Robert A Galemmo

Publications (16)59.79 Total impact

• Article: Studies with an orally bioavailable alpha V integrin antagonist in animal models of ocular vasculopathy: retinal neovascularization in mice and retinal vascular permeability in diabetic rats.

  Rosemary J Santulli, William A Kinney, Shyamali Ghosh, Bart L Decorte, Li Liu, Robert W A Tuman, Zhao Zhou, Norman Huebert, Sven E Bursell, Alan C Clermont, Maria B Grant, Lynn C Shaw, Shaker A Mousa, Robert A Galemmo, Dana L Johnson, Bruce E Maryanoff, Bruce P Damiano
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  ABSTRACT: The alpha(V) integrins are key receptors involved in mediating cell migration and angiogenesis. In age-related macular degeneration (AMD) and diabetic retinopathy, angiogenesis plays a critical role in the loss of vision. These ocular vasculopathies might be treatable with a suitable alpha(V) antagonist, and an oral drug would offer a distinct advantage over current therapies. (3,S,beta,S)-1,2,3,4-Tetrahydro-beta-[[1-[1-oxo-3-(1,5,6,7-tetrahydro-1,8-naphthyridin-2-yl)propyl]-4-piperidinyl]methyl]-3-quinolinepropanoic acid (JNJ-26076713) is a potent, orally bioavailable, nonpeptide alpha(V) antagonist derived from the arginine-glycine-asparagine binding motif in the matrix protein ligands (e.g., vitronectin). This compound inhibits alpha(V)beta(3) and alpha(V)beta(5) binding to vitronectin in the low nanomolar range, it has excellent selectivity over integrins alpha(IIb)beta(3) and alpha(5)beta(1), and it prevents adhesion to human, rat, and mouse endothelial cells. JNJ-26076713 blocks cell migration induced by vascular endothelial growth factor, fibroblast growth factor (FGF), and serum, and angiogenesis induced by FGF in the chick chorioallantoic membrane model. JNJ-26076713 is the first alpha(V) antagonist reported to inhibit retinal neovascularization in an oxygen-induced model of retinopathy of prematurity after oral administration. In diabetic rats, orally administered JNJ-26076713 markedly inhibits retinal vascular permeability, a key early event in diabetic macular edema and AMD. Given this profile, JNJ-26076713 represents a potential therapeutic candidate for the treatment of age-related macular degeneration, macular edema, and proliferative diabetic retinopathy.
  Journal of Pharmacology and Experimental Therapeutics 04/2008; 324(3):894-901. · 3.83 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
• Chapter: Progress in the Development of Agents to Control the Cell Cycle

  Kevin J. Moriarty, Holly Koblish, Dana L. Johnson, Robert A. Galemmo
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  ABSTRACT: Inhibitors of the kinases controlling the cell cycle have emerged as an important therapeutic modality for the treatment of cancer. Drug discovery efforts have focused on inhibitors of the cyclin-dependent kinases, the Aurora kinases, and Polo-like kinases. Agents for each kinase are now advancing in human clinical trials. In this review we will summarize the work in this area with special emphasis on the structural biology and structure–activity relationships developed for the many chemotypes explored.
  01/2007: pages 207-291;
• Article: The synthesis and SAR of 2-amino-pyrrolo[2,3-d]pyrimidines: a new class of Aurora-A kinase inhibitors.

  Kevin J Moriarty, Holly K Koblish, Thomas Garrabrant, Jahanvi Maisuria, Ehab Khalil, Farah Ali, Ioanna P Petrounia, Carl S Crysler, Anna C Maroney, Dana L Johnson, Robert A Galemmo
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  ABSTRACT: A new class of Aurora-A inhibitors have been identified based on the 2-amino-pyrrolo[2,3-d]pyrimidine scaffold. Here, we describe the synthesis and SAR of this novel series. We report compounds which exhibit nanomolar activity in the Aurora-A biochemical assay and are able to inhibit tumor cell proliferation. This study culminates in compound 30, an inhibitor with potent activity against Aurora A (IC50=0.008 microM), anti-proliferative activity against several tumor cell lines and induces polyploidy in H460 cells.
  Bioorganic & Medicinal Chemistry Letters 12/2006; 16(22):5778-83. · 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: 1-[3-Aminobenzisoxazol-5'-yl]-3-trifluoromethyl-6-[2'-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1']-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one (BMS-740808) a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa.

