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1.
Bioorg Med Chem Lett ; 21(5): 1532-5, 2011 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-21295466

RESUMEN

Although the S3 pocket of the thrombin active site is lined with lipophilic amino acid residues, the accommodation of polarity within the lipophilic P3 moiety of small molecule inhibitors is possible provided that the polar functionality is capable of pointing away from the binding pocket outwards toward solvent while simultaneously allowing the lipophilic portion of the P3 ligand to interact with the S3 amino acid residues. Manipulation of this motif provided the means to effect optimization of functional potency, in vivo antithrombotic efficacy and oral bioavailability in a series of 3-aminopyrazinone thrombin inhibitors which contained non-charged groups at the P1 position.


Asunto(s)
Anticoagulantes/síntesis química , Trastornos de la Coagulación Sanguínea/tratamiento farmacológico , Diseño de Fármacos , Pirazinas/síntesis química , Trombina/antagonistas & inhibidores , Administración Oral , Animales , Anticoagulantes/química , Anticoagulantes/farmacología , Sitios de Unión , Disponibilidad Biológica , Perros , Estructura Molecular , Pirazinas/química , Pirazinas/farmacología , Ratas , Relación Estructura-Actividad
2.
Bioorg Med Chem Lett ; 21(5): 1536-40, 2011 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-21295467

RESUMEN

A novel 1,3,5-trisubstituted benzamide thrombin inhibitor template was designed via hybridization of a known aminopyridinoneacetamide and a known 1,3,5-trisubstituted phenyl ether. Optimization of this lead afforded a novel potent series of biaryl 1,3,5-trisubstituted benzenes with excellent functional anticoagulant potency.


Asunto(s)
Antitrombinas/síntesis química , Benceno/síntesis química , Diseño de Fármacos , Trombina/antagonistas & inhibidores , Antitrombinas/química , Antitrombinas/farmacología , Benceno/química , Benceno/farmacología , Humanos , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad
3.
Bioorg Med Chem Lett ; 18(6): 2062-6, 2008 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-18291642

RESUMEN

Guided by X-ray crystallography of thrombin-inhibitor complexes and molecular modeling, alkylation of the N1 nitrogen of the imidazole P1 ligand of the pyridinoneacetamide thrombin inhibitor 1 with various acetamide moieties furnished inhibitors with significantly improved thrombin potency, trypsin selectivity, functional in vitro anticoagulant potency and in vivo antithrombotic efficacy. In the pyrazinoneacetamide series, oral bioavailability was also improved.


Asunto(s)
Anticoagulantes/farmacología , Antitrombinas/farmacología , Diseño de Fármacos , Imidazoles/síntesis química , Imidazoles/farmacología , Trombina/antagonistas & inhibidores , Administración Oral , Animales , Anticoagulantes/síntesis química , Anticoagulantes/química , Anticoagulantes/farmacocinética , Antitrombinas/síntesis química , Antitrombinas/química , Antitrombinas/farmacocinética , Disponibilidad Biológica , Cloruros , Cristalografía por Rayos X , Perros , Compuestos Férricos/farmacología , Imidazoles/química , Imidazoles/farmacocinética , Macaca mulatta , Modelos Moleculares , Estructura Molecular , Tiempo de Tromboplastina Parcial , Ratas , Relación Estructura-Actividad , Trombina/química , Trombina/metabolismo , Tripsina/metabolismo
4.
Bioorg Med Chem ; 14(20): 6900-16, 2006 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-16870455

RESUMEN

Previous reports from our laboratories described potent tripeptide thrombin inhibitors which incorporate heterocycle-substituted chlorophenyl groups in the P1 position. Using these as lead compounds for further optimization, we identified sites of metabolism and designed analogs with 4-fluoroproline in P2 and cyclopropane-containing side chains in P3 as an approach to reducing metabolism and improving their oral pharmacokinetic performance. The large (300-fold) difference in potency between analogs containing (4R)- and (4S)-4-fluoroproline was rationalized by analyzing inhibitor-enzyme interactions in crystal structures of related compounds and by molecular modeling which indicated that the more potent (4R)-4-fluoroproline isomer stabilizes a proline ring conformation that is preferred for binding to the enzyme. An optimal compound from this work, 41, exhibits high potency in a coagulation assay in human plasma (2xAPTT=190 nM), excellent selectivity versus the digestive enzyme trypsin (K(i)=3300 nM), and excellent oral bioavailability in dogs with moderate clearance (F=100%, CL=12 mL/min/kg).


