013","journal-title":"J Am Chem Soc"},{"key":"10.1016\/j.bmcl.2019.04.024_h0115","doi-asserted-by":"crossref","first-page":"4165","DOI":"10.1002\/chem.200801974","volume":"15","author":"Doi","year":"2009","journal-title":"Eur J"},{"key":"10.1016\/j.bmcl.2019.04.024_h0120","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1002\/anie.201208203","volume":"52","author":"Robbins","year":"2013","journal-title":"Angew Chem Int Ed"},{"key":"10.1016\/j.bmcl.2019.04.024_b0075","doi-asserted-by":"crossref","first-page":"7572","DOI":"10.1021\/ja400295v","volume":"135","author":"Preshlock","year":"2013","journal-title":"J Am Chem Soc"},{"key":"10.1016\/j.bmcl.2019.04.024_b0080","doi-asserted-by":"crossref","first-page":"4287","DOI":"10.1021\/ja412563e","volume":"136","author":"Larsen","year":"2014","journal-title":"J Am Chem Soc"},{"issue":"12","key":"10.1016\/j.bmcl.2019.04.024_h0135","doi-asserted-by":"crossref","first-page":"2976","DOI":"10.1021\/acs.accounts.7b00428","volume":"50","author":"Krska","year":"2017","journal-title":"ACC Chem Res"},{"key":"10.1016\/j.bmcl.2019.04.024_h0140","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1021\/acsmedchemlett.7b00165","volume":"8","author":"Shevlin","year":"2017","journal-title":"ACS Med Chem Lett"},{"key":"10.1016\/j.bmcl.2019.04.024_h0145","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1038\/nchem.2062","volume":"6","author":"Collins","year":"2014","journal-title":"Nat Chem"},{"key":"10.1016\/j.bmcl.2019.04.024_h0150","first-page":"91","volume":"11","author":"Wong","year":"2018","journal-title":"Curr Opin Green Sus Chem"},{"key":"10.1016\/j.bmcl.2019.04.024_b0090","unstructured":"HTE reaction screening equipment was purchased from Analytical Sales & Services. A 24-well aluminum reactor plate (catalog # 24253) was equipped with 1 mL clear glass shell vials (catalog # 84001) then moved to the glove box. A 10 mM stock solution of [(cod)Ir(OMe)]2 in THF (50\u202f\u03bcL\/vial), and 20 mM stock solutions of the ligands (a 40\u202fmM stock solution was used for monodentate ligand L2) in THF (50\u202f\u03bcL\/vial) were added to the desired vials. Solvents were removed in vacuo with a Genevac in the glovebox. A parylene-coated stir dowel (catalog # 13258) was then added to each vial, and 100\u202f\u03bcL of a solution of 20 and B2pin2 in the solvent noted was added to respective vials. The system was sealed in the glovebox, then stirred at 80\u202f\u00b0C for 14\u202fhours. Each reaction was quenched with 1 mL of 9:1 acetonitrile\u2013methanol (1\u202fmL), stirred 20 minutes, then diluted 10-fold into 8:1:1 acetonitrile-methanol-water containing biphenyl as an internal standard, and analyzed by UPLC-MS to obtain the UV (220\u202fnm) peak area percentages reported in Fig. 7."},{"issue":"7","key":"10.1016\/j.bmcl.2019.04.024_b0095","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1021\/acs.orglett.6b00356","volume":"18","author":"Shen","year":"2016","journal-title":"Org Lett"},{"issue":"22","key":"10.1016\/j.bmcl.2019.04.024_b0100","doi-asserted-by":"crossref","first-page":"11254","DOI":"10.1021\/jo502062z","volume":"79","author":"Loach","year":"2014","journal-title":"J Org Chem"},{"key":"10.1016\/j.bmcl.2019.04.024_b0105","doi-asserted-by":"crossref","first-page":"5308.","DOI":"10.1021\/acs.joc.5b00452","volume":"80","author":"Sadler","year":"2015","journal-title":"J Org Chem"},{"key":"10.1016\/j.bmcl.2019.04.024_b0110","doi-asserted-by":"crossref","first-page":"2552","DOI":"10.1021\/ja310909q","volume":"135","author":"Fier","year":"2013","journal-title":"J Am Chem Soc"},{"key":"10.1016\/j.bmcl.2019.04.024_h0180","doi-asserted-by":"crossref","first-page":"4575","DOI":"10.1021\/ja411699u","volume":"136","author":"Green","year":"2014","journal-title":"J Am Chem Soc"},{"key":"10.1016\/j.bmcl.2019.04.024_h0185","doi-asserted-by":"crossref","first-page":"10070","DOI":"10.1002\/anie.201701486","volume":"56","author":"Bickelhaupt","year":"2017","journal-title":"Angew Chem Int Ed Engl"},{"key":"10.1016\/j.bmcl.2019.04.024_b0120","unstructured":"All the calculations were carried out with Gaussian 09. Geometry optimizations were performed with B3LYP. The LANL2DZ basis set was used for Ir, and the 6-31G (d) basis set was used for other atoms. Frequency analysis was conducted at the same level of theory to verify that the stationary points are minima or saddle points. The single-point energies and solvent effects were computed with the more accurate M06\/SDD -6-311+G(d,p) method (density functional\/basis sets for Ir and other atoms). The SMD solvation model was for cyclohexane solvent. The relative Gibbs free energies (at 298.15 K) are given in kcal\/mol. Computed structures are illustrated using CYLView."},{"key":"10.1016\/j.bmcl.2019.04.024_b0125","unstructured":"The de novo synthesis procedure appears in Ref.8."}],"container-title":["Bioorganic & Medicinal Chemistry Letters"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0960894X19302446?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0960894X19302446?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T07:29:57Z","timestamp":1760772597000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0960894X19302446"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7]]},"references-count":39,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2019,7]]}},"alternative-id":["S0960894X19302446"],"URL":"https:\/\/doi.org\/10.1016\/j.bmcl.2019.04.024","relation":{},"ISSN":["0960-894X"],"issn-type":[{"type":"print","value":"0960-894X"}],"subject":[],"published":{"date-parts":[[2019,7]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Development of indazole mineralocorticoid receptor antagonists and investigation into their selective late-stage functionalization","name":"articletitle","label":"Article Title"},{"value":"Bioorganic & Medicinal Chemistry Letters","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.bmcl.2019.04.024","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2019 Elsevier Ltd. All rights reserved.","name":"copyright","label":"Copyright"}]}}