title: Discovery of novel pyrimidine and malonamide derivatives as TGR5 agonists.
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.
authors.affiliation: 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.
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Park
authors.affiliation: Hanmi Research Center, Hanmi Pharm. Co. Ltd, Gyeonggi-do 445-813, Republic of Korea.
authors.forename: Young Gil
authors.initials: YG
authors.lastname: Ahn
authors.affiliation: Hanmi Research Center, Hanmi Pharm. Co. Ltd, Gyeonggi-do 445-813, Republic of Korea.
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Jung
authors.affiliation: 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.
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Bang
authors.affiliation: 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.
authors.forename: Mira
authors.initials: M
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Dong Jin
authors.initials: DJ
authors.lastname: Hong
authors.affiliation: Hanmi Research Center, Hanmi Pharm. Co. Ltd, Gyeonggi-do 445-813, Republic of Korea.
authors.forename: Jisook
authors.initials: J
authors.lastname: Kim
authors.affiliation: Hanmi Research Center, Hanmi Pharm. Co. Ltd, Gyeonggi-do 445-813, Republic of Korea.
authors.forename: Kwee Hyun
authors.initials: KH
authors.lastname: Suh
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul 156-756, Republic of Korea.
authors.forename: Young Jin
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul 156-756, Republic of Korea.
authors.forename: Doran
authors.initials: D
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Korea University, Sejong 339-700, Republic of Korea.
authors.forename: Eun-Yeong
authors.initials: EY
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Korea University, Sejong 339-700, Republic of Korea.
authors.forename: Kiho
authors.initials: K
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul 156-756, Republic of Korea. Electronic address: khmin@cau.ac.kr.
authors.forename: Kyung Hoon
authors.initials: KH
authors.lastname: Min
mesh_terms: D000818:Animals; D001682:Biological Availability; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D008314:Malonates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D015394:Molecular Structure; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; C473772:GPBAR1 protein, human; D008314:Malonates; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D003577:Cytochrome P-450 Enzyme System; C030986:pyrimidine; C008314:malonamide
keywords: Agonist; Bioisostere; Malonamide; Pyrimidine; TGR5