title: Design, synthesis and discovery of 1-(2-(6-Chloro-3-methylsulfonyl)-naphthyl)-1H-pyrazole-5-carboxylamides as highly potent factor Xa inhibitors.
abstract: 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.
authors.affiliation: Portola Pharmaceuticals, Inc, USA. zjia@portola.com
authors.forename: Zhaozhong Jon
authors.initials: ZJ
authors.lastname: Jia
authors.forename: Robert Murry
authors.initials: RM
authors.lastname: Scarborough
authors.forename: Penglie
authors.initials: P
authors.lastname: Zhang
authors.forename: Sherin
authors.initials: S
authors.lastname: Halfon
authors.forename: Ann Elizabeth
authors.initials: AE
authors.lastname: Arfsten
authors.forename: Uma
authors.initials: U
authors.lastname: Sinha
authors.forename: Bing-Yan
authors.initials: BY
authors.lastname: Zhu
mesh_terms: 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
chemical_list: D000577:Amides; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors; D015951:Factor Xa