Patrick Y S Lam

Publications (34)90.77 Total impact

• Article: Discovery of diarylurea P2Y1 antagonists with improved aqueous solubility.

  Tammy C Wang, Jennifer X Qiao, Charles G Clark, Ji Jua, Laura A Price, Qimin Wu, Ming Chang, Joanna Zheng, Christine S Huang, Gerry Everlof, William A Schumacher, Pancras C Wong, Dietmar A Seiffert, Anne B Stewart, Jeffrey S Bostwick, Earl J Crain, Carol A Watson, Robert Rehfuss, Ruth R Wexler, Patrick Y S Lam
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  ABSTRACT: Preclinical data suggests that P2Y1 antagonists, such as diarylurea compound 1, may provide antithrombotic efficacy similar to P2Y12 antagonists and may have the potential of providing reduced bleeding liabilities. This manuscript describes a series of diarylureas bearing solublizing amine side chains as potent P2Y1 antagonists. Among them, compounds 2l and 3h had improved aqueous solubility and maintained antiplatelet activity compared with compound 1. Compound 2l was moderately efficacious in both rat and rabbit thrombosis models and had a moderate prolongation of bleeding time in rats similar to that of compound 1.
  Bioorganic & medicinal chemistry letters 04/2013; · 2.65 Impact Factor
• Article: Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor.

  Kan He, Joseph M Luettgen, Donglu Zhang, Bing He, James E Grace, Baomin Xin, Donald J P Pinto, Pancras C Wong, Robert M Knabb, Patrick Y S Lam, Ruth R Wexler, Scott J Grossman
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  ABSTRACT: Apixaban is a potent, highly selective, reversible, oral, direct factor Xa (fXa) inhibitor in development for thrombosis prevention and treatment. The preclinical pharmacokinetic (PK) attributes of apixaban feature small volume of distribution (Vd), low systemic clearance (CL), and good oral bioavailability. Apixaban is well absorbed in rat, dog, and chimpanzee, with absolute oral bioavailability of approximately 50% or greater. The steady-state Vd of apixaban is approximately 0.5, 0.2, and 0.17 l/kg in rats, dogs, and chimpanzees, while CL is approximately 0.9, 0.04, and 0.018 l/h/kg, respectively. In vitro metabolic clearance of apixaban is also low. Renal clearance comprises approximately 10-30% of systemic clearance in rat, dog, and chimpanzee. Anti-fXa activity, prothrombin time (PT), and HEPTEST(®) clotting time (HCT) prolongation correlated well with plasma apixaban concentration in rat, dog and chimpanzee. There was no lag time between apixaban plasma concentration and the pharmacodynamic (PD) markers, suggesting a rapid onset of action of apixaban. The PK/PD analyses were performed using an inhibitory E (max) model for anti-fXa assay and a linear model for PT and HCT assays. The IC(50) values for anti-fXa activity were 0.73 ± 0.03 and 1.5 ± 0.15 μM for rat and dog, respectively. The apparent K ( i ) values for PT were approximately 1.7, 6.6, and 4.8 μM for rat, dog and chimpanzee, respectively. The apparent K ( i ) for HCT was approximately 1.3 μM for dog. Apixaban exhibits desirable PK and PD properties for clinical development with good oral bioavailability, small Vd, low CL, and direct, predictable, concentration-dependent PD responses.
  European Journal of Drug Metabolism and Pharmacokinetics 04/2011; 36(3):129-39. · 0.36 Impact Factor
• Article: Transformation of anionically activated trifluoromethyl groups to heterocycles under mild aqueous conditions.

