(N-acyl-N-alkyl)glycyl borolysine analogs: A new class of potent thrombin inhibitors

Galemmo, Robert A.; Fevig, John M.; Carini, David J.; Cacciola, Joseph; Wells, Brian L.; Hillyer, Gregory L.; Buriak, Joseph; Rossi, Karen A.; Stouten, Pieter F. W.; Alexander, Richard; Hilmer, Richard; Bostrom, Lori L.; Abelman, Matthew M.; Lee, Sheng-Lian; Weber, Patricia C; Kettner, Charles A.; Knabb, Robert M.; Wexler, Ruth R.

doi:10.1016/s0960-894x(96)00525-2

Cited by 14 publications

(4 citation statements)

References 9 publications

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“…1, Table 1; Galemmo et al, 1996). The crystal structure of HPBK complexed with thrombin, described here, shows that the phenethyl ring of HPBK forms an edge-to-face interaction with the Trp215 side chain.…”

Section: Introductionmentioning

confidence: 73%

“…Having observed a speci®c edge-to-face interaction in the thrombin±HPBK complex, a strategy to modulate its strength was tested by the synthesis of four HPBK analogs (Galemmo et al, 1996). Crystallographic and kinetic analyses of these compounds binding to -thrombin show that the edge-to-face interaction can be weakly modulated by through-ring inductive effects.…”

Section: Discussionmentioning

confidence: 99%

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Biochemical and Crystallographic Characterization of Homologous Non-peptidic Thrombin Inhibitors Having Alternate Binding Modes

Strickland¹,

Fevig

Galemmo

et al. 1998

Acta Crystallogr D Biol Cryst

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The X-ray crystallographic structure of [N-(3-phenylpropionyl)-N-(phenethyl)]-Gly-boroLys-OH (HPBK, K i = 0.42 nM, crystallographic R factor to 1.8 A Ê resolution, 19.6%) complexed with human -thrombin shows that the boron adopts a tetrahedral geometry and is covalently bonded to the active serine, Ser195. The HPBK phenethyl aromatic ring forms an edge-to-face interaction with the indole side chain of Trp215. Four HPBK analogs containing either electron-withdrawing or electron-donating substitutents at the 3 H position of the phenethyl ring were synthesized in an attempt to modulate ligand af®nity by inductive stabilization of the edge-to-face interaction. Re®ned crystallographic structures of the tri¯uoromethyl (K i = 0.37 nM, crystallographic R factor to 2.0 A Ê resolution = 18.7%),¯uoro (K i = 0.60; R factor to 2.3 A Ê resolution = 18.4%), methoxy (K i = 0.91 nM, R factor to 2.2 A Ê resolution = 19.8%) and methyl (K i = 0.20 nM, R factor to 2.5 A Ê resolution = 16.9%) HPBK analogs complexed with thrombin revealed two binding modes for the closely related compounds. A less than 1.5-fold variation in af®nity was observed for analogs (tri¯uoromethyl-HPBK and¯uoro-HPBK) binding with the edge-to-face interaction. The slight inductive modulation is consistent with the overall weak nature of the edge-to-face interaction. Owing to an unexpected rotation of the phenethyl aromatic ring, the 3 H substituent of two analogs, methoxy-HPBK and methyl-HPBK, made direct contact with the Trp215 indole side chain. Increased af®nity of the 3 H methyl analog is attributed to favorable interactions between the methyl group and the Trp215 indole ring. Differences in inhibitor, thrombin and solvent structure are discussed in detail. These results demonstrate the subtle interplay of weak forces that determine the equilibrium binding orientation of inhibitor, solvent and protein.

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Section: Introductionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Biochemical and Crystallographic Characterization of Homologous Non-peptidic Thrombin Inhibitors Having Alternate Binding Modes

Strickland¹,

Fevig

Galemmo

et al. 1998

Acta Crystallogr D Biol Cryst

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View full text Add to dashboard Cite

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“…Determination of Inhibition Constants. The thrombin assay conditions are described in Jetten et al Human thrombin was used, and inhibition constants were calculated from plots using nine different inhibitor concentrations and always at least in duplicate . Assays for factor Xa, factor VIIa/TF, trypsin, protein C, tPA, plasmin, etc.…”

Section: Methodsmentioning

confidence: 99%

“…Starting points for the present series of compounds were peptidic structures 1 and 2 (see Scheme ) next to earlier work on D-Phe-Pro-Arg aldehydes and boronic acids and work on other serine protease inhibitors , Although very potent in vitro, no oral bioavailability has ever been reported or found for 1 and 2 .…”

Section: Introductionmentioning

confidence: 99%

Unique Overlap in the Prerequisites for Thrombin Inhibition and Oral Bioavailability Resulting in Potent Oral Antithrombotics

Adang¹,

Man²,

Vogel³

et al. 2002

J. Med. Chem.

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Despite intense research over the last 10 years, aided by the availability of X-ray structures of enzyme-inhibitor complexes, only very few truly orally active thrombin inhibitors have been found. We conducted a comprehensive study starting with peptide transition state analogues (TSA). Both hydrophobic nonpeptide analogues as well as hydrophilic peptidic analogues were synthesized. The bioavailability in rats and dogs could be drastically altered depending on the overall charge distribution in the molecule. Compound 27, a tripeptide TSA inhibitor of thrombin, showed an oral bioavailability of 32% in rats and 71% in dogs, elimination half-lives being 58 and 108 min, respectively. The thrombin inhibition constant of compound 27 was 1.1 nM, and in an in vivo arterial flow model, the ED(50) was 5.4 nmol/kg.min, comparable to known non-TSA inhibitors. A molecular design was found that combines antithrombotic efficiency with oral bioavailability at low dosages.

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ChemInform Abstract: (N‐Acyl‐N‐alkyl)glycyl Borolysine Analogues: A New Class of Potent Thrombin Inhibitors.

et al. 1997

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Various new title compounds, e.g. (V) and (VI) are synthesized using the procedure described in the scheme and proved for their thrombin inhibitory activity. The borolysine (VIb) is found to be a good orally active inhibitor (no yields given). -(GALEMMO, R. A. JUN.; FEVIG, J. M.; CARINI, D. J.; CACCIOLA, J.; WELLS, B. L.; HILLYER, G. L.; BURIAK, J. JUN.; ROSSI, K. A.; STOUTEN, P. F. W.; ALEXANDER, R. S.; HILMER, R.; BOSTROM, L.; ABELMAN, M. M.; LEE, S.-L.; WEBER, P. C.; KETTNER, C. A.; KNABB, R. M.; WEXLER, R. R.; Bioorg. Med.

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(N-acyl-N-alkyl)glycyl borolysine analogs: A new class of potent thrombin inhibitors

Cited by 14 publications

References 9 publications

Biochemical and Crystallographic Characterization of Homologous Non-peptidic Thrombin Inhibitors Having Alternate Binding Modes

Biochemical and Crystallographic Characterization of Homologous Non-peptidic Thrombin Inhibitors Having Alternate Binding Modes

Unique Overlap in the Prerequisites for Thrombin Inhibition and Oral Bioavailability Resulting in Potent Oral Antithrombotics

ChemInform Abstract: (N‐Acyl‐N‐alkyl)glycyl Borolysine Analogues: A New Class of Potent Thrombin Inhibitors.

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