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A Tiny Pocket Packs a Punch: Leveraging Pyridones for the Discovery of CNS-Penetrant Aza-indazole IRAK4 Inhibitors.
Bolduc, Philippe N; Pfaffenbach, Magnus; Evans, Ryan; Xin, Zhili; Henry, Kate L; Gao, Fang; Fang, Terry; Silbereis, John; Vera Rebollar, Jorge; Li, Pei; Chodaparambil, Jayanth V; Metrick, Claire; Peterson, Emily A.
Afiliación
  • Bolduc PN; Department of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Pfaffenbach M; Department of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Evans R; Department of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Xin Z; Department of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Henry KL; Department of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Gao F; Department of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Fang T; Department of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Silbereis J; Department of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Vera Rebollar J; Department of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Li P; Department of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Chodaparambil JV; Department of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Metrick C; Department of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Peterson EA; Department of Medicinal Chemistry;Department of Multiple Sclerosis and Immunology;Drug Metabolism and Pharmacokinetics;Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
ACS Med Chem Lett ; 15(5): 714-721, 2024 May 09.
Article en En | MEDLINE | ID: mdl-38746903
ABSTRACT
We herein report the discovery, synthesis, and evolution of a series of indazoles and azaindazoles as CNS-penetrant IRAK4 inhibitors. Described is the use of structure-based and property-based drug design strategically leveraged to guide the property profile of a key series into a favorable property space while maintaining potency and selectivity. Our rationale that led toward functionalities with potency improvements, CNS-penetration, solubility, and favorable drug-like properties is portrayed. In vivo evaluation of an advanced analogue showed significant, dose-dependent modulation of inflammatory cytokines in a mouse model. In pursuit of incorporating a highly engineered bridged ether that was crucial to metabolic stability in this series, significant synthetic challenges were overcome to enable the preparation of the analogues.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos