Discovery of 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton's Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked

Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure-activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, 14f (BMS-986142) was advanced into clinical studies.

[1]  K. McIntyre,et al.  Small Molecule Reversible Inhibitors of Bruton's Tyrosine Kinase (BTK): Structure-Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide (BMS-935177). , 2016, Journal of medicinal chemistry.

[2]  E. Lee,et al.  HM71224, a novel Bruton’s tyrosine kinase inhibitor, suppresses B cell and monocyte activation and ameliorates arthritis in a mouse model: a potential drug for rheumatoid arthritis , 2016, Arthritis Research & Therapy.

[3]  V. Hornak,et al.  Discovery of 8-Amino-imidazo[1,5-a]pyrazines as Reversible BTK Inhibitors for the Treatment of Rheumatoid Arthritis. , 2016, ACS medicinal chemistry letters.

[4]  J. Gustafson,et al.  The Preorganization of Atropisomers to Increase Target Selectivity , 2016, Synlett : Accounts and Rapid Communications in Synthetic Organic Chemistry.

[5]  Adam R. Johnson,et al.  Discovery of highly potent and selective Bruton's tyrosine kinase inhibitors: Pyridazinone analogs with improved metabolic stability. , 2016, Bioorganic & medicinal chemistry letters.

[6]  P. Keller,et al.  A twist of nature--the significance of atropisomers in biological systems. , 2015, Natural product reports.

[7]  Zheng Yang,et al.  Design and synthesis of carbazole carboxamides as promising inhibitors of Bruton's tyrosine kinase (BTK) and Janus kinase 2 (JAK2). , 2015, Bioorganic & medicinal chemistry letters.

[8]  A. Rheingold,et al.  Exploiting Atropisomerism to Increase the Target Selectivity of Kinase Inhibitors. , 2015, Angewandte Chemie.

[9]  J. M. Bradshaw,et al.  Prolonged and tunable residence time using reversible covalent kinase inhibitors , 2015, Nature chemical biology.

[10]  S. Hymowitz,et al.  Potent and selective Bruton's tyrosine kinase inhibitors: discovery of GDC-0834. , 2015, Bioorganic & medicinal chemistry letters.

[11]  B. Chang,et al.  Bruton's tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. , 2014, Drug discovery today.

[12]  J. K. Park,et al.  THU0499 Hm71224, A Novel Oral BTK Inhibitor, Inhibits Human Immune Cell Activation: New Drug Candidate to Treat B-Cell Associated Autoimmune Diseases , 2014 .

[13]  Andrew Tebben,et al.  Purine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors for autoimmune diseases. , 2014, Bioorganic & medicinal chemistry letters.

[14]  J. Burger.  Bruton’s Tyrosine Kinase (BTK) Inhibitors in Clinical Trials , 2014, Current Hematologic Malignancy Reports.

[15]  Jason M. Edmonds,et al.  Selective Inhibition of BTK Prevents Murine Lupus and Antibody-Mediated Glomerulonephritis , 2013, The Journal of Immunology.

[16]  Yamei Chen,et al.  Ibrutinib and novel BTK inhibitors in clinical development , 2013, Journal of Hematology & Oncology.

[17]  Juswinder Singh,et al.  Inhibition of Btk with CC-292 Provides Early Pharmacodynamic Assessment of Activity in Mice and Humans , 2013, The Journal of Pharmacology and Experimental Therapeutics.

[18]  Daigen Xu,et al.  RN486, a Selective Bruton's Tyrosine Kinase Inhibitor, Abrogates Immune Hypersensitivity Responses and Arthritis in Rodents , 2012, Journal of Pharmacology and Experimental Therapeutics.

[19]  O. Hucke,et al.  Assessing atropisomer axial chirality in drug discovery and development. , 2011, Journal of medicinal chemistry.

[20]  F. Staal,et al.  Biology and novel treatment options for XLA, the most common monogenetic immunodeficiency in man , 2011, Expert opinion on therapeutic targets.