Asunto(s)
Inhibidores Enzimáticos/farmacología , Prolina/análogos & derivados , Trombina/antagonistas & inhibidores , Sitios de Unión , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Técnicas In Vitro , Modelos Moleculares , Conformación Molecular , Prolina/química , Conformación Proteica , Estructura Terciaria de Proteína , Estereoisomerismo , Relación Estructura-Actividad , Trombina/metabolismo , Tripsina/efectos de los fármacos , Tripsina/metabolismo
5.
Bioorg Med Chem Lett ; 16(2): 338-42, 2006 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-16257203

RESUMEN

Despite their relatively weak basicity, simple azoles, specifically imidazoles and aminothiazoles, can function as potent surrogates for the more basic amines (e.g., alkyl amines, amidines, guanidines, etc.) which are most often employed as the P1 ligand in the design of noncovalent small molecule inhibitors of thrombin.


Asunto(s)
Azoles/farmacología , Inhibidores Enzimáticos/farmacología , Trombina/antagonistas & inhibidores , Azoles/química , Diseño de Fármacos , Ligandos , Estructura Molecular , Relación Estructura-Actividad , Tripsina/efectos de los fármacos
6.
Bioorg Med Chem Lett ; 15(20): 4411-6, 2005 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-16137886

RESUMEN

Thrombin-inhibitor X-ray crystal structures, in combination with the installation of binding elements optimized within the pyrazinone series of thrombin inhibitors, were utilized to transform a weak triazolopyrimidine lead into a series of potent oxazolopyridines. A modification intended to attenuate plasma protein binding (i.e., conversion of the P3 pyridine to a piperidine) conferred significant factor Xa activity to this series. Ultimately, these dual thrombin/factor Xa inhibitors demonstrated excellent in vitro and in vivo anticoagulant efficacy.


Asunto(s)
Antitrombinas/química , Antitrombinas/farmacología , Inhibidores del Factor Xa , Piridinas/química , Piridinas/farmacología , Cristalografía por Rayos X , Modelos Moleculares , Estructura Molecular
7.
Bioorg Med Chem Lett ; 15(11): 2771-5, 2005 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-15911253

RESUMEN

In this study, we have demonstrated that the critical hydrogen bonding motif of the established 3-aminopyrazinone thrombin inhibitors can be effectively mimicked by a 2-aminopyridine N-oxide. As this peptidomimetic core is more resistant toward oxidative metabolism, it also overcomes the metabolic liability associated with the pyrazinones. An optimization study of the P(1) benzylamide delivered the potent thrombin inhibitor 21 (K(i) = 3.2 nM, 2xaPTT = 360 nM), which exhibited good plasma levels and half-life after oral dosing in the dog (C(max) = 2.6 microM, t(1/2) = 4.5 h).


Asunto(s)
Antitrombinas/química , Pirimidinas/química , Enlace de Hidrógeno , Modelos Moleculares , Imitación Molecular
8.
J Med Chem ; 48(7): 2282-93, 2005 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-15801822

RESUMEN

Optimization of a previously reported thrombin inhibitor, 9-hydroxy-9-fluorenylcarbonyl-l-prolyl-trans-4-aminocyclohexylmethylamide (1), by replacing the aminocyclohexyl P1 group provided a new lead structure, 9-hydroxy-9-fluorenylcarbonyl-l-prolyl-2-aminomethyl-5-chlorobenzylamide (2), with improved potency (K(i) = 0.49 nM for human thrombin, 2x APTT = 0.37 microM in human plasma) and pharmacokinetic properties (F = 39%, iv T(1/2) = 13 h in dogs). An effective strategy for reducing plasma protein binding of 2 and improving efficacy in an in vivo thrombosis model in rats was to replace the lipophilic fluorenyl group in P3 with an azafluorenyl group. Systematic investigation of all possible azafluorenyl P3 isomers and azafluorenyl-N-oxide analogues of 2 led to the identification of an optimal compound, 3-aza-9-hydroxyfluoren-9(R)-ylcarbonyl-l-prolyl-2-aminomethyl-5-chlorobenzylamide (19b), with high potency (K(i) = 0.40 nM, 2x APTT = 0.18 microM), excellent pharmacokinetic properties (F = 55%, T(1/2) = 14 h in dogs), and complete efficacy in the in vivo thrombosis model in rats (inhibition of FeCl(3)-induced vessel occlusions in six of six rats receiving an intravenous infusion of 10 microg/kg/min of 19b). The stereochemistry of the azafluorenyl group in 19b was determined by X-ray crystallographic analysis of its N-oxide derivative (23b) bound in the active site of human thrombin.


