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Bioorg Med Chem Lett. 2014 Sep 1;24(17):4271-5. doi: 10.1016/j.bmcl.2014.07.026. Epub 2014 Jul 18.

Discovery of novel pyrimidine and malonamide derivatives as TGR5 agonists.

Author information

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: khmin@cau.ac.kr.

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

PMID:
25082126
DOI:
10.1016/j.bmcl.2014.07.026
[Indexed for MEDLINE]

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