79875-40-4Relevant academic research and scientific papers
Discovery of a Parenteral Small Molecule Coagulation Factor XIa Inhibitor Clinical Candidate (BMS-962212)
Pinto, Donald J. P.,Orwat, Michael J.,Smith, Leon M.,Quan, Mimi L.,Lam, Patrick Y. S.,Rossi, Karen A.,Apedo, Atsu,Bozarth, Jeffrey M.,Wu, Yiming,Zheng, Joanna J.,Xin, Baomin,Toussaint, Nathalie,Stetsko, Paul,Gudmundsson, Olafur,Maxwell, Brad,Crain, Earl J.,Wong, Pancras C.,Lou, Zhen,Harper, Timothy W.,Chacko, Silvi A.,Myers, Joseph E.,Sheriff, Steven,Zhang, Huiping,Hou, Xiaoping,Mathur, Arvind,Seiffert, Dietmar A.,Wexler, Ruth R.,Luettgen, Joseph M.,Ewing, William R.
supporting information, p. 9703 - 9723 (2017/12/26)
Factor XIa (FXIa) is a blood coagulation enzyme that is involved in the amplification of thrombin generation. Mounting evidence suggests that direct inhibition of FXIa can block pathologic thrombus formation while preserving normal hemostasis. Preclinical studies using a variety of approaches to reduce FXIa activity, including direct inhibitors of FXIa, have demonstrated good antithrombotic efficacy without increasing bleeding. On the basis of this potential, we targeted our efforts at identifying potent inhibitors of FXIa with a focus on discovering an acute antithrombotic agent for use in a hospital setting. Herein we describe the discovery of a potent FXIa clinical candidate, 55 (FXIa Ki = 0.7 nM), with excellent preclinical efficacy in thrombosis models and aqueous solubility suitable for intravenous administration. BMS-962212 is a reversible, direct, and highly selective small molecule inhibitor of FXIa.
Application of sequential Cu(I)/Pd(0)-catalysis to solution-phase parallel synthesis of combinatorial libraries of dihydroindeno[1,2-c]isoquinolines
Kumar, Sarvesh,Painter, Thomas O.,Pal, Benoy K.,Neuenswander, Benjamin,Malinakova, Helena C.
body text, p. 466 - 477 (2011/11/06)
Parallel solution-phase synthesis of combinatorial libraries of dihydroindenoisoquinolines employing a sequential Cu(I)/Pd(0)-catalyzed multicomponent coupling and annulation protocol was realized. The scope and limitations of the protocol with respect to the substitution pattern in the aryl ring of the indene core, as well as the N-substituent have been defined, revealing that the methodology is compatible with a wide-range of aliphatic linear, branched, and ester functionalized N-substituents. Unexpectedly, the formation of regioisomers featuring a 1,2,3-contiguous substitution pattern in the aromatic ring of the indene core was observed. Three distinct combinatorial libraries with a total of 111 of members were synthesized, and 80 highly substituted dihydroindenoisoquinolines structurally related to known medicinal agents including some consisting of mixtures of two regioisomers were made available for biological activity testing.