Asunto(s)
Fluorenos/síntesis química , Prolina/análogos & derivados , Prolina/síntesis química , Trombina/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Proteínas Sanguíneas/metabolismo , Cristalografía por Rayos X , Perros , Fluorenos/química , Fluorenos/farmacología , Semivida , Humanos , Técnicas In Vitro , Macaca mulatta , Masculino , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Prolina/química , Prolina/farmacología , Unión Proteica , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad
9.
Bioorg Med Chem Lett ; 14(16): 4161-4, 2004 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-15261262

RESUMEN

Modification of lead compound 1 by reducing lipophilicity in the P3 group produced a series of low molecular weight thrombin inhibitors with excellent potency in functional assays, metabolic stability, and oral bioavailability. These modifications led to the identification of two optimized compounds, 14 and 16.


Asunto(s)
Antitrombinas/farmacología , Administración Oral , Antitrombinas/administración & dosificación , Antitrombinas/farmacocinética , Disponibilidad Biológica , Estabilidad de Medicamentos , Peso Molecular
10.
J Med Chem ; 47(12): 2995-3008, 2004 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-15163182

RESUMEN

In an effort to discover potent, clinically useful thrombin inhibitors, a rapid analogue synthetic approach was used to explore the P(1) region. Various benzylamines were coupled to a pyridine/pyrazinone P(2)-P(3) template. One compound with an o-thiadiazole benzylic substitution was found to have a thrombin K(i) of 0.84 nM. A study of ortho-substituted five-membered-ring heterocycles was undertaken and subsequently demonstrated that the o-triazole and tetrazole rings were optimal. Combination of these potent P(1) aryl heterocycles with a variety of P(2)-P(3) groups produced a compound with an extraordinary thrombin inhibitory activity of 1.4 pM. It is hoped that this potency enhancement in P(1) will allow for more diversification in the P(2)-P(3) region to ultimately address additional pharmacological concerns.


Asunto(s)
Compuestos Heterocíclicos/síntesis química , Trombina/antagonistas & inhibidores , Bencilaminas/síntesis química , Bencilaminas/química , Sitios de Unión , Compuestos Heterocíclicos/química , Modelos Moleculares , Pirazinas/síntesis química , Pirazinas/química , Piridinas/síntesis química , Piridinas/química , Relación Estructura-Actividad , Tetrazoles/síntesis química , Tetrazoles/química , Tiadiazoles/síntesis química , Tiadiazoles/química , Trombina/química , Triazoles/síntesis química , Triazoles/química
11.
Bioorg Med Chem Lett ; 13(20): 3477-82, 2003 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-14505652

RESUMEN

Thrombin inhibitors incorporating o-aminoalkylbenzylamides in the P1 position were designed, synthesized and found to have enhanced potency and selectivity in several different structural classes. X-ray crystallographic analysis of compound 24 bound in the alpha-thrombin-hirugen complex provides an explanation for these unanticipated results.


Asunto(s)
Amidas/química , Antitrombinas/farmacología , Antitrombinas/química , Cristalografía por Rayos X , Estructura Molecular
12.
Bioorg Med Chem Lett ; 13(16): 2781-4, 2003 Aug 18.
Artículo en Inglés | MEDLINE | ID: mdl-12873514

RESUMEN

A series of potent and selective proline- and pyrazinone-based macrocyclic thrombin inhibitors is described. Detailed SAR studies led to the incorporation of specific functional groups in the tether that enhanced functional activity against thrombin and provided exquisite selectivity against trypsin and tPA. X-ray crystallography and molecular modeling studies revealed the inhibitor-enzyme interactions responsible for this selectivity.


Asunto(s)
Antitrombinas/síntesis química , Antitrombinas/farmacología , Sitios de Unión , Cristalografía por Rayos X , Diseño de Fármacos , Modelos Moleculares , Prolina/química , Pirazinas/química , Relación Estructura-Actividad , Trombina/química , Tripsina/química
13.
Bioorg Med Chem Lett ; 13(8): 1441-4, 2003 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-12668008

RESUMEN

We describe a series of highly potent and efficacious thrombin inhibitors based on a 3-amino-4-sulfonylpyridinone acetamide template. The functionally dense sulfonyl group stabilizes the aminopyridinone, conformationally constrains the 4-substituent, and forms a hydrogen bond to the insertion loop tyrosine OH. We also describe a related series of fused bicyclic dihydrothiadiazinedioxide derivatives, of which one had improved pharmacokinetics in dogs after oral dosing.


