Publications by authors named "Michael J Munchhof"

23 Publications

  • Page 1 of 1

Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666.

ACS Med Chem Lett 2016 Feb 2;7(2):162-6. Epub 2015 Dec 2.

Epizyme, Inc. , 400 Technology Square, Cambridge, Massachusetts 02139, United States.

The recent publication of a potent and selective inhibitor of protein methyltransferase 5 (PRMT5) provides the scientific community with in vivo-active tool compound EPZ015666 (GSK3235025) to probe the underlying pharmacology of this key enzyme. Herein, we report the design and optimization strategies employed on an initial hit compound with poor in vitro clearance to yield in vivo tool compound EPZ015666 and an additional potent in vitro tool molecule EPZ015866 (GSK3203591).
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http://dx.doi.org/10.1021/acsmedchemlett.5b00380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753547PMC
February 2016

Species differences in metabolism of EPZ015666, an oxetane-containing protein arginine methyltransferase-5 (PRMT5) inhibitor.

Xenobiotica 2016 ;46(3):268-77

1. Metabolite profiling and identification studies were conducted to understand the cross-species differences in the metabolic clearance of EPZ015666, a first-in-class protein arginine methyltransferase-5 (PRMT5) inhibitor, with anti-proliferative effects in preclinical models of Mantle Cell Lymphoma. EPZ015666 exhibited low clearance in human, mouse and rat liver microsomes, in part by introduction of a 3-substituted oxetane ring on the molecule. In contrast, a higher clearance was observed in dog liver microsomes (DLM) that translated to a higher in vivo clearance in dog compared with rodent. 2. Structure elucidation via high resolution, accurate mass LC-MS(n) revealed that the prominent metabolites of EPZ015666 were present in hepatocytes from all species, with the highest turnover rate in dogs. M1 and M2 resulted from oxidative oxetane ring scission, whereas M3 resulted from loss of the oxetane ring via an N-dealkylation reaction. 3. The formation of M1 and M2 in DLM was significantly abrogated in the presence of the specific CYP2D inhibitor, quinidine, and to a lesser extent by the CYP3A inhibitor, ketoconazole, corroborating data from human recombinant isozymes. 4. Our data indicate a marked species difference in the metabolism of the PRMT5 inhibitor EPZ015666, with oxetane ring scission the predominant metabolic pathway in dog mediated largely by CYP2D.
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http://dx.doi.org/10.3109/00498254.2015.1072253DOI Listing
October 2016

A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models.

Nat Chem Biol 2015 Jun 27;11(6):432-7. Epub 2015 Apr 27.

Departments of Biology and Molecular Discovery, Epizyme, Inc., Cambridge, Massachusetts, USA.

Protein arginine methyltransferase-5 (PRMT5) is reported to have a role in diverse cellular processes, including tumorigenesis, and its overexpression is observed in cell lines and primary patient samples derived from lymphomas, particularly mantle cell lymphoma (MCL). Here we describe the identification and characterization of a potent and selective inhibitor of PRMT5 with antiproliferative effects in both in vitro and in vivo models of MCL. EPZ015666 (GSK3235025) is an orally available inhibitor of PRMT5 enzymatic activity in biochemical assays with a half-maximal inhibitory concentration (IC50) of 22 nM and broad selectivity against a panel of other histone methyltransferases. Treatment of MCL cell lines with EPZ015666 led to inhibition of SmD3 methylation and cell death, with IC50 values in the nanomolar range. Oral dosing with EPZ015666 demonstrated dose-dependent antitumor activity in multiple MCL xenograft models. EPZ015666 represents a validated chemical probe for further study of PRMT5 biology and arginine methylation in cancer and other diseases.
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http://dx.doi.org/10.1038/nchembio.1810DOI Listing
June 2015

Defining the key pharmacophore elements of PF-04620110: discovery of a potent, orally-active, neutral DGAT-1 inhibitor.

