{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T18:22:07Z","timestamp":1789928527966,"version":"4.0.1"},"reference-count":33,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2018,5,18]],"date-time":"2018-05-18T00:00:00Z","timestamp":1526601600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81273376"],"award-info":[{"award-number":["81273376"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81673299"],"award-info":[{"award-number":["81673299"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chem Biol Drug Des"],"published-print":{"date-parts":[[2018,8]]},"abstract":"<jats:p>The free fatty acid receptor 1 (<jats:styled-content style=\"fixed-case\">FFA<\/jats:styled-content>1) is a potential target due to its function in enhancing of glucose\u2010stimulated insulin secretion. The <jats:styled-content style=\"fixed-case\">FFA<\/jats:styled-content>1 agonist <jats:styled-content style=\"fixed-case\">GW<\/jats:styled-content>9508 has great potential for the treatment of type 2 diabetes mellitus, but it has been suffering from high plasma clearance probably because the phenylpropanoic acid is vulnerable to \u03b2\u2010oxidation. To identify orally available analog without influence on the unique pharmacological mechanism of <jats:styled-content style=\"fixed-case\">GW<\/jats:styled-content>9508, we tried to interdict the metabolically labile group by incorporating two deuterium atoms at the \u03b1\u2010position of phenylpropionic acid affording compound <jats:bold>4<\/jats:bold> (<jats:styled-content style=\"fixed-case\">HWL<\/jats:styled-content>\u2010066). As expected, <jats:styled-content style=\"fixed-case\">HWL<\/jats:styled-content>\u2010066 revealed a lower clearance (<jats:styled-content style=\"fixed-case\">CL<\/jats:styled-content>\u00a0=\u00a00.23\u00a0L<jats:sup>\u22121<\/jats:sup>\u00a0hr<jats:sup>\u22121<\/jats:sup>\u00a0kg<jats:sup>\u22121<\/jats:sup>), higher maximum concentration (<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>\u00a0=\u00a05907.47\u00a0\u03bcg\/L), and longer half\u2010life (<jats:italic>T<\/jats:italic><jats:sub>1\/2<\/jats:sub>\u00a0=\u00a03.50\u00a0hr), resulting in a 2.8\u2010fold higher exposure than <jats:styled-content style=\"fixed-case\">GW<\/jats:styled-content>9508. Moreover, the glucose\u2010lowering effect of <jats:styled-content style=\"fixed-case\">HWL<\/jats:styled-content>\u2010066 was far better than that of <jats:styled-content style=\"fixed-case\">GW<\/jats:styled-content>9508 and comparable with <jats:styled-content style=\"fixed-case\">TAK<\/jats:styled-content>\u2010875. Different from glibenclamide, no side\u2010effect of hypoglycemia was observed in mice after oral administrating <jats:styled-content style=\"fixed-case\">HWL<\/jats:styled-content>\u2010066 (80\u00a0mg\/kg).<\/jats:p>","DOI":"10.1111\/cbdd.13321","type":"journal-article","created":{"date-parts":[[2018,5,19]],"date-time":"2018-05-19T06:05:19Z","timestamp":1526709919000},"page":"1547-1554","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Improving metabolic stability with deuterium: The discovery of <scp>HWL<\/scp>\u2010066, a potent and long\u2010acting free fatty acid receptor 1 agonists"],"prefix":"10.1111","volume":"92","author":[{"given":"Chunxia","family":"Liu","sequence":"first","affiliation":[{"name":"Center of Drug Discovery State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmacy Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Shi","sequence":"additional","affiliation":[{"name":"Center of Drug Discovery State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huilan","family":"Li","sequence":"additional","affiliation":[{"name":"Center of Drug Discovery State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nasi","family":"Wang","sequence":"additional","affiliation":[{"name":"Center of Drug Discovery State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxuan","family":"Dai","sequence":"additional","affiliation":[{"name":"Center of Drug Discovery State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Liao","sequence":"additional","affiliation":[{"name":"Center of Drug Discovery State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenlong","family":"Huang","sequence":"additional","affiliation":[{"name":"Center of Drug Discovery State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing China"},{"name":"Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3827-0992","authenticated-orcid":false,"given":"Hai","family":"Qian","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,5,18]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.2337\/db09-9028"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)60679-X"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1210\/10.1210\/er.2006-0038"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-0699"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/13543784.2016.1189530"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01478"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M211495200"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.2337\/db08-0307"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.11.5.661"},{"key":"e_1_2_7_11_1","author":"Li Z.","year":"2017","journal-title":"Med. 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