Discovery of BR102375, a new class of non-TZD PPARγ full agonist for the treatment of type 2 diabetes

  • Bioorg Med Chem Lett. 2019 Aug 15;29(16):2275-2282. doi: 10.1016/j.bmcl.2019.06.027.
Wonken Choung  1 ,  Deokmo Yang  1 ,  Hakdo Kim  1 ,  Hyukjoon Choi  1 ,  Bo Ram Lee  1 ,  Min Park  1 ,  Su Min Jang  1 ,  Jae Soo Lim  1 ,  Woo Sik Kim  1 ,  Kyung-Hee Kim  2 ,  Jungwook Chin  2 ,  Kyungjin Jung  2 ,  Geumwoo Lee  2 ,  Eunmi Hong  2 ,  Tae-Ho Jang  2 ,  Jeongmin Joo  2 ,  Hayoung Hwang  2 ,  Jayhyuk Myung  1 ,  Seong Heon Kim  3
Affiliations
  • 1. Central Research Center, Boryung Pharmaceuticals Co. Ltd., Republic of Korea.
  • 2. New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Republic of Korea.
  • 3. Central Research Center, Boryung Pharmaceuticals Co. Ltd., Republic of Korea. Electronic address: [email protected].
PMID: 31253533 DOI: 10.1016/j.bmcl.2019.06.027
Abstract

As a potential treatment of type 2 diabetes, a novel PPARγ non-TZD full agonist, compound 18 (BR102375) was identified from the original lead BR101549 by the SAR efforts of the labile metabolite control through bioisosteres approach. In vitro assessments of BR102375 demonstrated its activating potential of PPARγ comparable to Pioglitazone as well as the induction of related gene expressions. Further in vivo evaluation of BR102375 in diabetic rodent models successfully proved its glucose lowering effect as a potential antidiabetic agent, but the anticipated suppression of weight gain was not evident. The X-ray co-crystal analysis of BR102375-PPARγ LBD unexpectedly revealed binding modes totally different from those of BR101549, which was found, instead, closely resembled to those of TZD full agonists.

Keywords
Antidiabetics; Drug discovery; Non-TZD full agonist; PPARγ agonist.
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