发现具有中性P1基团的强效、有效且口服生物可利用的凝血因子Xa抑制剂。
Discovery of potent, efficacious, and orally bioavailable inhibitors of blood coagulation factor Xa with neutral P1 moieties.
作者信息
Pinto Donald J P, Galemmo Robert A, Quan Mimi L, Orwat Michael J, Clark Charles, Li Renhua, Wells Brian, Woerner Francis, Alexander Richard S, Rossi Karen A, Smallwood Angela, Wong Pancras C, Luettgen Joseph M, Rendina Alan R, Knabb Robert M, He Kan, Wexler Ruth R, Lam Patrick Y S
机构信息
Discovery Chemistry Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
出版信息
Bioorg Med Chem Lett. 2006 Nov 1;16(21):5584-9. doi: 10.1016/j.bmcl.2006.08.027. Epub 2006 Sep 11.
The bicyclic dihydropyrazolopyridinone scaffold allowed for incorporation of multiple P1 moieties with subnanomolar binding affinities for blood coagulation factor Xa. The compound 3-[6-(2'-dimethylaminomethyl-biphenyl-4-yl)-7-oxo-3-trifluoro-methyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridine-l-yl]-benzamide 6d shows good fXa potency, selectivity, in vivo efficacy and oral bioavailability. Compound 6d was selected for further pre-clinical evaluations.
双环二氢吡唑并吡啶酮骨架能够引入多个对凝血因子Xa具有亚纳摩尔结合亲和力的P1部分。化合物3-[6-(2'-二甲基氨基甲基-联苯-4-基)-7-氧代-3-三氟甲基-4,5,6,7-四氢-吡唑并[3,4-c]吡啶-1-基]-苯甲酰胺6d显示出良好的凝血因子Xa活性、选择性、体内疗效和口服生物利用度。选择化合物6d进行进一步的临床前评估。
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