  Donald J P Pinto, Michael J Orwat, Mimi L Quan, Qi Han, Robert A Galemmo, Eugene Amparo, Brian Wells, Christopher Ellis, Ming Y He, Richard S Alexander, [......], Pancras C Wong, Joseph M Luettgen, Alan R Rendina, Robert M Knabb, Lawrence Mersinger, Charles Kettner, Steven Bai, Kan He, Ruth R Wexler, Patrick Y S Lam
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  ABSTRACT: Attempts to further optimize the pyrazole factor Xa inhibitors centered on masking the aryl aniline P4 moiety. Scaffold optimization resulted in the identification of a novel bicyclic pyrazolo-pyridinone scaffold which retained fXa potency. The novel bicyclic scaffold preserved all binding interactions observed with the monocyclic counterpart and importantly the carboxamido moiety was integrated within the scaffold making it less susceptible to hydrolysis. These efforts led to the identification of 1-[3-aminobenzisoxazol-5'-yl]-3-trifluoromethyl-6-[2'-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1']-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one 6f (BMS-740808), a highly potent (fXa Ki=30 pM) with a rapid onset of inhibition (2.7x10(7) M-1 s-1) in vitro, selective (>1000-fold over other proteases), efficacious in the AVShunt thrombosis model, and orally bioavailable inhibitor of blood coagulation factor Xa.
  Bioorganic & Medicinal Chemistry Letters 08/2006; 16(15):4141-7. · 2.55 Impact Factor
• Article: Dihydroquinone ansamycins: toward resolving the conflict between low in vitro affinity and high cellular potency of geldanamycin derivatives.

  Anna C Maroney, Juan J Marugan, Tara M Mezzasalma, Alexander N Barnakov, Thomas A Garrabrant, Larry E Weaner, William J Jones, Ludmila A Barnakova, Holly K Koblish, Matthew J Todd, John A Masucci, Ingrid C Deckman, Robert A Galemmo, Dana L Johnson
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  ABSTRACT: Heat shock protein 90 (Hsp90) is critical for the maturation of numerous client proteins, many of which are involved in cellular transformation and oncogenesis. The ansamycins, geldanamycin (GA) and its derivative, 17-allylaminogeldanamycin (17-AAG), inhibit Hsp90. As such, the prototypical Hsp90 inhibitor, 17-AAG, has advanced into clinical oncology trials. GA and 17-AAG potently inhibit tumor cell proliferation and survival but have been reported to bind weakly to Hsp90 in vitro. Recent studies have suggested that the in vitro potency of ansamycins against Hsp90 may be enhanced in the presence of cochaperones. Here, we present evidence of an alternative explanation. Ansamycins reduced to their dihydroquinones in the presence of common reducing agents in vitro have approximately 40-fold greater affinity than the corresponding oxidized quinones. The dihydroquinone of 17-AAG is not generated in an aqueous environment in the absence of reducing agents but is produced in both tumor and normal quiescent epithelial cells. The reduced form of 17-AAG is differentiated from its oxidized form not only by the higher affinity for Hsp90 but also by a protracted K(off) rate. Therefore, the in vivo accumulation of the high-affinity dihydroquinone ansamycins in tumor cells contributes to the antitumor activity of these compounds and alters our understanding of the active species driving the efficacy of this class of compounds.
  Biochemistry 06/2006; 45(17):5678-85. · 3.42 Impact Factor
• Article: (6,7-Dimethoxy-2,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenylamines: platelet-derived growth factor receptor tyrosine kinase inhibitors with broad antiproliferative activity against tumor cells.