  Jennifer X Qiao, Tammy C Wang, Carol Hu, Jianqing Li, Ruth R Wexler, Patrick Y S Lam
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  ABSTRACT: The (hetero)aromatic trifluoromethyl group is present in many biologically active molecules and is generally considered to be chemically stable. In this paper, a convenient one-step synthesis of C-C linked aryl-heterocycles or heteroaryl-heterocycles in good to excellent yields via the reaction of anionically activated trifluoromethyl groups with amino nucleophiles containing a second NH, OH, or SH nucleophile in 1 N sodium hydroxide is reported. The method has high functional group tolerability and is potentially useful in parallel synthesis.
  Organic Letters 03/2011; 13(7):1804-7. · 5.86 Impact Factor
• Article: Highly efficacious factor Xa inhibitors containing alpha-substituted phenylcycloalkyl P4 moieties.

  Jennifer X Qiao, Sarah R King, Kan He, Pancras C Wong, Alan R Rendina, Joseph M Luettgen, Baomin Xin, Robert M Knabb, Ruth R Wexler, Patrick Y S Lam
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  ABSTRACT: We previously disclosed a series of highly potent FXa inhibitors bearing alpha-substituted (CH(2)NR(1)R(2)) phenylcyclopropyl P4 moieties in the pyrazolodihydropyridone core system. Herein, we describe our continuous SAR efforts in this series. Effects of the C-3 substitution of the pyrazolodihydropyridone core and the alpha-substitution (R group) of the cyclopropyl ring on FXa binding affinity (FXa K(i)), human plasma anticoagulant activity (PT EC(2x)) and permeability are discussed. A set of compounds obtained from optimization of the R group and the C-3 substituent were orally bioavailable in dogs. Furthermore, representative compounds were highly efficacious in the rabbit arterio-venous shunt thrombosis model (EC(50)s=29-81nM).
  Bioorganic & medicinal chemistry letters 12/2008; 19(2):462-8. · 2.65 Impact Factor
• Article: Achieving structural diversity using the perpendicular conformation of alpha-substituted phenylcyclopropanes to mimic the bioactive conformation of ortho-substituted biphenyl P4 moieties: discovery of novel, highly potent inhibitors of Factor Xa.

  Jennifer X Qiao, Daniel L Cheney, Richard S Alexander, Angela M Smallwood, Sarah R King, Kan He, Alan R Rendina, Joseph M Luettgen, Robert M Knabb, Ruth R Wexler, Patrick Y S Lam
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  ABSTRACT: Ortho-substituted biphenyl moieties are widely used in drug design. We herein report a successful use of the perpendicular conformation of the alpha-substituted phenylcyclopropyl groups to mimic the aplanar, biologically active conformation of the ortho-substituted biphenyl moieties to achieve structural diversity. This is exemplified by the design and synthesis of a series of highly potent pyrazole bicyclic-based Factor Xa (FXa) inhibitors bearing alpha-substituted phenylcyclopropyl P4 moieties. The designed perpendicular conformation was confirmed by the X-ray structure of FXa-bound compound 2r. The potential structural basis for the high FXa potency in the phenylcyclopropyl P4 analogs and their improved FXa inhibitory activities compared with the biphenyl P4 counterparts are discussed.
  Bioorganic & medicinal chemistry letters 08/2008; 18(14):4118-23. · 2.65 Impact Factor
• Article: N-in-1 dosing pharmacokinetics in drug discovery: experience, theoretical and practical considerations.

