Design, synthesis and discovery of 1-(2-(6-Chloro-3-methylsulfonyl)-naphthyl)-1H-pyrazole-5-carboxylamides as highly potent factor Xa inhibitors.
Based upon the biphenyl 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides reported in our previous communications, we designed and discovered 2-(6-chloro-3-methylsulfonyl)-naphthyl as an optimal factor Xa S1 binding element. Employing a key Diels-Alder reaction of 1,4-dihydro-2,3-benzoxathiin-3-oxide with maleic anhydride and a key Cu(I)-mediated methylsulfonylation, we prepared two biphenyl 1-(2-(6-chloro-3-methylsulfonyl)-naphthyl)-1H-pyrazole-5-carboxylamides as highly potent factor Xa inhibitors with K(i) values of 0.065 nM and 0.045 nM respectively, and demonstrated the synergistically enhanced binding interaction in the factor Xa S1 site.
Jia
Zhaozhong Jon
ZJ
Portola Pharmaceuticals, Inc, USA. zjia@portola.com
Scarborough
Robert Murry
RM
Zhang
Penglie
P
Halfon
Sherin
S
Arfsten
Ann Elizabeth
AE
Sinha
Uma
U
Zhu
Bing-Yan
BY
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D015195:Drug Design; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D011485:Protein Binding; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000577:Amides; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors; D015951:Factor Xa