Bioorganic and Medicinal Chemistry Letters p. 5925 - 5932 (2010)
Update date:2022-08-04
Topics:
Morriello, Gregori J.
Chicchi, Gary
Johnson, Tricia
Mills, Sander G.
Demartino, Julie
Kurtz, Marc
Tsao
Zheng, Song
Tong, Xinchun
Carlson, Emma
Townson, Karen
Wheeldon, Alan
Boyce, Susan
Collinson, Neil
Rupniak, Nadia
Devita, Robert J.
Previously, we had disclosed a novel class of hNK1 antagonists based on the 5,5-fused pyrrolidine core. These compounds displayed subnanomolar hNK1 affinity along with good efficacy in a gerbil foot-tapping (GFT) model, but unfortunately they had low to moderate functional antagonist (IP-1) activity. To elaborate on the SAR of this class of hNK1 compounds and to improve functional activity, we have designed and synthesized a new class of hNK1 antagonist with a third fused ring. Compared to the 5,5-fused pyrrolidine class, these 5,5,5-fused tricyclic hNK1 antagonists maintain subnanomolar hNK1 binding affinity with highly improved functional IP-1 activity (<10% SP remaining). A fused tricyclic methyl, hydroxyl geminally substituted pyrrolizinone (compound 20) had excellent functional IP (<2% SP remaining), hNK1 binding affinity, off-target selectivity, pharmacokinetic profile and in vivo activity. Complete inhibition of agonist activity was observed at both 0 and 24 h in the gerbil foot-tapping model with an ID50 of 0.02 mpk at both 0 and 24 h, respectively.
View MoreShenyang Xinyihan Chemical Technology Co., Ltd.
Contact:+86-18525026267
Address:362, aigongbeijei street 23 , tiexi district,Shenyang, Liaoning, China
Nanjing Samwon International Limited
Contact:+86-25-84873444
Address:1108, BLDG B, New Century Plaza, No 1, South Taiping Rd.,
Contact:+44 (0)161 367 9441
Address:
website:http://www.simagchem.com
Contact:+86-592-2680277
Address:21/F Hualong Office Building,No.6 Hubin East Road, Xiamen,China
Contact:86-551-63540590
Address:No 1388 Furong Rd., Hefei, Anhui, China
Doi:10.1021/acs.orglett.6b02008
(2016)Doi:10.1021/jm00167a025
(1990)Doi:10.1021/ol102323k
(2010)Doi:10.1002/jhet.1706
(2013)Doi:10.1016/j.bmc.2011.10.074
(2012)Doi:10.1007/BF00764622
(1989)