{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T11:26:55Z","timestamp":1792668415724,"version":"4.5.0"},"reference-count":52,"publisher":"National Academy of Sciences","issue":"28","license":[{"start":{"date-parts":[[2022,1,8]],"date-time":"2022-01-08T00:00:00Z","timestamp":1641600000000},"content-version":"vor","delay-in-days":184,"URL":"https:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"funder":[{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM-118176"],"award-info":[{"award-number":["GM-118176"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2021,7,13]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>Bioisoteric replacements for aromatic rings to improve medicinal properties are in high demand. This work presents a comprehensive analysis of heretofore-inaccessible 1,2-difunctionalized bicyclo[1.1.1]pentanes from both chemical and biological vantage points. This analysis will aid those in drug discovery regarding when the application of such systems makes sense and how to access them in such circumstances.<\/jats:p>","DOI":"10.1073\/pnas.2108881118","type":"journal-article","created":{"date-parts":[[2021,7,9]],"date-time":"2021-07-09T04:21:07Z","timestamp":1625804467000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":125,"title":["1,2-Difunctionalized bicyclo[1.1.1]pentanes: Long\u2013sought-after mimetics for\n                    <i>ortho<\/i>\n                    \/\n                    <i>meta<\/i>\n                    -substituted arenes"],"prefix":"10.1073","volume":"118","author":[{"given":"Jin-Xin","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;"},{"name":"State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People\u2019s Republic of China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Xuan","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi","family":"He","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin J.","family":"Burke","sequence":"additional","affiliation":[{"name":"Oncology Medicinal Chemistry, Pfizer Worldwide Research, Development and Medical, San Diego, CA 92121;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Collins","sequence":"additional","affiliation":[{"name":"Oncology Medicinal Chemistry, Pfizer Worldwide Research, Development and Medical, San Diego, CA 92121;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Del Bel","sequence":"additional","affiliation":[{"name":"Oncology Medicinal Chemistry, Pfizer Worldwide Research, Development and Medical, San Diego, CA 92121;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff","family":"Elleraas","sequence":"additional","affiliation":[{"name":"Oncology Medicinal Chemistry, Pfizer Worldwide Research, Development and Medical, San Diego, CA 92121;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary M.","family":"Gallego","sequence":"additional","affiliation":[{"name":"Oncology Medicinal Chemistry, Pfizer Worldwide Research, Development and Medical, San Diego, CA 92121;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. Patrick","family":"Montgomery","sequence":"additional","affiliation":[{"name":"Oncology Medicinal Chemistry, Pfizer Worldwide Research, Development and Medical, San Diego, CA 92121;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James J.","family":"Mousseau","sequence":"additional","affiliation":[{"name":"Discovery Sciences, Medicine Design, Pfizer Worldwide Research, Development and Medical, Groton, CT 06340"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sajiv K.","family":"Nair","sequence":"additional","affiliation":[{"name":"Oncology Medicinal Chemistry, Pfizer Worldwide Research, Development and Medical, San Diego, CA 92121;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A.","family":"Perry","sequence":"additional","affiliation":[{"name":"Discovery Sciences, Medicine Design, Pfizer Worldwide Research, Development and Medical, Groton, CT 06340"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jillian E.","family":"Spangler","sequence":"additional","affiliation":[{"name":"Oncology Medicinal Chemistry, Pfizer Worldwide Research, Development and Medical, San Diego, CA 92121;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien C.","family":"Vantourout","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9193-9053","authenticated-orcid":false,"given":"Phil S.","family":"Baran","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2021,7,8]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm901241e"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1039\/c2md20347b"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41557-018-0021-z"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201703801"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201800193"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201702362"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1039\/C8OB02812E"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201804225"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad6252"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201608116"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.7b11865"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1039\/C8SC01355A"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201810061"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201706799"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.9b01947"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201914875"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41929-019-0417-1"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202000140"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202009340"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2060-z"},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","unstructured":"J.