Discovery of novel hydroxy pyrazole based factor IXa inhibitor

Investigation on the binding mode of benzothiophene analogues as potent factor IXa (FIXa) inhibitors in thrombosis by CoMFA, docking and molecular dynamic studies

“…These H-bonds at the P1 position could be found in all these benzothiophene analogues, which may be one classical characteristics for almost all FIXa inhibitors (including not only the benzothiophene-based ones) with an amidine tail in the P1 position. This investigation is consistent with the previous reports 1,11,12 and the X-ray result (PDB ID: 3LC5), and recent studies have demonstrated that in the absence of the amidine, for any of the serine proteases, they are completely lack of potency due to the loss of key interactions with Asp189 in the S1 pocket 8 . In P4 region, two big blue-coloured regions exist suggesting the possibility of increasing the potency by an introduction of electropositive substituent at the region.…”

“…This is in agreement with our docking result that the residues Gln192, Cys191 on the left and Trp215, Gly216 on the right, just as two walls, clamp the benzothiophene core and, in this way, produce strong hydrophobic interactions among them. This might be one of the reasons why the researchers tend to select this kind of rigid template as the core structure 1,[8][9][10] . A small yellow-coloured contour in the middle of the two walls (P2) suggests that the group with a big bulk in this position is disfavoured.…”

“…Consequently, at the initiation stage of the cascade, the upstream inhibition of FIXa would represent a wonderful method for the development of anticoagulants with good selectivity and safety. Recently, several classes of compounds, such as 5-amidinoindoles 1 , pyrazole analogues 8,9 , 5-amidinobenzo[b]thiophenes 10 , benzothiophenes 11,12 and so on, have been reported as FIXa inhibitors. Among them, the benzothiophenes, designed on the basis of FIXa X-ray crystallography, illustrate high potential and selectivity for FIXa.…”

A review of recent progress (2002-2012) on the biological activities of pyrazoles

“…[35][36][37] Amongst these compounds, the most interesting is 29 (MK-0354) which has been the subject of many studies and structural modifications. [38][39][40] A compound for the treatment of ischemic stroke, 31 (a potent pan-JNK inhibitor) 41 and an inhibitor of coagulation to treat thromboembolic disorders 32 (inhibitor of factors IXa and XIa) 42 have been reported. Compound 33 that increases testosterone levels in male rats is a LHR (Gonadotropin luteinizing hormone) agonist.…”

Development of a novel class of potent and selective FIXa inhibitors

“…4 Previously, we have reported our early hit-to-lead efforts leading to an acyclic lead class of FIXa inhibitors with moderate potency and selectivity over FXa (compound 1). Herein, we continue the discussion on further SAR studies covering the acyclic series, leading to potent and selective FIXa inhibitors which achieved oral bioavailability in PK studies and demonstrated efficacy in PD assay.…”