Kamaura, Masahiro; Kubo, Osamu; Sugimoto, Hiromichi; Noguchi, Naoyoshi; Miyashita, Hirohisa; Abe, Shinichi; Matsuda, Kae; Tsujihata, Yoshiyuki; Odani, Tomoyuki; Iwasaki, Shinji; Murata, Toshiki; Sato, Kenjiro published an article in 2021. The article was titled 《Discovery of a novel series of indolinylpyrimidine-based GPR119 agonists: Elimination of ether-a-go-go-related gene liability using a hydrogen bond acceptor-focused approach》, and you may find the article in Bioorganic & Medicinal Chemistry.Product Details of 1193-21-1 The information in the text is summarized as follows:
We previously identified a novel series of indolinylpyrimidine derivatives exemplified by 2 in Figure 1, which is an indoline based derivative, as potent GPR119 agonists. Despite the attractive potency of 2, this compound inhibited the human ether-a-go-go-related gene (hERG) K+ channel. We elucidated crucial roles of the methylsulfonyl group of 2 in its interaction with the hERG channel and the GPR119 receptor, presumably as a hydrogen bond acceptor (HBA). To remove the undesirable hERG inhibitory activity, a strategy was implemented to arrange an HBA on a less conformationally flexible framework at the indoline 5-position instead of the methylsulfonyl group. This successfully led to the discovery of a piperidinone ring as a desirable motif at the indoline 5-position, which could minimize hERG liability as shown by 24b. Further optimization focused on the reduction of lipophilicity in terms of more favorable drug-like properties. Consequently, the introduction of a hydroxy group at the 3-position of the piperidinone ring effectively reduced lipophilicity without compromising GPR119 potency, resulting in the identification of (3S)-3-hydroxy-1-{1-[6-({1-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}oxy)pyrimidin-4-yl]- 2,3-dihydro-1H-indol-5-yl}piperidin-2-one ((S)-29) as a novel, potent, and orally bioavailable GPR119 agonist with a well-balanced profile. The pharmacol. effects of this compound were also confirmed after single and chronic oral administration in diabetic animal models. In the experiment, the researchers used 4,6-Dichloropyrimidine(cas: 1193-21-1Product Details of 1193-21-1)
4,6-Dichloropyrimidine(cas: 1193-21-1) is a member of organic chlorides. Organic chloride content in crude oil can be detected through specialized laboratory analysis. Care and attention are essential while sampling and testing.Product Details of 1193-21-1
Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia