78277-21-1Relevant articles and documents
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
Kamaura, Masahiro,Kubo, Osamu,Sugimoto, Hiromichi,Noguchi, Naoyoshi,Miyashita, Hirohisa,Abe, Shinichi,Matsuda, Kae,Tsujihata, Yoshiyuki,Odani, Tomoyuki,Iwasaki, Shinji,Murata, Toshiki,Sato, Kenjiro
, (2021/02/09)
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 pharmacological effects of this compound were also confirmed after single and chronic oral administration in diabetic animal models.
Zr(IV)-Fe(III), -Ga(III), and -Sn(IV) binary metal complexes as synergistic and reusable esterification catalysts
Sato, Atsushi,Nakamura, Yuka,Maki, Toshikatsu,Ishihara, Kazuaki,Yamamoto, Hisashi
, p. 1337 - 1340 (2007/10/03)
Synergism in catalytic activity with the combined use of Hf(O-i-Pr) 4 or Zr(O-i-Pr)4 and Fe(O-i-Pr)3 for direct esterification and a very simple method for their extraction with ionic liquids for their recovery and reuse are described. This Zr(IV)-Fe(III) complex is an environmentally benign catalyst due to its high turnover number, extremely mild Lewis acidity, low toxicity, reusability, and commercial availability at low cost.
A scalable chemoenzymatic preparation of (R)-tetrahydrofuran-2-carboxylic acid
Fujima, Yoshito,Hirayama, Yoshihiro,Ikunaka, Masaya,Nishimoto, Yukifumi
, p. 1385 - 1391 (2007/10/03)
To develop a practical scalable approach to (R)-tetrahydrofuran-2-carboxylic acid (THFC) 1, a chiral building block for furopenem 2, enantioselective hydrolysis of its esters is explored: When ethyl (±)-tetrahydrofuran-2-carboxylate 3d (2 M, 288 g/L) is digested by an Aspergillus melleus protease {0.2% (w/v)} in a 1.5 M potassium phosphate buffer (pH 8) for 20 h, enantioselective hydrolysis proceeds with E=60 to give (R)-THFC 1 in 94.4% ee. On separation from the left-over antipodal ester (S)-3d by partition, (R)-THFC 1 is treated with N,N-dicyclohexylamine (DCHA) in methyl ethyl ketone/methanol (5:1) to precipitate the crystalline salt 4 that contains (R)-THFC 1 of >99% ee in 22% overall yield from (±)-3d.
