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. (15th March 2021)

• Record Type: Journal Article
• Authors: Kamaura, Masahiro; Kubo, Osamu; Sugimoto, Hiromichi; Noguchi, Naoyoshi; Miyashita, Hirohisa; Abe, Shinichi; Matsuda, Kae; Tsujihata, Yoshiyuki; Odani, Tomoyuki; Iwasaki, Shinji; Murata, Toshiki; Sato, Kenjiro
• Is Part Of: Bioorganic & medicinal chemistry. Volume 34(2021)
• Publication Date: 2021-03-15
• Subjects: GPR119 agonist -- GPCR -- Type 2 diabetes mellitus -- Indolinylpyrimidine -- hERG -- Hydrogen bond acceptor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2021.116034
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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 (3 S )-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-1 H -indol-5-yl}piperidin-2-one (( S )-29) as a novel, potent, and orally bioavailable GPR119 agonist with a well-balanced profile. The pharmacological effects of this compound were also confirmed after single and chronic oral administration in diabetic animal models.