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Richard C A Isaacs,
Christina L Newton,
Kellie J Cutrona,
Swati P Mercer,
Bruce D Dorsey,
Colleen M McDonough,
Jacquelynn J Cook, Julie A Krueger,
S Dale Lewis,
Bobby J Lucas,
Elizabeth A Lyle,
Joseph J Lynch,
Cynthia Miller-Stein,
Maria T Michener,
Audrey A Wallace,
Rebecca B White,
Bradley K Wong
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ABSTRACT: 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.
Bioorganic & medicinal chemistry letters 03/2011; 21(5):1532-5. · 2.65 Impact Factor
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Richard C A Isaacs,
Christina L Newton,
Kellie J Cutrona,
Swati P Mercer,
Linda S Payne,
Kenneth J Stauffer,
Peter D Williams,
Jacquelynn J Cook, Julie A Krueger,
S Dale Lewis,
Bobby J Lucas,
Elizabeth A Lyle,
Joseph J Lynch,
Daniel R McMasters,
Adel M Naylor-Olsen,
Maria T Michener,
Audrey A Wallace
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ABSTRACT: 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.
Bioorganic & medicinal chemistry letters 03/2011; 21(5):1536-40. · 2.65 Impact Factor
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Mark J Evans,
Paige E Mahaney,
Lisa Borges-Marcucci,
KehDih Lai,
Shuguang Wang, Julie A Krueger,
Stephen J Gardell,
Christine Huard,
Robert Martinez,
George P Vlasuk,
Douglas C Harnish
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ABSTRACT: The nuclear hormone receptor farnesoid X receptor (FXR) plays a critical role in the regulation of bile acid, triglyceride (TG), and cholesterol homeostasis. WAY-362450 (FXR-450/XL335) is a potent synthetic FXR agonist as characterized in luciferase reporter assays and in mediating FXR target gene regulation in primary human and immortalized mouse hepatocytes. In vivo, WAY-362450 dose dependently decreased serum TG levels after 7 days of oral dosing in western diet-fed low-density lipoprotein receptor-/- mice and in the diabetic mouse strains KK-Ay and db/db comparable to that achieved with the peroxisome proliferator activated receptor-alpha agonist, fenofibrate. WAY-362450 treatment also reduced serum cholesterol levels via reductions in LDLc, VLDLc, and HDLc lipoprotein fractions that were not accompanied by hepatic cholesterol accumulation. This cholesterol lowering was dependent on FXR as demonstrated in a hypothyroid-induced hypercholesterolemia setting in FXR-/- mice. In fructose-fed models, WAY-362450 also decreased TG and VLDLc levels in rats and hamsters but significantly increased HDLc levels in rats while reducing HDLc levels in hamsters. The differential effect of WAY-362450 on HDLc is likely due to a murine-specific induction of endothelial lipase and scavenger receptor-BI that does not occur in rats. These studies demonstrate a consistent ability of WAY-362450 to lower both serum TG and cholesterol levels and suggest that synthetic FXR agonists may have clinical utility in the treatment of mixed dyslipidemia.
AJP Gastrointestinal and Liver Physiology 02/2009; 296(3):G543-52. · 3.43 Impact Factor
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ABSTRACT: The role of farnesoid X receptor (FXR) in the development of atherosclerosis has been unclear. Here, LDL receptor (LDLR(-/-)) or apolipoprotein E (apoE(-/-)) female or male mice were fed a Western diet and treated with a potent synthetic FXR agonist, WAY-362450. Activation of FXR blocked diet-induced hypertriglyceridemia and elevations of non-HDL cholesterol and produced a near complete inhibition of aortic lesion formation. WAY-362450 also induced small heterodimer partner (SHP) expression and repressed cholesterol 7alpha-hydroxylase (CYP7A1) and sterol 12 alpha-hydroxylase (CYP8B1) expression. To determine if SHP was essential for these protective activities, LDLR(-/-)SHP(-/-) and apoE(-/-)SHP(-/-) mice were similarly treated with WAY-362450. Surprisingly, a notable sex difference was observed in these mice. In male LDLR(-/-)SHP(-/-) or apoE(-/-)SHP(-/-) mice, WAY-362450 still repressed CYP7A1 and CYP8B1 expression by 10-fold and still strongly reduced non-HDL cholesterol levels and aortic lesion area. In contrast, in the female LDLR(-/-)SHP(-/-) or apoE(-/-)SHP(-/-) mice, WAY-362450 only slightly repressed CYP7A1 and CYP8B1 expression and did not reduce non-HDL cholesterol or aortic lesion size. WAY-362450 inhibition of hypertriglyceridemia remained intact in LDLR(-/-) or apoE(-/-) mice lacking SHP of both sexes. These results suggest that activation of FXR protects against atherosclerosis in the mouse, and this protective effect correlates with repression of bile acid synthetic genes, with mechanistic differences between male and female mice.
