Discovery of novel pyrimidine and malonamide derivatives as TGR5 agonists

  • Bioorg Med Chem Lett. 2014 Sep 1;24(17):4271-5. doi: 10.1016/j.bmcl.2014.07.026.
Eun Ju Park  1 ,  Young Gil Ahn  2 ,  Seung Hyun Jung  2 ,  Hyo Jeong Bang  1 ,  Mira Kim  1 ,  Dong Jin Hong  1 ,  Jisook Kim  2 ,  Kwee Hyun Suh  2 ,  Young Jin Kim  3 ,  Doran Kim  3 ,  Eun-Yeong Kim  4 ,  Kiho Lee  4 ,  Kyung Hoon Min  5
Affiliations
  • 1. Hanmi Research Center, Hanmi Pharm. Co. Ltd, Gyeonggi-do 445-813, Republic of Korea; College of Pharmacy, Chung-Ang University, Seoul 156-756, Republic of Korea.
  • 2. Hanmi Research Center, Hanmi Pharm. Co. Ltd, Gyeonggi-do 445-813, Republic of Korea.
  • 3. College of Pharmacy, Chung-Ang University, Seoul 156-756, Republic of Korea.
  • 4. College of Pharmacy, Korea University, Sejong 339-700, Republic of Korea.
  • 5. College of Pharmacy, Chung-Ang University, Seoul 156-756, Republic of Korea. Electronic address: [email protected].
PMID: 25082126 DOI: 10.1016/j.bmcl.2014.07.026
Abstract

Takeda G-protein-coupled receptor 5 (TGR5) is a promising molecular target for metabolic diseases. A series of 4-(2,5-dichlorophenoxy)pyrimidine and cyclopropylmalonamide derivatives were synthesized as potent agonists of TGR5 based on a bioisosteric replacement strategy. Several compounds exhibited improved potency, compared to a reference compound with a pyridine scaffold. The pharmacokinetic profile of the representative compound 18 was considered moderate.

Keywords
Agonist; Bioisostere; Malonamide; Pyrimidine; TGR5.