  Chih Y Ho, Donald W Ludovici, Umar S M Maharoof, Jay Mei, Jan L Sechler, Robert W Tuman, Eric D Strobel, Laura Andraka, Hwa-Kwo Yen, Gregory Leo, [......], Harold Almond, Hong Lu, Ann DeVine, Rose M Tominovich, Judith Baker, Stuart Emanuel, Robert H Gruninger, Steven A Middleton, Dana L Johnson, Robert A Galemmo
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  ABSTRACT: A series of (6,7-dimethoxy-2,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenylamines has been optimized to preserve both potent kinase inhibition activity against the angiogenesis target, the receptor tyrosine kinase of Platelet-Derived Growth Factor-BB (PDGF-BB), and to improve the broad tumor cell antiproliferative activity of these compounds. This series culminates in the discovery of 17 (JNJ-10198409), a compound with anti-PDGFR-beta kinase activity (IC(50)=0.0042 microM) and potent antiproliferative activity in six of eight human tumor cell lines (IC(50) < 0.033 microM).
  Journal of Medicinal Chemistry 01/2006; 48(26):8163-73. · 5.25 Impact Factor
• Article: Validation of in vivo pharmacodynamic activity of a novel PDGF receptor tyrosine kinase inhibitor using immunohistochemistry and quantitative image analysis.

  Michael R D'Andrea, Jay M Mei, Robert W Tuman, Robert A Galemmo, Dana L Johnson
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  ABSTRACT: With the advent of agents directed against specific molecular targets in drug discovery, it has become imperative to show a compound's cellular impact on the intended biomolecule in vivo. The objective of the present study was to determine if we could develop an assay to validate the in vivo effects of a compound. Hence, we investigated the in vivo pharmacodynamic activity of JNJ-10198409, a relatively selective inhibitor of platelet-derived growth factor receptor tyrosine kinase (PDGF-RTK), in tumor tissues after administering the compound orally in a nude mouse xenograft model of human LoVo colon cancer. We developed a novel assay to quantify the in vivo anti-PDGF-RTK activity of the inhibitor in tumor tissue by determining the phosphorylation status of phospholipase Cgamma1 (PLCgamma1), a key downstream cellular molecule in the PDGF-RTK signaling cascade. We used two antibodies, one specific for the total (phosphorylated and unphosphorylated forms) PLCgamma1 (pan-PLCgamma1) and the other, specific for phosphorylated form of PLCgamma1 (ph-PLCgamma1) to immunohistochemically detect their expression in tumor tissues. Computer-assisted image analysis was then used to directly compare the ratio of ph-PLCgamma1 to pan-PLCgamma1 immunolabeling intensities in serial sections (5 mum) of tumors obtained from vehicle- and JNJ-10198409-treated tumor-bearing mice. Our data showed statistically significant, dose-dependent differences in the ph-PLC/pan-PLC ratio among the four treatment groups (vehicle, 25, 50, and 100 mg/kg b.i.d.). These results confirmed this compound's ability to suppress PDGF-RTK downstream signaling in tumor tissues in vivo. In addition to this specific application of this in vivo validation approach to those targets that use PLCgamma as a downstream signaling partner, these methods may also benefit other drug discovery targets.
  Molecular Cancer Therapeutics 09/2005; 4(8):1198-204. · 5.23 Impact Factor
• Article: Improved solution- and solid-phase preparation of hydroxamic acids from esters.

  Chih Y Ho, Eric Strobel, Janet Ralbovsky, Robert A Galemmo
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  ABSTRACT: The addition of small amounts of solid KCN to solution and solid-phase esters in THF/MeOH/50% aqueous NH2OH increases the efficiency of their transformation to the corresponding hydroxamic acids.
  The Journal of Organic Chemistry 07/2005; 70(12):4873-5. · 4.45 Impact Factor
• Article: 1,2,3,4-Tetrahydroquinoline-containing alphaVbeta3 integrin antagonists with enhanced oral bioavailability.

  Shyamali Ghosh, Rosemary J Santulli, William A Kinney, Bart L Decorte, Li Liu, Joan M Lewis, Jef C Proost, Gregory C Leo, John Masucci, William E Hageman, Andrew S Thompson, Ian Chen, Reiko Kawahama, Robert W Tuman, Robert A Galemmo, Dana L Johnson, Bruce P Damiano, Bruce E Maryanoff
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  ABSTRACT: Reduction of the quinoline ring in an alpha(v)beta(3) antagonist yielded a 1,2,3,4-tetrahydro derivative as two diastereomers, the four isomers of which were separated by sequential chiral HPLC. Two isomers had significant alpha(V)beta(3) antagonist activity with improved oral bioavailability, relative to the corresponding quinoline derivative.
  Bioorganic & Medicinal Chemistry Letters 01/2005; 14(23):5937-41. · 2.55 Impact Factor
• Source

  Available from: Livia Franzini-Brunner

  Article: Piperidine-containing beta-arylpropionic acids as potent antagonists of alphavbeta3/alphavbeta5 integrins.