The Journal of Lipid Research 02/2009; 50(6):1090-100. · 5.56 Impact Factor
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Eric I Rossman,
Kun Liu,
Gwen A Morgan,
Robert E Swillo, Julie A Krueger,
Stephen J Gardell,
John Butera,
Matthew Gruver,
Joel Kantrowitz,
Hal S Feldman,
Jørgen S Petersen,
Ketil Haugan,
James K Hennan
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ABSTRACT: Gap junction uncoupling can alter conduction pathways and promote cardiac re-entry mechanisms that potentiate many supraventricular arrhythmias, such as atrial fibrillation (AF) and atrial flutter (AFL). Our objective was to determine whether GAP-134 [(2S,4R)-1-(2-aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic acid], a small dipeptide gap junction modifier, can improve conduction and ultimately prevent AF/AFL. In rat atrial strips subjected to metabolic stress, GAP-134 prevented significantly conduction velocity slowing at 10 nM compared with vehicle (p < 0.01). In the canine sterile pericarditis model, conduction time (CT; n = 5), atrial effective refractory period (AERP; n = 3), and AF/AFL duration/inducibility (n = 16) were measured 2 to 3 days postoperatively in conscious dogs. CT was significantly faster after GAP-134 infusion (average plasma concentration, 250 nM) at cycle lengths of 300 ms (66.2 +/- 1.0 versus 62.0 +/- 1.0 ms; p < 0.001) and 200 ms (64.4 +/- 0.9 versus 61.0 +/- 1.3 ms; p < 0.001). No significant changes in AERP were noted after GAP-134 infusion. The mean number of AF/AFL inductions per animal was significantly decreased after GAP-134 infusion (2.7 +/- 0.6 versus 1.6 +/- 0.8; p < 0.01), with total AF/AFL burden being decreased from 12,280 to 6063 s. Western blot experiments showed no change in connexin 43 expression. At concentrations exceeding those described in the AF/AFL experiments, GAP-134 had no effect on heart rate, blood pressure, or any electrocardiogram parameters. In conclusion, GAP-134 shows consistent efficacy on measures of conduction and AF/AFL inducibility in the canine sterile pericarditis model. These findings, along with its oral bioavailability, underscore its potential antiarrhythmic efficacy.
Journal of Pharmacology and Experimental Therapeutics 02/2009; 329(3):1127-33. · 3.83 Impact Factor
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Richard C A Isaacs,
Mark G Solinsky,
Kellie J Cutrona,
Christina L Newton,
Adel M Naylor-Olsen,
Daniel R McMasters, Julie A Krueger,
S Dale Lewis,
Bobby J Lucas,
Lawrence C Kuo,
Youwei Yan,
J J Lynch,
E A Lyle
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ABSTRACT: 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.
Bioorganic & medicinal chemistry letters 04/2008; 18(6):2062-6. · 2.65 Impact Factor
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ABSTRACT: PAI-749 is a potent and selective synthetic antagonist of plasminogen activator inhibitor 1 (PAI-1) that preserved tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) activities in the presence of PAI-1 (IC(50) values, 157 and 87 nM, respectively). The fluorescence (Fl) of fluorophore-tagged PAI-1 (PAI-NBD119) was quenched by PAI-749; the apparent K(d) (254 nM) was similar to the IC(50) (140 nM) for PAI-NBD119 inactivation. PAI-749 analogs displayed the same potency rank order for neutralizing PAI-1 activity and perturbing PAI-NBD119 Fl; hence, binding of PAI-749 to PAI-1 and inactivation of PAI-1 activity are tightly linked. Exposure of PAI-1 to PAI-749 for 5 min (sufficient for full inactivation) followed by PAI-749 sequestration with Tween 80 micelles yielded active PAI-1; thus, PAI-749 did not irreversibly inactivate PAI-1, a known metastable protein. Treatment of PAI-1 with a PAI-749 homolog (producing less assay interference) blocked the ability of PAI-1 to displace p-aminobenzamidine from the uPA active site. Consistent with this observation, PAI-749 abolished formation of the SDS-stable tPA/PAI-1 complex. PAI-749-mediated neutralization of PAI-1 was associated with induction of PAI-1 polymerization as assessed by native gel electrophoresis. PAI-749 did not turn PAI-1 into a substrate for tPA; however, PAI-749 promoted plasmin-mediated degradation of PAI-1. In conclusion, PAI-1 inactivation by PAI-749 using purified components can result from a dual mechanism of action. First, PAI-749 binds directly to PAI-1, blocks PAI-1 from accessing the active site of tPA, and abrogates formation of the SDS-stable tPA/PAI-1 complex. Second, binding of PAI-749 to PAI-1 renders PAI-1 vulnerable to plasmin-mediated proteolytic degradation.