Asunto(s)
Acetamidas/química , Acetamidas/farmacología , Piridonas/química , Piridonas/farmacología , Tiadiazinas/química , Tiadiazinas/farmacología , Trombina/antagonistas & inhibidores , Acetamidas/farmacocinética , Administración Oral , Animales , Modelos Animales de Enfermedad , Perros , Compuestos Férricos/toxicidad , Humanos , Modelos Moleculares , Piridonas/farmacocinética , Ratas , Relación Estructura-Actividad , Sulfonas/química , Sulfonas/farmacocinética , Sulfonas/farmacología , Tiadiazinas/farmacocinética , Trombosis/inducido químicamente , Inhibidores de Tripsina/química , Inhibidores de Tripsina/farmacocinética , Inhibidores de Tripsina/farmacología
14.
Bioorg Med Chem Lett ; 13(5): 795-8, 2003 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-12617893

RESUMEN

Starting from a 2-amino-6-methylpyridine P1 group and following a strategy of enlarging it whilst reducing its polarity, we have developed a series of potent, moderately basic azaindoles which are intrinsically much more selective for thrombin versus trypsin. Certain pyrazinone acetamide azaindole derivatives have pharmacokinetic parameters after oral administration to dogs, or efficacy in vitro, comparable to an optimized pyrazinone acetamide 2-amino-6-methylpyridine derivative.


Asunto(s)
Compuestos Aza/química , Compuestos Aza/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Indoles/química , Indoles/farmacología , Trombina/antagonistas & inhibidores , Administración Oral , Animales , Compuestos Aza/farmacocinética , Perros , Inhibidores Enzimáticos/farmacocinética , Humanos , Indoles/farmacocinética , Modelos Moleculares , Tiempo de Tromboplastina Parcial , Piridinas/química , Piridinas/farmacología , Relación Estructura-Actividad , Especificidad por Sustrato , Trombina/metabolismo , Tripsina/metabolismo
15.
Bioorg Med Chem Lett ; 13(7): 1353-7, 2003 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-12657281

RESUMEN

In this manuscript we demonstrate that a modification principally directed toward the improvement of the aqueous solubility (i.e., introduction a P3 pyridine N-oxide) of the previous lead compound afforded a new series of potent orally bioavailable P1 N-benzylamide thrombin inhibitors. An expedited investigation of the P1 SAR with respect to oral bioavailability, plasma half-life, and human liver microsome stability revealed 5 as the best candidate for advanced evaluation.


Asunto(s)
Acetamidas/síntesis química , Acetamidas/farmacología , Pirazinas/síntesis química , Pirazinas/farmacología , Piridinas/química , Trombina/antagonistas & inhibidores , Animales , Disponibilidad Biológica , Fenómenos Químicos , Química Física , Cristalografía por Rayos X , Perros , Semivida , Humanos , Técnicas In Vitro , Inyecciones Intravenosas , Macaca mulatta , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Óxidos/química , Ratas , Solubilidad , Relación Estructura-Actividad , Trombosis/inducido químicamente , Trombosis/tratamiento farmacológico
16.
J Med Chem ; 46(4): 461-73, 2003 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-12570369

RESUMEN

Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.


Asunto(s)
Acetamidas/farmacocinética , Anticoagulantes/farmacocinética , Inhibidores de Proteasas/síntesis química , Pirazinas/farmacocinética , Piridinas/farmacocinética , Trombina/antagonistas & inhibidores , Acetamidas/síntesis química , Acetamidas/farmacología , Administración Oral , Animales , Anticoagulantes/síntesis química , Anticoagulantes/farmacología , Disponibilidad Biológica , Cristalografía por Rayos X , Perros , Macaca mulatta , Modelos Moleculares , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Pirazinas/síntesis química , Pirazinas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Relación Estructura-Actividad
17.
Bioorg Med Chem Lett ; 13(2): 161-4, 2003 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-12482415

RESUMEN

Use of a chlorophenoxyacetamide P1 group with a pyridinone acetamide P2/P3 gave an exceptionally potent thrombin inhibitor (K(i)=40 pM). Truncation of the molecule at the N-terminus gave unique, low nanomolar, non-covalent thrombin inhibitors which do not have a group to fill thrombin's 'distal binding pocket'. A co-crystal structure indicates the importance of an intramolecular hydrogen bond between the P1 side chain and P1/P2 amide link in this series.


Asunto(s)
Acetamidas/síntesis química , Acetamidas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Piridonas/síntesis química , Piridonas/farmacología , Trombina/antagonistas & inhibidores , Sitios de Unión , Cristalización , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Conformación Molecular , Trombina/química
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