Bioorg Med Chem 2013 Sep 1;21(17):5081-97. Epub 2013 Jul 1.

PharmaTherapeutics Research & Development, Pfizer Inc., 620 Memorial Drive, Cambridge, MA 02139, United States.

DGAT-1 is an enzyme that catalyzes the final step in triglyceride synthesis. mRNA knockout experiments in rodent models suggest that inhibitors of this enzyme could be of value in the treatment of obesity and type II diabetes. The carboxylic acid-based DGAT-1 inhibitor 1 was advanced to clinical trials for the treatment of type 2 diabetes, despite of the low passive permeability of 1. Because of questions relating to the potential attenuation of distribution and efficacy of a poorly permeable agent, efforts were initiated to identify compounds with improved permeability. Replacement of the acid moiety in 1 with an oxadiazole led to the discovery of 52, which possesses substantially improved passive permeability. The resulting pharmacodynamic profile of this neutral DGAT-1 inhibitor was found to be similar to 1 at comparable plasma exposures.
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http://dx.doi.org/10.1016/j.bmc.2013.06.045DOI Listing
September 2013

Design and synthesis of diazatricyclodecane agonists of the G-protein-coupled receptor 119.

J Med Chem 2013 Jan 31;56(1):301-19. Epub 2012 Dec 31.

Departments of Medicinal Chemistry, Discovery Biology, Drug Metabolism, and Pharmaceutical Sciences, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, USA.

A series of GPR119 agonists based on a 2,6-diazatricyclo[3.3.1.1∼3,7∼]decane ring system is described. Also provided is a detailed account of the development of a multigram scale synthesis of the diazatricyclic ring system, which was achieved using a Hofmann-Löffler-Freytag reaction as the key step. The basis for the use of this complex framework lies in an attempt to constrain one end of the molecule in the "agonist conformation" as was previously described for 3-oxa-7-aza-bicyclo[3.3.1]nonanes. Optimization of carbamate analogues of the diazatricylic compounds led to the identification of 32i as a potent agonist of the GPR119 receptor with low unbound human liver microsomal clearance. The use of an agonist response weighted ligand lipophilic efficiency (LLE) termed AgLLE is discussed along with the issues of applying efficiency measures to agonist programs. Ultimately, solubility limited absorption and poor exposure reduced further interest in these molecules.
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http://dx.doi.org/10.1021/jm301626pDOI Listing
January 2013

From partial to full agonism: identification of a novel 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole as a full agonist of the human GPR119 receptor.

Bioorg Med Chem Lett 2013 Jan 5;23(1):194-7. Epub 2012 Nov 5.

Pfizer Worldwide Research & Development, Groton Laboratories, Eastern Point Rd, Groton, CT 06340, United States.

A novel GPR119 agonist based on the 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole scaffold was designed through lead optimization starting from pyrazole-based GPR119 agonist 1. The design is centered on the conformational restriction of the core scaffold, while minimizing the change in spatial relationships of two key pharmacophoric elements (piperidine-carbamate and aryl sulfone).
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http://dx.doi.org/10.1016/j.bmcl.2012.10.119DOI Listing
January 2013

Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened.

ACS Med Chem Lett 2012 Feb 21;3(2):106-11. Epub 2011 Dec 21.

Pfizer Global Research and Development , Groton, Connecticut 06340, United States.

Inhibitors of the Hedgehog signaling pathway have generated a great deal of interest in the oncology area due to the mounting evidence of their potential to provide promising therapeutic options for patients. Herein, we describe the discovery strategy to overcome the issues inherent in lead structure 1 that resulted in the identification of Smoothened inhibitor 1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea (PF-04449913, 26), which has been advanced to human clinical studies.
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http://dx.doi.org/10.1021/ml2002423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025788PMC
February 2012

Design and synthesis of potent, orally-active DGAT-1 inhibitors containing a dioxino[2,3-d]pyrimidine core.

Bioorg Med Chem Lett 2011 Oct 12;21(20):6122-5. Epub 2011 Aug 12.