Molecular Pharmacology 11/2007; 72(4):897-906. · 4.88 Impact Factor
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Donnette D Staas,
Kelly L Savage,
Vanessa L Sherman,
Heidi L Shimp,
Terry A Lyle,
Lekhanh O Tran,
Catherine M Wiscount,
Daniel R McMasters,
Philip E J Sanderson,
Peter D Williams,
Bobby J Lucas, Julie A Krueger,
S Dale Lewis,
Rebecca B White,
Sean Yu,
Bradley K Wong,
Christopher J Kochansky,
M Reza Anari,
Youwei Yan,
Joseph P Vacca
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ABSTRACT: 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).
Bioorganic & Medicinal Chemistry 11/2006; 14(20):6900-16. · 2.92 Impact Factor
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Michael R Wood,
Kathy M Schirripa,
June J Kim,
Bang-Lin Wan,
Kathy L Murphy,
Richard W Ransom,
Raymond S L Chang,
Cuyue Tang,
Thomayant Prueksaritanont,
Theodore J Detwiler,
Lisa A Hettrick,
Elizabeth R Landis,
Yvonne M Leonard, Julie A Krueger,
Sidney D Lewis,
Douglas J Pettibone,
Roger M Freidinger,
Mark G Bock
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ABSTRACT: Antagonism of the bradykinin B1 receptor represents a potential treatment for chronic pain and inflammation. Novel antagonists were designed that display low-nanomolar affinity for the human bradykinin B1 receptor and good bioavailability in the rat.
Journal of Medicinal Chemistry 03/2006; 49(4):1231-4. · 5.25 Impact Factor
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ABSTRACT: 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.
Bioorganic & Medicinal Chemistry Letters 02/2006; 16(2):338-42. · 2.55 Impact Factor
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James Z Deng,
Daniel R McMasters,
Philippe M A Rabbat,
Peter D Williams,
Craig A Coburn,
Youwei Yan,
Lawrence C Kuo,
S Dale Lewis,
Bobby J Lucas, Julie A Krueger,
Berta Strulovici,
Joseph P Vacca,
Terry A Lyle,
Christopher S Burgey
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ABSTRACT: 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.
Bioorganic & Medicinal Chemistry Letters 11/2005; 15(20):4411-6. · 2.55 Impact Factor
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Philippe G Nantermet,
Christopher S Burgey,
Kyle A Robinson,
Janetta M Pellicore,
Christina L Newton,
James Z Deng,
Harold G Selnick,
S Dale Lewis,
Bobby J Lucas, Julie A Krueger, [......],
Daniel R McMasters,
Audrey A Wallace,
Joseph J Lynch,
Youwei Yan,
Zhongguo Chen,
Lawrence Kuo,
Stephen J Gardell,
Jules A Shafer,
Joseph P Vacca,
Terry A Lyle
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ABSTRACT: 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).
Bioorganic & Medicinal Chemistry Letters 07/2005; 15(11):2771-5. · 2.55 Impact Factor
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Kenneth J Stauffer,
Peter D Williams,
Harold G Selnick,
Philippe G Nantermet,
Christina L Newton,
Carl F Homnick,
Matthew M Zrada,
S Dale Lewis,
Bobby J Lucas, Julie A Krueger, [......],
Bradley Wong,
Audrey A Wallace,
Gary R Sitko,
Jacquelyn J Cook,
Marie A Holahan,
Maria Stranieri-Michener,
Yvonne M Leonard,
Joseph J Lynch,
Daniel R McMasters,
Youwei Yan
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ABSTRACT: 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.