  Bart L De Corte, William A Kinney, Li Liu, Shyamali Ghosh, Livia Brunner, William J Hoekstra, Rosemary J Santulli, Robert W Tuman, Judith Baker, Candace Burns, Jef C Proost, Brett A Tounge, Bruce P Damiano, Bruce E Maryanoff, Dana L Johnson, Robert A Galemmo
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  ABSTRACT: The synthesis and SAR of a new class of piperidine-based alphavbeta3/alphavbeta5 integrin antagonists is described. Replacement of an amide bond in a prototype isonipecotamide by a C-C isostere, and adjustment of the spacer length between the carboxylic acid and basic moieties, led to low nanomolar antagonists of alphavbeta3 and/or alphavbeta5 integrins with excellent selectivity versus alpha(IIb)beta3.
  Bioorganic & Medicinal Chemistry Letters 11/2004; 14(20):5227-32. · 2.55 Impact Factor
• Article: Small molecule inhibitors of methionine aminopeptidase type 2 (MetAP-2).

  Thomas Garrabrant, Robert W Tuman, Don Ludovici, Rose Tominovich, Richard L Simoneaux, Robert A Galemmo, Dana L Johnson
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  ABSTRACT: The protein processing enzyme, methionine aminopeptidase-2 (MetAP-2), has been identified as a molecular target of fumagillin and its derivative, TNP-470, compounds known to inhibit endothelial cell proliferation and angiogenesis. A high-throughput screening program was undertaken to identify selective, reversible inhibitors of MetAP-2 in an attempt to discover structurally novel anti-angiogenic agents for potential therapeutic use in oncology. Approximately 90 small-molecule, reversible, selective inhibitors of rhMetAP-2 were identified. The most potent of these compounds contained a singly-substituted triazole moiety which exhibited an IC50 of 8 nM (95% confidence limits 5 to 13 nM) and was highly selective for MetAP-2 over MetAP-1 (approximately 60-fold difference in IC50 values). Unlike fumagillin, these MetAP-2 inhibitors failed to significantly inhibit growth factor-stimulated endothelial cell (HUVEC) proliferation or to suppress angiogenesis in the in vitro aortic ring explant model of microvessel outgrowth. The MetAP-2-inhibitory activity of these compounds was dependent on the divalent cation used as the metalloenzyme activating cofactor for MetAP-2. These inhibitors were identified using cobalt(II)-activated recombinant human MetAP-2 for screening compound libraries. When manganese (Mn2+) was substituted for cobalt following EDTA treatment and extensive dialysis of the MetAP-2 protein, these inhibitors were significantly less potent (40-fold increase in IC50) as inhibitors of MetAP-2. These results support the recent hypothesis that cobalt may not be the relevant divalent metal ion cofactor for MetAP-2 in cells and may explain the observed absence of cell-based activity using potent triazole inhibitors of cobalt-activated MetAP-2.
  Angiogenesis 02/2004; 7(2):91-6. · 6.06 Impact Factor
• Article: Discovery of 1-(2-aminomethylphenyl)-3-trifluoromethyl-N- [3-fluoro-2'-(aminosulfonyl)[1,1'-biphenyl)]-4-yl]-1H-pyrazole-5-carboxyamide (DPC602), a potent, selective, and orally bioavailable factor Xa inhibitor(1).

