Design, synthesis, and evaluation of an improved enantioselective naproxen selector

Pirkle, William H.; Welch, Christopher J.; Lamm, Bo

doi:10.1021/jo00040a026

Cited by 239 publications

(101 citation statements)

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“…Pirkle proposed a chiral recognition model for the N-DNBPG phase based on p-p interactions, dipole stacking and hydrogen bondings [46]. Several specially designed CSPs were developed making use of the reciprocal nature of chiral recognition by immobilizing the target analyte and checking several compounds as potential chiral selectors [47]. Thereby, special phases for the chiral separation of bblockers [48] or NSAIDs [49][50][51], for example, were developed.…”

Section: Direct Methodsmentioning

confidence: 99%

Chiral separation by chromatographic and electromigration techniques. A Review

Gübitz

Schmid

2001

Biopharm & Drug Disp

223

135

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This review gives a survey of different chiral separation principles and their use in high-performance liquid chromatography (HPLC), gas chromatography (GC), supercritical fluid chromatography (SFC), thin-layer chromatography (TLC), capillary electrophoresis (CE) and capillary electrochromatography (CEC) highlighting new developments and innovative techniques. The mechanisms of the different separation principles are briefly discussed and some selected applications are shown.

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Section: Direct Methodsmentioning

confidence: 99%

Chiral separation by chromatographic and electromigration techniques. A Review

Gübitz

Schmid

2001

Biopharm & Drug Disp

223

135

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“…The purity of the non-racemic sulfones was determined by high performance liquid chromatography (HPLC) on a (S,S)-Whelk-O-1 chiral stationary phase (CSP) [43] with AcOEt/hexane 1 : 1 as eluent (Fig. 10).…”

Section: Preparation Of Inhibitors With Lipophilicmentioning

confidence: 99%

Synthesis of Novel Nonpeptidic Thrombin Inhibitors

Obst¹,

Betschmann²,

Lerner³

et al. 2000

HCA

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A novel class of nonpeptidic, active, and selective thrombin inhibitors has resulted from X‐ray‐structure‐based design and subsequent improvement of the initial lead molecules. These inhibitors possess a bi‐ or tricyclic central core structure with attached side chains to reach the three binding pockets (selectivity S1 pocket, distal D pocket, and proximal P pocket) present in the active site of the enzyme. The key step in the preparation of these compounds is the 1,3‐dipolar cycloaddition between an azomethine ylide, prepared in situ by the decarboxylative method from an aromatic aldehyde and an α‐amino acid, with an N‐substituted maleimide (e.g., see Schemes 1 and 2). All potent inhibitors contain an amidinium residue in the side chain for incorporation into the S1 pocket, which was introduced in the last step of the synthesis by a Pinner reaction. The compounds were tested in biological assays for activity against thrombin and the related serine protease trypsin. The first‐generation lead compounds (±)‐11 and (±)‐19 (Scheme 1) with a bicyclic central scaffold showed Ki values for thrombin inhibition of 18 μM and 0.67 μM, respectively. Conformationally more restricted second‐generation analogs (Scheme 2) were more active ((±)‐22i: Ki=90 nM (Table 1)); yet the selectivity for thrombin over trypsin remained weak. In the third‐generation compounds, a small lipophilic side chain for incorporation into the hydrophobic P pocket was introduced (Schemes 7 and 8). Since this pocket is present in thrombin but not in trypsin, an increase in binding affinity was accompanied by an increase in selectivity for thrombin over trypsin. The most selective inhibitor (Ki=13 nM, 760‐fold selectivity for thrombin over trypsin; Table 2) was (±)‐1 with an i‐Pr group for incorporation into the P pocket. Optical resolution of (±)‐1 (Scheme 9) provided (+)‐1 with a Ki value of 7 nM and a 740‐fold selectivity, whereas (−)‐1 was 800‐fold less active (Ki=5.6 μM, 21‐fold selectivity). The absolute configuration of the stronger‐binding enantiomer was assigned based on the X‐ray crystal structure of the complex formed between thrombin and this inhibitor. Compound (+)‐1 mimics the natural thrombin substrate, fibrinogen, which binds to the enzyme with the Ph group of a phenylalanine (piperonyl in (+)‐1) in the distal D pocket, with the i‐Pr group of a valine (i‐Pr in (+)‐1) in the proximal P pocket, and with a guanidinium side chain of an arginine residue (phenylamidinium group in (+)‐1) in the selectivity S1 pocket of thrombin. A series of analogs of (±)‐1 with the phenylamidinium group replaced by aromatic and aliphatic rings bearing OH or NH2 groups (Schemes 10 – 14) were not effectively bound by thrombin. A number of X‐ray crystal‐structure analyses of free inhibitors confirmed the high degree of preorganization of these compounds in the unbound state. Since all inhibitors prefer similar modes of association with thrombin, detailed information on the strength of individual intermolecular bonding interactions and their incremental con...

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“…The complex is stabilised through additional interactions such as hydrogen bonding, dipole-dipole interactions or steric repulsion [125]. An improved chiral stationary phase synthesised by Pirkle's group possesses both dinitrobenzoyl and naphtyl moieties, allowing for simultaneous face-to-face  interactions and phase-to-edge interactions [126]. The elution order is controlled through the configuration of the CSP.…”

Section: Chiral Separation Through a Combination Of Charge Transfer mentioning

confidence: 99%