SSR182289A, a selective and potent orally active thrombin inhibitor (original) (raw)
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Technical Scale Synthesis of a New and Highly Potent Thrombin Inhibitor
Synthesis, 2004
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 ®).
Bioorganic & Medicinal Chemistry Letters, 1998
We describe the in vitro evaluation and crystallographic analysis of a new class of potent and selective, non-aminoacid-based, small-molecule thrombin inhibitors, exemplified by 14. This class of achiral inhibitors lacks an amide-based backbone, exhibits nM inhibition of thrombin, and is selective for thrombin. Compound 14 does not interact with the active-site catalytic apparatus and is anchored to the enzyme via a single network of hydrogen bonds to Asp189 of the S 1 pocket. 0
Protein Science, 2008
The crystal structures of two new thrombin inhibitors, P498 and P500, complexed with human α-thrombin have been determined at 2.0 Å resolution and refined to crystallographic R-factors of 0.170 and 0.169, respectively. These compounds, with picomolar binding constants, belong to a family of potent bifunctional inhibitors that bind thrombin at two remote sites: the active site and the fibrinogen recognition exosite (FRE). The inhibitors incorporate a nonsubstrate type active site binding fragment: Dansyl-Arg-(D)Pipecolic acid (Dns-Arg-(D)Pip), reminiscent of the active-site directed inhibitors MD-805 and MQPA, rendering them resistant to thrombin-induced hydrolysis. The FRE binding fragment of these inhibitors corresponds to the hirudin55–65 sequence. They differ in the chemical nature of the nonpeptidyl linker bridging these two functional activities. In both cases, the active site binding fragment is well defined in the electron density. The DnsH1, ArgH2, and (D)PipH3 groups occupy the S3, S1, and S2 subsites of thrombin, respectively, in a way similar to that observed in the thrombin-MQPA complexes. Binding in the active site of thrombin is characterized by numerous van der Waals contacts and ring-ring system interactions. Unlike in the substrate-like inhibitors, ArgH2 enters the S1 specificity pocket from the P2 position and adopts a bent conformation to make an hydrogen bond to the carboxylate of Asp189. In this noncanonical position, its carbonyl points away from the oxyanion hole, which is now occupied by well-ordered solvent molecules. The linkers fit in the groove extending from the active site to the FRE. The C-terminal fragments of both inhibitors bind in the same way as analogous FRE binding elements in previously described complexes.
Structure of a novel thrombin inhibitor with an uncharged d-amino acid as P1 residue
European Journal of Medicinal Chemistry, 2008
Thrombin, the ultimate proteinase of the coagulation cascade, is an attractive target for the treatment of a variety of cardiovascular diseases. Previously, a series of novel thrombin inhibitors, discovered by employing a powerful and new computer-assisted multiparameter optimization process (CADDIS Ò ), have been synthesized. We have now crystallized the complex of human a-thrombin with the most potent of these inhibitors, 8-5 (K i ¼ 3 nM), and have determined its 2.3 Å X-ray crystal structure. The Fourier map displayed clear electron density for the inhibitor. The central part of the inhibitor binds in an improved melagatran-like mode, while the structure identifies a D-tyrosine as P1 residue which forms a charged hydrogen bond with Asp 189 of thrombin. This is the first crystal structure of a thrombineinhibitor complex, where an uncharged inhibitor residue makes hydrogen bonds within the thrombin S1 pocket. Additionally, novel favourable intermolecular hydrogen bonds of the inhibitor with the thrombin backbone become possible due to the D-configuration of the P1 residue. Two flanking voluminous side chains increase the strength of the subjacent hydrogen bonding system by shielding it from the bulk solvent. Ó 2007 Published by Elsevier Masson SAS.
European Journal of Medicinal Chemistry, 1998
Thrombin plays a central role in thrombosis. Because of the medical need for novel antithrombotic drugs, a search for structurally novel thrombin inhibitors was undertaken. In the absence of a crystal structure, a class was designed based on a modeling approach which involved placing the essential functional groups of the thrombin antagonist MD-805 [1] (Argatroban) into the benzodiazepine nucleus. The best superposition was obtained with a 1,4-benzodiazepin-2-one containing a 1,2,3,4-tetrahydro quinolylsulfonyl moiety in the 3-position, a guanidino-phenyl at the 5-position, and Nt-substituted with an acetic acid. Synthesis of these molecules provided compounds with an inhibitory activity with K, in the range of 40-1000 11M. A report on the crystal structure of thrombin*hirudin(55-65)*MD-805 complex [2] suggested subsequent molecular modeling investigations to rationalize the pharmacological results. © Elsevier, Paris thrombin inhibitors I molecular modeling I Argatroban I benzodiazepinones
Rational Design and Characterization of D-Phe-Pro-D-Arg-Derived Direct Thrombin Inhibitors
PLOS One, 2012
The tremendous social and economic impact of thrombotic disorders, together with the considerable risks associated to the currently available therapies, prompt for the development of more efficient and safer anticoagulants. Novel peptide-based thrombin inhibitors were identified using in silico structure-based design and further validated in vitro. The best candidate compounds contained both L-and D-amino acids, with the general sequence D-Phe(P3)-Pro(P2)-D-Arg(P1)-P19-CONH 2 . The P19 position was scanned with L-and D-isomers of natural or unnatural amino acids, covering the major chemical classes. The most potent non-covalent and proteolysis-resistant inhibitors contain small hydrophobic or polar amino acids (Gly, Ala, Ser, Cys, Thr) at the P19 position. The lead tetrapeptide, D-Phe-Pro-D-Arg-D-Thr-CONH 2 , competitively inhibits a-thrombin's cleavage of the S2238 chromogenic substrate with a K i of 0.92 mM. In order to understand the molecular details of their inhibitory action, the three-dimensional structure of three peptides (with P19 L-isoleucine (fPrI), L-cysteine (fPrC) or Dthreonine (fPrt)) in complex with human a-thrombin were determined by X-ray crystallography. All the inhibitors bind in a substrate-like orientation to the active site of the enzyme. The contacts established between the D-Arg residue in position P1 and thrombin are similar to those observed for the L-isomer in other substrates and inhibitors. However, fPrC and fPrt disrupt the active site His57-Ser195 hydrogen bond, while the combination of a P1 D-Arg and a bulkier P19 residue in fPrI induce an unfavorable geometry for the nucleophilic attack of the scissile bond by the catalytic serine. The experimental models explain the observed relative potency of the inhibitors, as well as their stability to proteolysis. Moreover, the newly identified direct thrombin inhibitors provide a novel pharmacophore platform for developing antithrombotic agents by exploring the conformational constrains imposed by the D-stereochemistry of the residues at positions P1 and P19.