  James R Pruitt, Donald J P Pinto, Robert A Galemmo, Richard S Alexander, Karen A Rossi, Brian L Wells, Spencer Drummond, Lori L Bostrom, Debra Burdick, Robert Bruckner, Haiying Chen, Angela Smallwood, Pancras C Wong, Matthew R Wright, Steven Bai, Joseph M Luettgen, Robert M Knabb, Patrick Y S Lam, Ruth R Wexler
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  ABSTRACT: Factor Xa, a serine protease, is at the critical juncture between the intrinsic and extrinsic pathways of the coagulation cascade. Inhibition of factor Xa has the potential to provide effective treatment for both venous and arterial thrombosis. We recently described a series of meta-substituted phenylpyrazoles that are highly potent, selective, and orally bioavailable factor Xa inhibitors. In this paper we report our efforts to further optimize the selectivity profile of our factor Xa inhibitors with a series of ortho- and/or para-substituted phenylpyrazole derivatives. The most potent compounds display sub-nanomolar inhibition constants for factor Xa and show greater than 1000-fold selectivity against other serine proteases. These compounds are also effective in a rabbit model of arteriovenous shunt thrombosis. Optimization of this series led to the preclinical development of DPC602, a 2-(aminomethyl)phenylpyrazole analogue, as a highly potent, selective, and orally bioavailable factor Xa inhibitor.
  Journal of Medicinal Chemistry 01/2004; 46(25):5298-315. · 5.25 Impact Factor
• Article: Structure-based design of novel guanidine/benzamidine mimics: potent and orally bioavailable factor Xa inhibitors as novel anticoagulants.

  Patrick Y S Lam, Charles G Clark, Renhua Li, Donald J P Pinto, Michael J Orwat, Robert A Galemmo, John M Fevig, Christopher A Teleha, Richard S Alexander, Angela M Smallwood, Karen A Rossi, Matthew R Wright, Stephen A Bai, Kan He, Joseph M Luettgen, Pancras C Wong, Robert M Knabb, Ruth R Wexler
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  ABSTRACT: As part of an ongoing effort to prepare orally active factor Xa inhibitors using structure-based drug design techniques and molecular recognition principles, a systematic study has been performed on the pharmacokinetic profile resulting from replacing the benzamidine in the P1 position with less basic benzamidine mimics or neutral residues. It is demonstrated that lowering the pK(a) of the P1 ligand resulted in compounds (3-benzylamine, 15a; 1-aminoisoquinoline, 24a; 3-aminobenzisoxazole, 23a; 3-phenylcarboxamide, 22b; and 4-methoxyphenyl, 22a) with improved pharmacokinetic features mainly as a result of decreased clearance, increased volume of distribution, and enhanced oral absorption. This work resulted in a series of potent and orally bioavailable factor Xa inhibitors that ultimately led to the discovery of SQ311, 24a. SQ311, which utilizes a 1-aminoisoquinoline as the P1 ligand, inhibits factor Xa with a K(i) of 0.33 nM and demonstrates both good in vivo antithrombotic efficacy and oral bioavailability.
  Journal of Medicinal Chemistry 11/2003; 46(21):4405-18. · 5.25 Impact Factor
• Article: Inhibition of factor Xa reduces ischemic brain damage after thromboembolic stroke in rats.

  Xinkang Wang, Lin Xu, Hugh Wang, Reinhard Grzanna, Yutian Zhan, Robert M Knabb, Joseph M Luettgen, Tracy A Bozarth, Robert A Galemmo, Pancras C Wong, Roberta Bernard, Hugo Vargas, Michael Chopp, Steven M Friedman, Giora Z Feuerstein
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  ABSTRACT: Factor Xa (FXa) is a key coagulation protease and target for novel antithrombotic agents for prevention and treatment of diverse thromboembolic disorders. In the present study we describe the effect of a novel, potent, and selective FXa inhibitor, DPC602, on brain damage and neurobehavioral consequence in a rat thromboembolic model of stroke. Thromboembolic stroke was induced in rats by placement of an autologous clot into the middle cerebral artery. Laser-Doppler monitoring of cerebral blood flow demonstrated that DPC602 (8 mg/kg, single IV/IP bolus pretreatment) markedly improved cerebral blood flow after thromboembolic stroke by 25% to 160% (n=6; P<0.001) at 1 to 6 hours. DPC602 demonstrated concentration- and time-dependent reductions in infarct size, with maximal effect (89% reduction; n=14; P<0.001) at the highest dose over controls. Neurological function was also significantly improved in DPC602-treated rats at days 1, 3, and 7 (n=13; P<0.01). DPC602 treatment did not cause cerebral hemorrhage, assessed by free hemoglobin in the ischemic brain tissues. These data suggest that anticoagulation with a selective FXa inhibitor might ameliorate the extent of ischemic brain damage and neurological deficits after a thromboembolic event. Enhanced clot dissolution and early reperfusion may account for the cerebrovascular-protective effect of the drug.
  Stroke 02/2003; 34(2):468-74. · 5.73 Impact Factor