Pfizer Global Research and Development, Groton, CT 06340, USA.

A novel series of potent DGAT-1 inhibitors was developed originating from the lactam-based clinical candidate PF-04620110. Incorporation of a dioxino[2,3-d]pyrimidine-based core afforded good alignment of pharmacophore features and resulted in improved passive permeability. Development of an efficient, homochiral synthesis of these targets facilitated confirmation of predictions regarding the stereochemical-dependence of DGAT-1 inhibition for this series. Compound 10 was shown to be a potent inhibitor of human DGAT-1 (10 nM) and to suppress triglyceride synthesis at oral doses of <3mg/kg.
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http://dx.doi.org/10.1016/j.bmcl.2011.08.028DOI Listing
October 2011

Understanding the impact of the P-loop conformation on kinase selectivity.

J Chem Inf Model 2011 Jun 24;51(6):1199-204. Epub 2011 May 24.

This work addresses the link between selectivity and an unusual, folded conformation for the P-loop observed initially for MAP4K4 and subsequently for other kinases. Statistical and computational analyses of our crystal structure database demonstrate that inhibitors that induce the P-loop folded conformation tend to be more selective, especially if they take advantage of this specific conformation by interacting more favorably with a conserved Tyr or Phe residue from the P-loop.
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http://dx.doi.org/10.1021/ci200153cDOI Listing
June 2011

Discovery of PF-04620110, a Potent, Selective, and Orally Bioavailable Inhibitor of DGAT-1.

ACS Med Chem Lett 2011 May 18;2(5):407-12. Epub 2011 Mar 18.

Pfizer Global Research and Development , Groton, Connecticut 06340, United States.

Acyl-CoA:diacylglycerol acyltransferase-1 (DGAT-1) catalyzes the final committed step in the biosynthesis of triglycerides. DGAT-1 knockout mice have been shown to be resistant to diet-induced obesity and have increased insulin sensitivity. Thus, inhibition of DGAT-1 may represent an attractive target for the treatment of obesity or type II diabetes. Herein, we report the discovery and characterization of a potent and selective DGAT-1 inhibitor PF-04620110 (3). Compound 3 inhibits DGAT-1 with an IC50 of 19 nM and shows high selectivity versus a broad panel of off-target pharmacologic end points. In vivo DGAT-1 inhibition has been demonstrated through reduction of plasma triglyceride levels in rodents at doses of ≥0.1 mg/kg following a lipid challenge. On the basis of this pharmacologic and pharmacokinetic profile, compound 3 has been advanced to human clinical studies.
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http://dx.doi.org/10.1021/ml200051pDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018057PMC
May 2011

Activation of the G-protein-coupled receptor 119: a conformation-based hypothesis for understanding agonist response.

J Med Chem 2011 Mar 1;54(6):1948-52. Epub 2011 Mar 1.

Department of Medicinal Chemistry, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States.

The synthesis and properties of the bridged piperidine (oxaazabicyclo) compounds 8, 9, and 11 are described. A conformational analysis of these structures is compared with the representative GPR119 ligand 1. These results and the differences in agonist pharmacology are used to formulate a conformation-based hypothesis to understand activation of the GPR119 receptor. We also show for these structures that the agonist pharmacology in rat masks the important differences in human pharmacology.
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http://dx.doi.org/10.1021/jm200003pDOI Listing
March 2011

Design and evaluation of a 2-(2,3,6-trifluorophenyl)acetamide derivative as an agonist of the GPR119 receptor.

Bioorg Med Chem Lett 2011 Mar 25;21(5):1306-9. Epub 2011 Jan 25.

Pfizer Global Research & Development, Groton, CT 06340, USA.