Journal of Medicinal Chemistry 05/2005; 48(7):2282-93. · 5.25 Impact Factor
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Matthew M Morrissette,
Kenneth J Stauffer,
Peter D Williams,
Terry A Lyle,
Joseph P Vacca, Julie A Krueger,
S Dale Lewis,
Bobby J Lucas,
Bradley K Wong,
Rebecca B White,
Cynthia Miller-Stein,
Elizabeth A Lyle,
Audrey A Wallace,
Yvonne M Leonard,
Denise C Welsh,
Joseph J Lynch,
Daniel R McMasters
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ABSTRACT: 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.
Bioorganic & Medicinal Chemistry Letters 09/2004; 14(16):4161-4. · 2.55 Impact Factor
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Mary Beth Young,
James C Barrow,
Kristen L Glass,
George F Lundell,
Christina L Newton,
Janetta M Pellicore,
Kenneth E Rittle,
Harold G Selnick,
Kenneth J Stauffer,
Joseph P Vacca, [......],
S Dale Lewis,
Bobby J Lucas,
Daniel R McMasters,
Cynthia Miller-Stein,
Beth L Pietrak,
Audrey A Wallace,
Rebecca B White,
Bradley Wong,
Youwei Yan,
Philippe G Nantermet
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ABSTRACT: 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.
Journal of Medicinal Chemistry 07/2004; 47(12):2995-3008. · 5.25 Impact Factor
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Kenneth E Rittle,
James C Barrow,
Kellie J Cutrona,
Kristen L Glass, Julie A Krueger,
Lawrence C Kuo,
S Dale Lewis,
Bobby J Lucas,
Daniel R McMasters,
Matthew M Morrissette,
Philippe G Nantermet,
Christina L Newton,
William M Sanders,
Youwei Yan,
Joseph P Vacca,
Harold G Selnick
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ABSTRACT: 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.
Bioorganic & Medicinal Chemistry Letters 11/2003; 13(20):3477-82. · 2.55 Impact Factor
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Philippe G Nantermet,
James C Barrow,
Christina L Newton,
Janetta M Pellicore,
MaryBeth Young,
S Dale Lewis,
Bobby J Lucas, Julie A Krueger,
Daniel R McMasters,
Youwei Yan,
Lawrence C Kuo,
Joseph P Vacca,
Harold G Selnick
[show abstract]
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ABSTRACT: 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.
Bioorganic & Medicinal Chemistry Letters 09/2003; 13(16):2781-4. · 2.55 Impact Factor
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Christopher S Burgey,
Kyle A Robinson,
Terry A Lyle,
Philippe G Nantermet,
Harold G Selnick,
Richard C A Isaacs,
S Dale Lewis,
Bobby J Lucas, Julie A Krueger,
Rominder Singh, [......],
Franklin C Clayton,
Dennis Bohn,
Denise C Welsh,
Joseph J Lynch,
Youwei Yan,
Zhongguo Chen,
Lawrence Kuo,
Stephen J Gardell,
Jules A Shafer,
Joseph P Vacca
[show abstract]
[hide abstract]
ABSTRACT: 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.
Bioorganic & Medicinal Chemistry Letters 05/2003; 13(7):1353-7. · 2.55 Impact Factor
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Philip E J Sanderson,
Kellie J Cutrona,
Kelly L Savage,
Adel M Naylor-Olsen,
Denise J Bickel,
Dennis L Bohn,
Franklin C Clayton, Julie A Krueger,
S Dale Lewis,
Bobby J Lucas,
Elizabeth A Lyle,
Audrey A Wallace,
Denice C Welsh,
Youwei Yan
[show abstract]
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ABSTRACT: 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.
Bioorganic & Medicinal Chemistry Letters 05/2003; 13(8):1441-4. · 2.55 Impact Factor
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Philip E J Sanderson,
Matthew G Stanton,
Bruce D Dorsey,
Terry A Lyle,
Colleen McDonough,
William M Sanders,
Kelly L Savage,
Adel M Naylor-Olsen, Julie A Krueger,
S Dale Lewis,
Bobby J Lucas,
Joseph J Lynch,
Youwei Yan
[show abstract]
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ABSTRACT: 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.
Bioorganic & Medicinal Chemistry Letters 04/2003; 13(5):795-8. · 2.55 Impact Factor
