53135-24-3Relevant articles and documents
Discovery of a Pyrimidinedione Derivative as a Potent and Orally Bioavailable Axl Inhibitor
Zhang, Hefeng,Peng, Xia,Dai, Yang,Shao, Jingwei,Ji, Yinchun,Sun, Yiming,Liu, Bo,Cheng, Xu,Ai, Jing,Duan, Wenhu
supporting information, p. 3956 - 3975 (2021/04/12)
The receptor tyrosine kinase Axl plays important roles in promoting cancer progression, metastasis, and drug resistance and has been identified as a promising target for anticancer therapeutics. We used molecular modeling-assisted structural optimization starting with the low micromolar potency compound 9 to discover compound 13c, a highly potent and orally bioavailable Axl inhibitor. Selectivity profiling showed that 13c could inhibit the well-known oncogenic kinase Met with equal potency to its inhibition of Axl superfamily kinases. Compound 13c significantly inhibited cellular Axl and Met signaling, suppressed Axl- and Met-driven cell proliferation, and restrained Gas6/Axl-mediated cancer cell migration or invasion. Furthermore, 13c exhibited significant antitumor efficacy in Axl-driven and Met-driven tumor xenograft models, causing tumor stasis or regression at well-tolerated doses. All these favorable data make 13c a promising therapeutic candidate for cancer treatment.
PHARMACEUTICAL CONSISTING OF CYCLIC AMINOMETHYL PYRIMIDINE DERIVATIVE
-
Paragraph 0224; 0225, (2016/10/10)
PROBLEM TO BE SOLVED: To provide a cyclic aminomethyl pyrimidine derivative and a pharmaceutically acceptable salt thereof exhibiting effects on dopamine D4 receptor with high selectivity and useful as a treatment agent of central nervous system diseases such as attention deficit hyperkinesis disorder. SOLUTION: There is provide a compound represented by the formula (1) and a pharmaceutically acceptable salt thereof. (1), where n and m are each independently 1 or 2, Ra is a C1-6 alkyl group, a C3-6 cycloalkyl group or an amino group, Rb is H, a C1-6 alkyl group or an alkyl group-substituted/unsubstituted amino group, Rb is H when Ra is the amino group, Rc1 and Rc2 are each independently H or a C1-6 alkyl group, Rd1 and Rd2 are each independently H, F or a C1-6 alkyl group, a ring Q is substituted/unsubstituted 5- to 10-membered nitrogen-containing heteroaryl group and bond containing break lines is a single bond or a double bond. SELECTED DRAWING: None COPYRIGHT: (C)2016,JPOandINPIT
Structure-based design of a new series of N-(piperidin-3-yl)pyrimidine-5-carboxamides as renin inhibitors
Imaeda, Yasuhiro,Tawada, Michiko,Suzuki, Shinkichi,Tomimoto, Masaki,Kondo, Mitsuyo,Tarui, Naoki,Sanada, Tsukasa,Kanagawa, Ray,Snell, Gyorgy,Behnke, Craig A.,Kubo, Keiji,Kuroita, Takanobu
, p. 5771 - 5780 (2016/10/30)
The action of the aspartyl protease renin is the rate-limiting initial step of the renin-angiotensin-aldosterone system. Therefore, renin is a particularly promising target for blood pressure as well as onset and progression of cardiovascular and renal diseases. New pyrimidine derivatives 5–14 were designed in an attempt to enhance the renin inhibitory activity of compound 3 identified by our previous fragment-based drug design approach. Introduction of a basic amine essential for interaction with the two aspartic acids in the catalytic site and optimization of the S1/S3 binding elements including an induced-fit structural change of Leu114 (‘Leu-in’ to ‘Leu-out’) by a rational structure-based drug design approach led to the discovery of N-(piperidin-3-yl)pyrimidine-5-carboxamide 14, a 65,000-fold more potent renin inhibitor than compound 3. Surprisingly, this remarkable enhancement in the inhibitory activity of compound 14 has been achieved by the overall addition of only seven heavy atoms to compound 3. Compound 14 demonstrated excellent selectivity over other aspartyl proteases and moderate oral bioavailability in rats.