The design and synthesis of a GPR119 agonist bearing a 2-(2,3,6-trifluorophenyl)acetamide group is described. The design capitalized on the conformational restriction found in N-β-fluoroethylamide derivatives to help maintain good levels of potency while driving down both lipophilicity and oxidative metabolism in human liver microsomes. The chemical stability and bioactivation potential are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2011.01.088DOI Listing
March 2011

Intrinsic electrophilicity of a 4-substituted-5-cyano-6-(2-methylpyridin-3-yloxy)pyrimidine derivative: structural characterization of glutathione conjugates in vitro.

Chem Res Toxicol 2011 Feb 3;24(2):269-78. Epub 2011 Feb 3.

Pharmacokinetics, Dynamics, and Metabolism Department, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States.

Isopropyl 9-anti-[5-cyano-6-(2-methyl-pyridin-3-yloxy)-pyrimidin-4-yloxy]-3-oxa-7-aza-bicyclo[3.3.1]nonane-7-carboxylate (1) represents a prototypic compound from a lead chemical series of G protein-coupled receptor 119 agonists, intended for treatment of type 2 diabetes. When compound 1 was incubated with NADPH-supplemented human liver microsomes in the presence of glutathione, two thioether conjugates M4-1 and M5-1 were observed. Omission of NADPH from the microsomal incubations prevented the formation of M5-1 but not M4-1. The formation of M4-1 was also discerned in incubations of 1 and glutathione with human liver cytosol, partially purified glutathione transferase, and in phosphate buffer at pH 7.4. M4-1 was isolated, and its structure ascertained from LC-MS/MS and NMR analysis. The mass spectral and NMR data suggested that M4-1 was obtained from a nucleophilic displacement of the 6-(2-methylpyridin-3-yloxy) group in 1 by glutathione. In addition, mass spectral studies revealed that M5-1 was derived from an analogous displacement reaction on a monohydroxylated metabolite of 1; the regiochemistry of hydroxylation was established to be on the isopropyl group. Of great interest were the findings that replacement of the 5-cyano group in 1 with a 5-methyl group resulted in 2, which was practically inert toward reaction with glutathione. This observation suggests that the electron-withdrawing potential of the C5 cyano group serves to increase the electrophilicity of the C6 carbon (via stabilization of the transition state) and favors reaction with the nucleophilic thiol. The mechanistic insights gained from these studies should assist medicinal chemistry efforts toward the design of analogs that retain primary pharmacology but are latent toward reaction with biological nucleophiles, thus mitigating the potential for toxicological outcome due to adduction with glutathione or proteins.
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http://dx.doi.org/10.1021/tx100429xDOI Listing
February 2011

Discovery of CP-690,550: a potent and selective Janus kinase (JAK) inhibitor for the treatment of autoimmune diseases and organ transplant rejection.

J Med Chem 2010 Dec 24;53(24):8468-84. Epub 2010 Nov 24.

Groton Laboratories, Pfizer Global Research & Development, Groton, Connecticut 06340, USA.

There is a critical need for safer and more convenient treatments for organ transplant rejection and autoimmune disorders such as rheumatoid arthritis. Janus tyrosine kinases (JAK1, JAK3) are expressed in lymphoid cells and are involved in the signaling of multiple cytokines important for various T cell functions. Blockade of the JAK1/JAK3-STAT pathway with a small molecule was anticipated to provide therapeutic immunosuppression/immunomodulation. The Pfizer compound library was screened against the catalytic domain of JAK3 resulting in the identification of a pyrrolopyrimidine-based series of inhibitors represented by CP-352,664 (2a). Synthetic analogues of 2a were screened against the JAK enzymes and evaluated in an IL-2 induced T cell blast proliferation assay. Select compounds were evaluated in rodent efficacy models of allograft rejection and destructive inflammatory arthritis. Optimization within this chemical series led to identification of CP-690,550 1, a potential first-in-class JAK inhibitor for treatment of autoimmune diseases and organ transplant rejection.
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http://dx.doi.org/10.1021/jm1004286DOI Listing
December 2010

Structure-activity relationships and hepatic safety risks of thiazole agonists of the thrombopoietin receptor.