  Kan He, Mingxin Qian, Harvey Wong, Stephen A Bai, Bing He, Bernice Brogdon, James E Grace, Baomin Xin, Jingtao Wu, Shelly X Ren, [......], Steve E Unger, Joseph M Luettgen, Robert M Knabb, Donald J Pinto, Patrick Y S Lam, James Duan, Ruth R Wexler, Carl P Decicco, David D Christ, Scott J Grossman
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  ABSTRACT: N-in-1 (or cassette) dosing pharmacokinetics (PK) has been used in drug discovery for rapid assessment of PK properties of new chemical entities. However, because of potential for drug-drug interactions this procedure is still controversial. This study was to retrospectively evaluate the N-in-1 dosing approach in drug discovery with an emphasis on the potential for drug-drug interactions. The systemic clearance, volume of distribution, oral bioavailability, and renal excretion of the 31 lead compounds in rats, dogs or chimpanzees were significantly correlated between the N-in-1 dosing and discrete studies with r values of 0.69, 0.91, 0.53, and 0.83 (p < 0.005 for all), respectively. PK parameters for 11 quality control compounds which were involved in 194 N-in-1 studies for screening approximately 1000 compounds had coefficient of variations of less than 70%. The intrinsic microsomal clearances generated from the N-in-1 and discrete incubations were nearly identical (r = 0.97, p < 0.0001). The intrinsic clearances of quality control compound from the N-in-1 incubations were consistent with its discrete CL(int) estimate (cv: 5.4%). Therefore, N-in-1 dosing is a useful approach in drug discovery to quickly obtain initial PK estimates. Potential drug-drug interactions that result in confounding PK estimates do not occur as frequently as expected.
  Journal of Pharmaceutical Sciences 07/2008; 97(7):2568-80. · 3.06 Impact Factor
• Article: Structure-activity relationships of anthranilamide-based factor Xa inhibitors containing piperidinone and pyridinone P4 moieties.

  James R Corte, Tianan Fang, Donald J P Pinto, Wei Han, Zilun Hu, Xiang-Jun Jiang, Yun-Long Li, Jolicia F Gauuan, Mark Hadden, Darren Orton, Alan R Rendina, Joseph M Luettgen, Pancras C Wong, Kan He, Paul E Morin, Chong-Hwan Chang, Daniel L Cheney, Robert M Knabb, Ruth R Wexler, Patrick Y S Lam
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  ABSTRACT: Introduction of the phenyl piperidinone and phenyl pyridinone P4 moieties in the anthranilamide scaffold led to potent, selective, and orally bioavailable inhibitors of factor Xa. Anthranilamide 28 displayed comparable efficacy to apixaban in the rabbit arteriovenous-shunt (AV) thrombosis model.
  Bioorganic & medicinal chemistry letters 06/2008; 18(9):2845-9. · 2.65 Impact Factor
• Article: Sulfonamidolactam inhibitors of coagulation factor Xa.

  Joanne M Smallheer, Shuaige Wang, Mia L Laws, Suanne Nakajima, Zilun Hu, Wei Han, Irina Jacobson, Joseph M Luettgen, Karen A Rossi, Alan R Rendina, Robert M Knabb, Ruth R Wexler, Patrick Y S Lam, Mimi L Quan
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  ABSTRACT: As part of an effort to identify novel backups for previously reported pyrazole-based coagulation Factor Xa inhibitors, the pyrazole 5-carboxamide moiety was replaced by 3-(sulfonylamino)-2-piperidone. This led to the identification of a structurally diverse chemotype that was further optimized to incorporate neutral or weakly basic aryl and heteroaryl P1 groups while maintaining good potency versus Factor Xa. Substitution at the sulfonamide nitrogen provided further improvements in potency and as did introduction of alternate P4 moieties.
  Bioorganic & medicinal chemistry letters 05/2008; 18(7):2428-33. · 2.65 Impact Factor
• Article: Structure-activity relationship and pharmacokinetic profile of 5-ketopyrazole factor Xa inhibitors.

  Jeffrey G Varnes, Dean A Wacker, Donald J P Pinto, Michael J Orwat, Jay P Theroff, Brian Wells, Robert A Galemo, Joseph M Luettgen, Robert M Knabb, Steven Bai, Kan He, Patrick Y S Lam, Ruth R Wexler
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  ABSTRACT: Efforts to further optimize the clinical candidate razaxaban have led to a new series of pyrazole-based factor Xa (fXa) inhibitors. Designed to prevent the potential formation of primary aniline metabolites in vivo, the nitrogen of the carboxamido linker between the pyrazole and proximal phenyl moiety of the razaxaban scaffold was replaced with a methylene group. The resulting ketones demonstrated excellent potency and selectivity for fXa but initially had poor oral bioavailability. Optimization by conversion from a P1 aminobenzisoxazole to a P1 p-methoxyphenyl residue, replacing the 3-trifluoromethylpyrazole with a 3-amidopyrazole, and employing a pyridone P4 group provided a fXa inhibitor with a potency and pharmacokinetic profile equivalent to that of razaxaban and improved selectivity over thrombin.
  Bioorganic & medicinal chemistry letters 02/2008; 18(2):749-54. · 2.65 Impact Factor
• Article: Reductive isoxazole ring opening of the anticoagulant razaxaban is the major metabolic clearance pathway in rats and dogs.

