- Orally active thrombin inhibitors. Part 1: Optimization of the P1-moiety
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The synthesis and SAR of novel nanomolar thrombin inhibitors with the common backbone HOOC-CH2-d-cyclohexylalanyl-3,4-dehydroprolyl-NH-CH 2-aryl-C(double bond, long NH)NH2 are described together with their ecarin clotting
- Mack, Helmut,Baucke, Dorit,Hornberger, Wilfried,Lange, Udo E.W.,Seitz, Werner,Hoeffken, H. Wolfgang
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p. 2641 - 2647
(2008/12/21)
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- Orally active thrombin inhibitors. Part 2: Optimization of the P2-moiety
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Synthesis and SAR of orally active thrombin inhibitors of the d-Phe-Pro-Arg type with focus on the P2-moiety are described. The unexpected increase in in vitro potency, oral bioavailability, and in vivo activity of inhibitors with dehydroproline as P2-isostere is discussed. Over a period of 24 h the antithrombin activity of the most active inhibitors with IC50s in the nanomolar range was determined in dogs demonstrating high thrombin inhibitory activity in plasma and an appropriate duration of action after oral administration.
- Lange, Udo E.W.,Baucke, Dorit,Hornberger, Wilfried,Mack, Helmut,Seitz, Werner,Hoeffken, H. Wolfgang
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p. 2648 - 2653
(2008/12/20)
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- Technical scale synthesis of a new and highly potent thrombin inhibitor
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In this account, we describe the development of an efficient and convergent process for the peptidomimetic thrombin inhibitor 1 on production plant scale. Starting from nicotinonitrile (13), (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2- pyrrolidinecarboxylic acid (5) and (2R)-2-amino-3-cyclohexylpropanoic acid (29) compound 1 was obtained in 16 chemical steps. New methods had been developed for the preparation of the key intermediate dehydroproline 22 and the transformation of nitriles into amidines. The thrombin inhibitor 1 was isolated by special techniques (nanofiltration and spray drying). Almost all salts of 1 are amorphous, however, a crystalline complex was obtained with 1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Saccharin).
- Bernard, Harald,Buelow, Gerd,Lange, Udo E. W.,Mack, Helmut,Pfeiffer, Thomas,Schaefer, Bernd,Seitz, Werner,Zierke, Thomas
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p. 2367 - 2375
(2007/10/03)
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