Bioorg Med Chem Lett 2010 Jul 26;20(14):4069-72. Epub 2010 May 26.

Pfizer Worldwide Research and Development, Groton, CT 06340, USA.

5-F substitution of an aminothiazole moiety within a series of thrombopoietin receptor agonists leads to potent agents with an improved hepatic safety profile in rodent toxicology studies.
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http://dx.doi.org/10.1016/j.bmcl.2010.05.087DOI Listing
July 2010

The identification of orally bioavailable thrombopoietin agonists.

Bioorg Med Chem Lett 2009 Mar 15;19(5):1428-30. Epub 2009 Jan 15.

Pfizer Global Research and Development, Groton Laboratories, MS8220-2405, Eastern Point Road, Groton, CT 06340, USA.

Recently, we disclosed a series of potent pyrimidine benzamide-based thrombopoietin receptor agonists. Unfortunately, the structural features required for the desired activity conferred physicochemical properties that were not favorable for the development of an oral agent. The physical properties of the series were improved by replacing the aminopyrimidinyl group with a piperidine-4-carboxylic acid moiety. The resulting compounds possessed favorable in vivo pharmacokinetic properties, including good bioavailability.
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http://dx.doi.org/10.1016/j.bmcl.2009.01.032DOI Listing
March 2009

Molecular features crucial to the activity of pyrimidine benzamide-based thrombopoietin receptor agonists.

Bioorg Med Chem Lett 2008 May 20;18(9):3000-6. Epub 2008 Mar 20.

Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA.

The identification of small molecule modulators of biological processes mediated via protein-protein interactions has generally proved to be a challenging endeavor. In the case of the thrombopoietin receptor (TPOr), however, a number of small molecule types have been reported to display biological activity similar to that of the agonist protein TPO. Through a detailed analysis of structure-activity relationships, X-ray crystal structures, NMR coupling constants, nuclear Overhauser effects, and computational data, we have determined the agonism-inducing conformation of one series of small molecule TPOr agonists. The relationship of this agonism-inducing conformation to that of other series of TPO receptor agonists is discussed.
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http://dx.doi.org/10.1016/j.bmcl.2008.03.052DOI Listing
May 2008

The specificity of JAK3 kinase inhibitors.

Blood 2008 Feb 19;111(4):2155-7. Epub 2007 Dec 19.

Pfizer Global Research and Development, Groton, CT, USA.

PF-956980 is a selective inhibitor of JAK3, related in structure to CP-690550, a compound being evaluated in clinical trials for rheumatoid arthritis and prevention of allograft rejection. PF-956980 has been evaluated against a panel of 30 kinases, and found to have nanomolar potency against only JAK3. Cellular and whole blood activity of this compound parallels its potency and selectivity in enzyme assays. It was effective in vivo at inhibiting the delayed type hypersensivity reaction in mice. We compared 2 commercially available JAK3 inhibitors (WHI-P131 and WHI-P154) in the same panel of biochemical and cellular assays and found them to be neither potent nor selective for JAK3. Both were found to be nanomolar inhibitors of the EGF receptor family of kinases. As these compounds have been used in numerous publications in the transplant and autoimmune disease literature, their specificity should be considered when interpreting these results.
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http://dx.doi.org/10.1182/blood-2007-09-115030DOI Listing
February 2008

A rational chemical intervention strategy to circumvent bioactivation liabilities associated with a nonpeptidyl thrombopoietin receptor agonist containing a 2-amino-4-arylthiazole motif.

Chem Res Toxicol 2007 Dec 13;20(12):1954-65. Epub 2007 Oct 13.

Pharmacokinetics, Dynamics and Metabolism Department, Pfizer Global Research and Development, Groton, Connecticut 06340, USA.