-X. Zhao . 1 2-Difunctionalized bicyclo[1.1.1]pentanes: Long sought after bioisosteres for ortho\/meta-substituted arenes. ChemRxiv [Preprint] (2020). https:\/\/chemrxiv.org\/engage\/chemrxiv\/article-details\/60c7511fbb8c1a389e3dbc11 (Accessed 25 June 2021).","DOI":"10.26434\/chemrxiv.13120283"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.0c03612"},{"key":"e_1_3_4_23_2","unstructured":"Y. Yang . Synthesis of multi-substituted bicycloalkyl boronates: An intramolecular coupling approach to alkyl bioisosteres. ChemRxiv [Preprint] (2021). https:\/\/chemrxiv.org\/engage\/chemrxiv\/article-details\/60c754cc9abda2e4b5f8e231 (Accessed 25 June 2021)."},{"key":"e_1_3_4_24_2","unstructured":"DrugBank DrugBank online (2021). https:\/\/go.drugbank.com\/. Accessed 25 June 2021."},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202004183"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/0040-4020(95)00628-L"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.8b02928"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.6b00250"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf6123"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201605463"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201609662"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aam7355"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature22307"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201705107"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201809310"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.8b12035"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201814524"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.9b02238"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2012.07.019"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1002\/jps.22674"},{"key":"e_1_3_4_41_2","unstructured":"J. S. Bajwa M. De La Cruz S. K. Dodd L. M. Waykole R. Wu \u201cSalts of N -[6-cis-2 6-dimethylmorpholin-4yl)pyridine-3yl]-2-methyl-4\u2032-(trifluoromethoxy)[1 1\u2032-biphenyl]-3-carboxamide\u201d (Novartis AG). Patent WO 2010033481 A1 20100325 (2010)."},{"key":"e_1_3_4_42_2","unstructured":"H. Mayer D. Golsch H. Isak J. Schr\u00f6der \u201cMethod for producing 2-halogen-pyridine-carboxylic acid amides\u201d (BASF Aktiengesellschaf). Patent WO 2003037868 A1 20030508 (2003)."},{"key":"e_1_3_4_43_2","unstructured":"H. Ogawa . \u201cVasopressin antagonistic agent\u201d (Otsuka Pharmaceutical Co. Ltd.). Patent JP 04321669 A 19921111 (1992)."},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1021\/op060200g"},{"key":"e_1_3_4_45_2","unstructured":"R. S. Kania . \u201cIndazole compounds and pharmaceutical compositions for inhibiting protein kinases and methods for their use\u201d (Agouron Pharmaceuticals Inc.) US 6534524 B1 (2003)."},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1002\/9780470524961.ch7"},{"key":"e_1_3_4_47_2","unstructured":"B. Lal . \u201cNovel water based process for the preparation of substituted diphenylmethyl piperazines\u201d (Calyx Chemicals and Pharmaceuticals Pvt. Ltd.) Patent WO 2010046908 A2 (2010)."},{"key":"e_1_3_4_48_2","unstructured":"L. R. Vadali E. R. Yerva G. P. S. Vemavarapu P. B. Rao \u201cProcess for making lomitapide mesylate\u201d (Mylan Laboratories Ltd.). Patent WO 2016012934 A1 (2016)."},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja01259a023"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm0306430"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1002\/qua.24481"},{"key":"e_1_3_4_52_2","unstructured":"Schr\u00f6dinger LLC Schr\u00f6dinger Release 2019-1: Glide and Jaguar (Schr\u00f6dinger LLC New York 2021)."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.pnas.org\/syndication\/doi\/10.1073\/pnas.2108881118","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2108881118","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T08:34:53Z","timestamp":1649838893000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.2108881118"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,8]]},"references-count":52,"journal-issue":{"issue":"28","published-print":{"date-parts":[[2021,7,13]]}},"alternative-id":["10.1073\/pnas.2108881118"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2108881118","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,8]]},"assertion":[{"value":"2021-07-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2108881118"}}