Discovery of 5-Amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Inhibitors of IRAK4.

Autor: Lim J; Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Altman MD; Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Baker J; Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Brubaker JD; Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Chen H; Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Chen Y; Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Fischmann T; Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Gibeau C; Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Kleinschek MA; Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Leccese E; Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Lesburg C; Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Maclean JK; Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Moy LY; Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Mulrooney EF; Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Presland J; Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Rakhilina L; Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Smith GF; Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Steinhuebel D; Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States., Yang R; Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2015 Apr 20; Vol. 6 (6), pp. 683-8. Date of Electronic Publication: 2015 Apr 20 (Print Publication: 2015).
DOI: 10.1021/acsmedchemlett.5b00107
Abstrakt: Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential signal transducer downstream of the IL-1R and TLR superfamily, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides was developed via sequential modifications to the 5-position of the pyrazolopyrimidine ring and the 3-position of the pyrazole ring. Replacement of substituents responsible for poor permeability and improvement of physical properties guided by cLogD led to the identification of IRAK4 inhibitors with excellent potency, kinase selectivity, and pharmacokinetic properties suitable for oral dosing.
Databáze: MEDLINE