The current study examined the bioactivation potential of a nonpeptidyl thrombopoietin receptor agonist, 1-(3-chloro-5-((4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-yl)carbamoyl)pyridine-2-yl)piperidine-4-carboxylic acid (1), containing a 2-carboxamido-4-arylthiazole moiety in the core structure. Toxicological risks arising from P450-catalyzed C4-C5 thiazole ring opening in 1 via the epoxidation-->diol sequence were alleviated, since mass spectrometric analysis of human liver microsome and/or hepatocyte incubations of 1 did not reveal the formation of reactive acylthiourea and/or glyoxal metabolites, which are prototypic products derived from thiazole ring scission. However, 4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-amine (2), the product of hydrolysis of 1 in human liver microsomes, hepatocytes, and plasma, underwent oxidative bioactivation in human liver microsomes, since trapping studies with glutathione led to the formation of two conjugates derived from the addition of the thiol nucleophile to 2 and a thiazole- S-oxide metabolite of 2. Mass spectral fragmentation and NMR analysis indicated that the site of attachment of the glutathionyl moiety in both conjugates was the C5 position in the thiazole ring. Based on the structures of the glutathione conjugates, two bioactivation pathways are proposed, one involving beta-elimination of an initially formed hydroxylamine metabolite and the other involving direct two-electron oxidation of the electron-rich 2-aminothiazole system to electrophilic intermediates. This mechanistic insight into the bioactivation process allowed the development of a rational chemical intervention strategy that involved blocking the C5 position with a fluorine atom or replacing the thiazole ring with a 1,2,4-thiadiazole group. These structural changes not only abrogated the bioactivation liability associated with 1 but also resulted in compounds that retained the attractive pharmacological and pharmacokinetic attributes of the prototype agent.
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http://dx.doi.org/10.1021/tx700270rDOI Listing
December 2007

Pyrimidine benzamide-based thrombopoietin receptor agonists.

Bioorg Med Chem Lett 2007 Oct 31;17(19):5447-54. Epub 2007 Jul 31.

Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA.

A series of pyrimidine benzamide-based thrombopoietin receptor agonists is described. The lead molecule contains a 2-amino-5-unsubstituted thiazole, a group that has been associated with idiosyncratic toxicity. The potential for metabolic oxidation at C-5 of the thiazole, the likely source of toxic metabolites, was removed by substitution at C-5 or by replacing the thiazole with a thiadiazole. Potency in the series was improved by modifying the substituents on the pyrimidine and/or on the thiazole or thiadiazole pendant aryl ring. In vivo examination revealed that compounds from the series are not highly bioavailable. This is attributed to low solubility and poor permeability.
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http://dx.doi.org/10.1016/j.bmcl.2007.07.038DOI Listing
October 2007

Design and SAR of thienopyrimidine and thienopyridine inhibitors of VEGFR-2 kinase activity.

Bioorg Med Chem Lett 2004 Jan;14(1):21-4

Pfizer Global Research and Development, Groton Laboratories MS8220-2405, Eastern Point Road, Groton, CT 06340, USA.

Novel classes of thienopyrimidines and thienopyridines have been identified as potent inhibitors of VEGFR-2 kinase. The synthesis and SAR of these compounds is presented, along with successful efforts to diminish EGFR activity present in the lead series.
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http://dx.doi.org/10.1016/j.bmcl.2003.10.030DOI Listing
January 2004

Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor.

Science 2003 Oct;302(5646):875-8

Immunology Group, Department of Antibacterials and Immunology, Pfizer Global Researchand Development, Groton, CT 06340, USA.

Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation and in other clinical settings.
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http://dx.doi.org/10.1126/science.1087061DOI Listing
October 2003

A Novel Asymmetric Route to the 1,3-Disubstituted Tetrahydroisoquinoline, (-)-Argemonine.

J Org Chem 1996 Jul;61(14):4607-4610

Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523.

Chiral bicyclic lactam 13 was converted to the natural product (-)-argemonine 9 in six steps. This novel route to argemonine represents a general strategy for the preparation of chiral 1,3-disubstituted tetrahydroisoquinolines.
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http://dx.doi.org/10.1021/jo960110hDOI Listing
July 1996