420797-67-7Relevant academic research and scientific papers
Design, parallel synthesis, and crystal structures of biphenyl antithrombotics as selective inhibitors of tissue factor FVIIa complex. Part 1: Exploration of S2 pocket pharmacophores
Kotian, Pravin L.,Krishnan, Raman,Rowland, Scott,El-Kattan, Yahya,Saini, Surendra K.,Upshaw, Ramanda,Bantia, Shanta,Arnold, Shane,Sudhakar Babu,Chand, Pooran
experimental part, p. 3934 - 3958 (2009/10/02)
Factor VIIa (FVIIa), a serine protease enzyme, coupled with tissue factor (TF) plays an important role in a number of thrombosis-related disorders. Inhibition of TF·FVIIa occurs early in the coagulation cascade and might provide some safety advantages over other related enzymes. We report here a novel series of substituted biphenyl derivatives that are highly potent and selective TF·FVIIa inhibitors. Parallel synthesis coupled with structure-based drug design allowed us to explore the S2 pocket of the enzyme active site. A number of compounds with IC50 value of 10 nM were synthesized. The X-ray crystal structures of some of these compounds complexed with TF·FVIIa were determined and results were applied to design the next round of inhibitors. All the potent inhibitors were tested for inhibition against a panel of related enzymes and selectivity of 17,600 over thrombin, 450 over trypsin, 685 over FXa, and 76 over plasmin was achieved. Two groups, vinyl 36b and 2-furan 36ab, were identified as the optimum binding substituents on the phenyl ring in the S2 pocket. Compounds with these two substituents are the most potent compounds in this series with good selectivity over related serine proteases. These compounds will be further explored for structure-activity relationship.
Potent and selective TF/FVIIa inhibitors containing a neutral P1 ligand
Miura, Masanori,Seki, Norio,Koike, Takanori,Ishihara, Tsukasa,Niimi, Tatsuya,Hirayama, Fukushi,Shigenaga, Takeshi,Sakai-Moritani, Yumiko,Kawasaki, Tomihisa,Sakamoto, Shuichi,Okada, Minoru,Ohta, Mitsuaki,Tsukamoto, Shin-ichi
, p. 7688 - 7705 (2007/10/03)
Inhibition of tissue factor/factor VIIa complex (TF/FVIIa) is an attractive strategy for antithrombotic therapies. We began with an investigation of a non-amidine TF/FVIIa inhibitor based on a modification of amidine compound 1. Optimization of the substituents on the P1 phenyl portion of the compound 1 led to a neutral or less basic alternative for the 4-amidinophenyl moiety. By further optimization of the substituents on the central phenyl ring, a highly potent and selective TF/FVIIa inhibitor 17d was discovered.
Biarylmethyl indolines, indoles and tetrahydroquinolines, useful as serine protease inhibitors
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Page 27, (2010/02/09)
The present invention provides compounds of Formula (I): or a stereoisomer or pharmaceutically acceptable salt or hydrate form thereof, wherein the variables A, B, L1, L2, X1, X2, X3, X4 an
TETRAHYDROQUINOLINE DERIVATIVES USEFUL AS SERINE PROTEASE INHIBITORS
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Page 70, (2008/06/13)
The present invention provides compounds of Formula (I) ; or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein the variables A, B, L1, L2, X1, X2, X3, X4, R4/su