  Donglu Zhang, Nirmala Raghavan, Shiang-Yuan Chen, Haiying Zhang, Mimi Quan, Lloyd Lecureux, Laura M Patrone, Patrick Y S Lam, Samuel J Bonacorsi, Robert M Knabb, Gary L Skiles, Kan He
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  ABSTRACT: Razaxaban is a selective, potent, and orally bioavailable inhibitor of coagulation factor Xa. The molecule contains a 1,2-benzisoxazole structure. After oral administration of [(14)C]razaxaban to intact and bile duct-cannulated rats (300 mg/kg) and dogs (20 mg/kg), metabolism followed by biliary excretion was the major elimination pathway in both species, accounting for 34 to 44% of the dose, whereas urinary excretion accounted for 3 to 13% of the dose. Chromatographic separation of radioactivity in urine, bile, and feces of rats and dogs showed that razaxaban was extensively metabolized in both species. Metabolites were identified on the basis of liquid chromatography/tandem mass spectrometry and comparison with synthetic standards. Among the 12 metabolites identified, formation of an isoxazole-ring opened benzamidine metabolite (M1) represented a major metabolic pathway of razaxaban in rats and dogs. However, razaxaban was the major circulating drug-related component (>70%) in both species, and M1, M4, and M7 were minor circulating components. In addition to the in vivo observations, M1 was formed as the primary metabolite in rat and dog hepatocytes and in the rat liver cytosolic fraction. The formation of M1 in the rat liver fraction required the presence of NADH. Theses results suggest that isoxazole ring reduction, forming a stable benzamidine metabolite (M1), represents the primary metabolic pathway of razaxaban in vivo and in vitro. The reduction reaction was catalyzed by NADH-dependent reductase(s) in the liver and possibly by intestinal microflora on the basis of the recovery of M1 in feces of bile duct-cannulated rats.
  Drug metabolism and disposition: the biological fate of chemicals 02/2008; 36(2):303-15. · 3.74 Impact Factor
• Article: Design, structure-activity relationship, and pharmacokinetic profile of pyrazole-based indoline factor Xa inhibitors.

  Jeffrey G Varnes, Dean A Wacker, Irina C Jacobson, Mimi L Quan, Christopher D Ellis, Karen A Rossi, Ming Y He, Joseph M Luettgen, Robert M Knabb, Steven Bai, Kan He, Patrick Y S Lam, Ruth R Wexler
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  ABSTRACT: A new series of pyrazole-based factor Xa inhibitors have been identified as part of our ongoing efforts to optimize previously reported clinical candidate razaxaban. Concern over the possible formation of primary aniline metabolites via amide hydrolysis led to the replacement of the primary amide linker between the pyrazole and phenyl moieties with secondary amides. This was accomplished by replacing the aniline with a variety of heterobicycles, of which indolines were the most potent. The indoline series demonstrated subnanomolar factor Xa binding K(i)s, modest to high selectivity versus other serine proteases, and good in vitro clotting activity. A small number of indoline fXa inhibitors were profiled in a dog pharmacokinetic model, one of which demonstrated pharmacokinetic parameters similar to that of clinical candidate razaxaban.
  Bioorganic & medicinal chemistry letters 01/2008; 17(23):6481-8. · 2.65 Impact Factor
• Article: Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa.