[21]  D. Moras,et al.  Cysteine mapping in conformationally distinct kinase nucleotide binding sites: application to the design of selective covalent inhibitors. , 2011, Journal of medicinal chemistry.

[22]  Stephen D Pickett,et al.  The impact of aromatic ring count on compound developability: further insights by examining carbo- and hetero-aromatic and -aliphatic ring types. , 2011, Drug discovery today.

[23]  Brandon J. Bravo,et al.  Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis. , 2011, Nature chemical biology.

[24]  Peter Ertl,et al.  The graphical representation of ADME-related molecule properties for medicinal chemists. , 2011, Drug discovery today.

[25]  B. Vanhaesebroeck,et al.  Btk-dependent Rac activation and actin rearrangement following FcεRI aggregation promotes enhanced chemotactic responses of mast cells , 2010, Journal of Cell Science.

[26]  Douglas H. Thamm,et al.  The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy , 2010, Proceedings of the National Academy of Sciences.

[27]  S. LaPlante,et al.  The challenge of atropisomerism in drug discovery. , 2009, Angewandte Chemie.

[28]  Mauno Vihinen,et al.  Bruton’s tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain , 2009, Immunological reviews.

[29]  P. Mease.  B cell-targeted therapy in autoimmune disease: rationale, mechanisms, and clinical application. , 2008, The Journal of rheumatology.

[30]  M. Cybulsky,et al.  Dual Functions of Bruton’s Tyrosine Kinase and Tec Kinase during Fcγ Receptor-Induced Signaling and Phagocytosis1 , 2008, The Journal of Immunology.

[31]  Taesoo Kim,et al.  The Tec Family Tyrosine Kinase Btk Regulates RANKL-induced Osteoclast Maturation* , 2008, Journal of Biological Chemistry.

[32]  Michael S. Cohen,et al.  Structural Bioinformatics-Based Design of Selective, Irreversible Kinase Inhibitors , 2005, Science.

[33]  J. Puck.  Molecular and genetic basis of X-linked immunodeficiency disorders , 1994, Journal of Clinical Immunology.

[34]  R. Hendriks,et al.  Function of Bruton’s Tyrosine Kinase during B Cell Development Is Partially Independent of Its Catalytic Activity 1 , 2003, The Journal of Immunology.

[35]  A. Satterthwaite,et al.  Haploinsufficiency of B cell linker protein enhances B cell signaling defects in mice expressing a limiting dosage of Bruton's tyrosine kinase. , 2003, International immunology.

[36]  J. Caldwell,et al.  Putting chirality to work: the strategy of chiral switches , 2002, Nature Reviews Drug Discovery.

[37]  W. Khan,et al.  Bruton's Tyrosine Kinase Is Required for Activation of Iκb Kinase and Nuclear Factor κb in Response to B Cell Receptor Engagement , 2000, The Journal of experimental medicine.

[38]  Mohamed,et al.  Signalling of Bruton's Tyrosine Kinase, Btk , 1999, Scandinavian journal of immunology.

[39]  T. Kurosaki,et al.  A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2 , 1996, The Journal of experimental medicine.

[40]  Norio Miyaura,et al.  Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds , 1995 .

[41]  O. Witte,et al.  Role of Bruton's tyrosine kinase in immunodeficiency. , 1994, Current opinion in immunology.

[42]  R. Holmdahl,et al.  Genes on the X chromosome affect development of collagen‐induced arthritis in mice , 1993, Clinical and Experimental Immunology.

[43]  A. M. Glazer,et al.  A nitrogen‐gas‐stream cryostat for general X‐ray diffraction studies , 1986 .

[44]  J. Winkelstein,et al.  X‐Linked Agammaglobulinemia: An Analysis of 96 Patients , 1985, Medicine.

[45]  K. Frederiksen,et al.  Ability of the xid gene to prevent autoimmunity in (NZB X NZW)F1 mice during the course of their natural history, after polyclonal stimulation, or following immunization with DNA. , 1982, The Journal of clinical investigation.