دورية أكاديمية
Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin.
| العنوان: | Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin. |
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| المؤلفون: | Jones P; Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.; Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.; Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K., Storer RI; Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.; Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.; Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K., Sabnis YA; Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.; Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.; Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K., Wakenhut FM; Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.; Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.; Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K., Whitlock GA; Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.; Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.; Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K., England KS; Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.; Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.; Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K., Mukaiyama T; Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.; Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.; Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K., Dehnhardt CM; Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.; Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.; Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K., Coe JW; Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.; Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.; Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K., Kortum SW; Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.; Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.; Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K., Chrencik JE; Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.; Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.; Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K., Brown DG; Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.; Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.; Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K., Jones RM; Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.; Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.; Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K., Murphy JR; Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.; Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.; Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K., Yeoh T; Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.; Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.; Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K., Morgan P; Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.; Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.; Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K., Kilty I; Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.; Medicine Design, and ⊥Medicinal Sciences, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.; Worldwide Medicinal Chemistry, ∇Structural Biology and Biophysics, and ○Pharmaceutical Sciences, Pfizer Ltd. , Ramsgate Road, Sandwich, CT13 9NJ, U.K. |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2017 Jan 26; Vol. 60 (2), pp. 767-786. Date of Electronic Publication: 2017 Jan 04. |
| نوع المنشور: | Journal Article; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| مواضيع طبية MeSH: | Anti-Inflammatory Agents/*pharmacology , Heterocyclic Compounds, 2-Ring/*pharmacology , Indazoles/*pharmacology , Janus Kinases/*antagonists & inhibitors , Lung Diseases/*drug therapy , Protein Kinase Inhibitors/*pharmacology , Skin Diseases/*drug therapy, Administration, Cutaneous ; Administration, Inhalation ; Animals ; Anti-Inflammatory Agents/administration & dosage ; Anti-Inflammatory Agents/chemical synthesis ; Anti-Inflammatory Agents/toxicity ; Binding Sites ; Crystallography, X-Ray ; Dogs ; Drug Design ; Hepatocytes/metabolism ; Heterocyclic Compounds, 2-Ring/administration & dosage ; Heterocyclic Compounds, 2-Ring/chemical synthesis ; Heterocyclic Compounds, 2-Ring/toxicity ; Humans ; Indazoles/administration & dosage ; Indazoles/chemical synthesis ; Indazoles/toxicity ; Janus Kinase 1/antagonists & inhibitors ; Janus Kinase 2/antagonists & inhibitors ; Janus Kinase 3/antagonists & inhibitors ; Mice, Inbred BALB C ; Microsomes, Liver/metabolism ; Phosphorylation ; Protein Kinase Inhibitors/administration & dosage ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/toxicity ; Rats ; Solubility |
| مستخلص: | By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization of the series for potency and increased duration of action commensurate with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies. |
| المشرفين على المادة: | 0 (Anti-Inflammatory Agents) 0 (Heterocyclic Compounds, 2-Ring) 0 (Indazoles) 0 (PF-06263276) 0 (Protein Kinase Inhibitors) EC 2.7.10.2 (JAK1 protein, human) EC 2.7.10.2 (JAK2 protein, human) EC 2.7.10.2 (JAK3 protein, human) EC 2.7.10.2 (Janus Kinase 1) EC 2.7.10.2 (Janus Kinase 2) EC 2.7.10.2 (Janus Kinase 3) EC 2.7.10.2 (Janus Kinases) |
| تواريخ الأحداث: | Date Created: 20161217 Date Completed: 20170704 Latest Revision: 20181104 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1021/acs.jmedchem.6b01634 |
| PMID: | 27983835 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4804 |
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| DOI: | 10.1021/acs.jmedchem.6b01634 |