  Donald J P Pinto, Michael J Orwat, Stephanie Koch, Karen A Rossi, Richard S Alexander, Angela Smallwood, Pancras C Wong, Alan R Rendina, Joseph M Luettgen, Robert M Knabb, Kan He, Baomin Xin, Ruth R Wexler, Patrick Y S Lam
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  ABSTRACT: Efforts to identify a suitable follow-on compound to razaxaban (compound 4) focused on modification of the carboxamido linker to eliminate potential in vivo hydrolysis to a primary aniline. Cyclization of the carboxamido linker to the novel bicyclic tetrahydropyrazolopyridinone scaffold retained the potent fXa binding activity. Exceptional potency of the series prompted an investigation of the neutral P1 moieties that resulted in the identification of the p-methoxyphenyl P1, which retained factor Xa binding affinity and good oral bioavailability. Further optimization of the C-3 pyrazole position and replacement of the terminal P4 ring with a neutral heterocycle culminated in the discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, compound 40). Compound 40 exhibits a high degree of fXa potency, selectivity, and efficacy and has an improved pharmacokinetic profile relative to 4.
  Journal of Medicinal Chemistry 12/2007; 50(22):5339-56. · 5.25 Impact Factor
• Article: Amino(methyl) pyrrolidines as novel scaffolds for factor Xa inhibitors.

  Yan Shi, Doree Sitkoff, Jing Zhang, Wei Han, Zilun Hu, Philip D Stein, Ying Wang, Lawrence J Kennedy, Stephen P O'Connor, Saleem Ahmad, Eddie C-K Liu, Steve M Seiler, Patrick Y S Lam, Jeffrey A Robl, John E Macor, Karnail S Atwal, Robert Zahler
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  ABSTRACT: The design and synthesis of a novel class of amino(methyl) pyrrolidine-based sulfonamides as potent and selective FXa inhibitors is reported. The amino(methyl) pyrrolidine scaffolds were designed based on the proposed bioisosterism to the piperazine core in known FXa inhibitors. The SAR study led to compound 15 as the most potent FXa inhibitor in this series, with an IC(50) of 5.5 nM and PT EC(2x) of 1.7 microM. The proposed binding models show that the pyrrolidine cores are in van der Waals contact with the enzyme surface, and the flexibility of amino(methyl) pyrrolidines allows the two nitrogen atoms to anchor both the P1 and P4 groups to fit similarly in the S1 and S4 pockets.
  Bioorganic & Medicinal Chemistry Letters 12/2007; 17(21):5952-8. · 2.55 Impact Factor
• Article: Enantiopure five-membered cyclicdiamine derivatives as potent and selective inhibitors of factor Xa. Improving in vitro metabolic stability via core modifications.

  Jennifer X Qiao, Tammy C Wang, Gren Z Wang, Daniel L Cheney, Kan He, Alan R Rendina, Baomin Xin, Joseph M Luettgen, Robert M Knabb, Ruth R Wexler, Patrick Y S Lam
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  ABSTRACT: We previously reported a series of enantiopure cis-(1R,2S)-cyclopentyldiamine derivatives as potent and selective inhibitors of Factor Xa (FXa). Herein, we describe our approach to improve the metabolic stability of this series via core modifications. Multiple resulting series of compounds demonstrated similarly high FXa potency and improved metabolic stability in human liver microsomes compared with the cyclopentyldiamide 1. (3R,4S)-Pyrrolidinyldiamide 31 was the best overall compound with human FXa K(i) of 0.50 nM, PT EC(2x) of 2.1 microM in human plasma, bioavailability of 25% and t(1/2)of 2.7h in dogs. Further biochemical characterization of compound 31 is also presented.
  Bioorganic & Medicinal Chemistry Letters 10/2007; 17(18):5041-8. · 2.55 Impact Factor
• Article: SAR and X-ray structures of enantiopure 1,2-cis-(1R,2S)-cyclopentyldiamine and cyclohexyldiamine derivatives as inhibitors of coagulation Factor Xa.

