Pinto Donald J P, Orwat Michael J, Quan Mimi L, Han Qi, Galemmo Robert A, Amparo Eugene, Wells Brian, Ellis Christopher, He Ming Y, Alexander Richard S, Rossi Karen A, Smallwood Angela, Wong Pancras C, Luettgen Joseph M, Rendina Alan R, Knabb Robert M, Mersinger Lawrence, Kettner Charles, Bai Steven, He Kan, Wexler Ruth R, Lam Patrick Y S
Discovery Chemistry Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
Bioorg Med Chem Lett. 2006 Aug 1;16(15):4141-7. doi: 10.1016/j.bmcl.2006.02.069. Epub 2006 May 30.
Attempts to further optimize the pyrazole factor Xa inhibitors centered on masking the aryl aniline P4 moiety. Scaffold optimization resulted in the identification of a novel bicyclic pyrazolo-pyridinone scaffold which retained fXa potency. The novel bicyclic scaffold preserved all binding interactions observed with the monocyclic counterpart and importantly the carboxamido moiety was integrated within the scaffold making it less susceptible to hydrolysis. These efforts led to the identification of 1-[3-aminobenzisoxazol-5'-yl]-3-trifluoromethyl-6-[2'-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1']-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one 6f (BMS-740808), a highly potent (fXa Ki=30 pM) with a rapid onset of inhibition (2.7x10(7) M-1 s-1) in vitro, selective (>1000-fold over other proteases), efficacious in the AVShunt thrombosis model, and orally bioavailable inhibitor of blood coagulation factor Xa.
进一步优化吡唑类凝血因子Xa抑制剂的尝试主要集中在对芳基苯胺P4部分进行掩蔽。骨架优化导致鉴定出一种新型双环吡唑并吡啶酮骨架，其保留了凝血因子Xa活性。这种新型双环骨架保留了与单环对应物观察到的所有结合相互作用，重要的是，羧酰胺部分整合在骨架内，使其不易水解。这些努力促成了1-[3-氨基苯并异恶唑-5'-基]-3-三氟甲基-6-[2'-(3-(R)-羟基-N-吡咯烷基)甲基-[1,1']-联苯-4-基]-1,4,5,6-四氢吡唑并-[3,4-c]-吡啶-7-酮6f（BMS-740808）的鉴定，它是一种高效的（凝血因子Xa Ki = 30 pM）体外抑制作用起效迅速（2.7×10(7) M-1 s-1）、具有选择性（对其他蛋白酶的选择性大于1000倍）、在动静脉分流血栓形成模型中有效的且口服生物利用度良好的凝血因子Xa抑制剂。