  Jennifer X Qiao, Chong-Hwan Chang, Daniel L Cheney, Paul E Morin, Gren Z Wang, Sarah R King, Tammy C Wang, Alan R Rendina, Joseph M Luettgen, Robert M Knabb, Ruth R Wexler, Patrick Y S Lam
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  ABSTRACT: In the search of Factor Xa (FXa) inhibitors structurally different from the pyrazole-based series, we identified a viable series of enantiopure cis-(1R,2S)-cycloalkyldiamine derivatives as potent and selective inhibitors of FXa. Among them, cyclohexyldiamide 7 and cyclopentyldiamide 9 were the most potent neutral compounds, and had good anticoagulant activity comparable to the pyrazole-based analogs. Crystal structures of 7-FXa and 9-FXa illustrate binding similarities and differences between the five- and the six-membered core systems, and provide rationales for the observed SAR of P1 and linker moieties.
  Bioorganic & Medicinal Chemistry Letters 09/2007; 17(16):4419-27. · 2.55 Impact Factor
• Article: Razaxaban, a direct factor Xa inhibitor, in combination with aspirin and/or clopidogrel improves low-dose antithrombotic activity without enhancing bleeding liability in rabbits.

  Pancras C Wong, Earl J Crain, Carol A Watson, Ruth R Wexler, Patrick Y S Lam, Mimi L Quan, Robert M Knabb
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  ABSTRACT: Coactivation of platelets and the blood coagulation cascade contributes to the pathophysiology of arterial thrombosis. Combination therapy with antiplatelet and anticoagulant drugs may be needed for maximizing the prevention and treatment of arterial thrombosis. Few studies have thoroughly investigated the combined antithrombotic and bleeding effects of these antithrombotic agents. We, therefore, evaluated the antithrombotic and bleeding profiles of dual and triple therapy with razaxaban, a direct factor Xa inhibitor, plus aspirin and/or clopidogrel in rabbit models of electrolytic injury-induced carotid artery thrombosis and cuticle bleeding time, respectively. Compounds were infused either IV or into the portal vein from 1 h before arterial injury or cuticle transection to the end of experiment. Carotid blood flow was used as a marker of antithrombotic effect. We first evaluated the antithrombotic potency of razaxaban, and examined its ex vivo effects on coagulation parameters to confirm its selectivity. Antithrombotic ED(50) of razaxaban averaged 0.22 +/- 0.05 mg/kg/h (n = 6). Razaxaban at 3 mg/kg/h IV produced full antithrombotic efficacy, increased significantly ex vivo activated partial thromboplastin time and prothrombin time by 2.2 +/- 0.1- and 2.3 +/- 0.1-fold, respectively, and inhibited ex vivo factor Xa activity significantly by 91 +/- 5% (n = 6, P < 0.05) without affecting ex vivo thrombin activity. Razaxaban at concentrations up to 10 muM did not alter in vitro platelet aggregation responses to ADP, gamma-thrombin or collagen. To identify additive or synergistic antithrombotic effects of the various combination therapies, we purposefully used marginally effective doses of razaxaban at 0.1 mg/kg/h, aspirin at 0.3 mg/kg/h and clopidogrel at 1 mg/kg/h. Dual combination of threshold doses of razaxaban and aspirin or clopidogrel produced an enhanced antithrombotic effect without further increases in bleeding time. When compared with dual therapy with aspirin and clopidogrel (38 +/- 5% increase in blood flow), addition of razaxaban increased blood flow to 75 +/- 5% without additional bleeding time effects (n = 6/group, P < 0.05). In summary, razaxaban was an effective antithrombotic agent in a rabbit model of arterial thrombosis. Low-dose razaxaban was useful in combination with sub-optimal doses of aspirin and/or clopidogrel for the prevention of occlusive arterial thrombosis without excessive bleeding.
  Journal of Thrombosis and Thrombolysis 08/2007; 24(1):43-51. · 1.48 Impact Factor
• Article: Pyrazole-based factor Xa inhibitors containing N-arylpiperidinyl P4 residues.

  Jennifer X Qiao, Xuhong Cheng, Joanne M Smallheer, Robert A Galemmo, Spencer Drummond, Donald J P Pinto, Daniel L Cheney, Kan He, Pancras C Wong, Joseph M Luettgen, Robert M Knabb, Ruth R Wexler, Patrick Y S Lam
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  ABSTRACT: The synthesis, SAR, pharmacokinetic profile, and modeling studies of both monocyclic and fused pyrazoles containing substituted N-arylpiperidinyl P4 moieties that are potent and selective factor Xa inhibitors will be discussed. Fused pyrazole analog 16a, with a 2'-methylsulfonylphenyl piperidine P4 group, was shown to be the best compound in this series (FXa Ki = 0.35 nM) based on potency, selectivity, and pharmacokinetic profile.
  Bioorganic & Medicinal Chemistry Letters 04/2007; 17(5):1432-7. · 2.55 Impact Factor
• Article: Discovery of potent, efficacious, and orally bioavailable inhibitors of blood coagulation factor Xa with neutral P1 moieties.

  Donald J P Pinto, Robert A Galemmo, Mimi L Quan, Michael J Orwat, Charles Clark, Renhua Li, Brian Wells, Francis Woerner, Richard S Alexander, Karen A Rossi, Angela Smallwood, Pancras C Wong, Joseph M Luettgen, Alan R Rendina, Robert M Knabb, Kan He, Ruth R Wexler, Patrick Y S Lam
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  ABSTRACT: The bicyclic dihydropyrazolopyridinone scaffold allowed for incorporation of multiple P1 moieties with subnanomolar binding affinities for blood coagulation factor Xa. The compound 3-[6-(2'-dimethylaminomethyl-biphenyl-4-yl)-7-oxo-3-trifluoro-methyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridine-l-yl]-benzamide 6d shows good fXa potency, selectivity, in vivo efficacy and oral bioavailability. Compound 6d was selected for further pre-clinical evaluations.
  Bioorganic & Medicinal Chemistry Letters 12/2006; 16(21):5584-9. · 2.55 Impact Factor
• Article: Preparation of 1-(3-aminobenzo[d]isoxazol-5-yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-ones as potent, selective, and efficacious inhibitors of coagulation factor Xa.

  Yun-Long Li, John M Fevig, Joseph Cacciola, Joseph Buriak, Karen A Rossi, Janan Jona, Robert M Knabb, Joseph M Luettgen, Pancras C Wong, Stephen A Bai, Ruth R Wexler, Patrick Y S Lam
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  ABSTRACT: Previously, potent factor Xa inhibitors were described based on the 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one bicyclic core and a 4-methoxyphenyl P1 moiety. This manuscript describes 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one and related bicyclic cores with the 3-aminobenzisoxazole P1 moiety. Many of these compounds are potent, selective, and efficacious inhibitors of coagulation factor Xa.
  Bioorganic & Medicinal Chemistry Letters 11/2006; 16(19):5176-82. · 2.55 Impact Factor
• Article: Preparation of 1-(4-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-ones as potent, selective and bioavailable inhibitors of coagulation factor Xa.

  John M Fevig, Joseph Cacciola, Joseph Buriak, Karen A Rossi, Robert M Knabb, Joseph M Luettgen, Pancras C Wong, Stephen A Bai, Ruth R Wexler, Patrick Y S Lam
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  ABSTRACT: Previously, potent factor Xa inhibitors were described based on a pyrazole core. Modifications of the pyrazole core have provided additional novel, highly potent factor Xa inhibitors. This manuscript will describe the synthesis and biological activity of factor Xa inhibitors containing the 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one and related bicyclic cores. Many of these compounds are potent, selective, and orally bioavailable inhibitors of coagulation factor Xa.
  Bioorganic & Medicinal Chemistry Letters 08/2006; 16(14):3755-60. · 2.55 Impact Factor