ABSTRACT
Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFα). Structure-activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic-pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed.
Subject(s)
Naphthyridines/pharmacology , Quinolines/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Animals , Arthritis, Experimental/drug therapy , Arthritis, Rheumatoid/drug therapy , Drug Design , Female , Humans , Mice, Inbred C57BL , Microsomes, Liver/metabolism , Molecular Structure , Naphthyridines/chemical synthesis , Naphthyridines/pharmacokinetics , Naphthyridines/therapeutic use , Proof of Concept Study , Quinolines/chemical synthesis , Quinolines/pharmacokinetics , Quinolines/therapeutic use , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Bone marrow kinase in the X chromosome, a member of the Tec family of tyrosine kinases, plays a role in both monocyte/macrophage trafficking as well as cytokine secretion. Although the structures of Tec family kinases Bruton's tyrosine kinase and IL-2-inducible T-cell kinase are known, the crystal structures of other Tec family kinases have remained elusive. We report the X-ray crystal structures of bone marrow kinase in the X chromosome in complex with dasatinib at 2.4 Å resolution and PP2 at 1.9 Å resolution. The bone marrow kinase in the X chromosome structures reveal a typical kinase protein fold; with well-ordered protein conformation that includes an open/extended activation loop and a stabilized DFG-motif rendering the kinase in an inactive conformation. Dasatinib and PP2 bind to bone marrow kinase in the X chromosome in the ATP binding pocket and display similar binding modes to that observed in other Tec and Src protein kinases. The bone marrow kinase in the X chromosome structures identify conformational elements of the DFG-motif that could potentially be utilized to design potent and/or selective bone marrow kinase in the X chromosome inhibitors.
Subject(s)
Chromosomes, Human, X , Protein-Tyrosine Kinases/chemistry , Agammaglobulinaemia Tyrosine Kinase , Binding Sites , Crystallography, X-Ray , Dasatinib , Humans , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Structure, Tertiary , Protein-Tyrosine Kinases/metabolism , Pyrimidines/chemistry , Thiazoles/chemistry , src-Family Kinases/chemistry , src-Family Kinases/metabolismABSTRACT
Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or alpha(L)beta(2), belongs to the beta(2) integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion molecules 1, 2, and 3 (ICAM 1, 2, and 3). The interactions between LFA-1 and the ICAMs are critical for cell adhesion, and preclinical animal studies and clinical data from the humanized anti-LFA-1 antibody efalizumab have provided proof-of-concept for LFA-1 as an immunological target. This article will detail the structure-activity relationships (SAR) leading to a novel second generation series of highly potent spirocyclic hydantoin antagonists of LFA-1. With significantly enhanced in vitro and ex vivo potency relative to our first clinical compound (1), as well as demonstrated in vivo activity and an acceptable pharmacokinetic and safety profile, 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro-[4.4]nonan-7-yl)nicotinic acid (2e) was selected to advance into clinical trials.
Subject(s)
Hydantoins/pharmacokinetics , Immunologic Factors/chemistry , Lymphocyte Function-Associated Antigen-1/drug effects , Nicotinic Acids/pharmacokinetics , Humans , Hydantoins/pharmacology , Lymphocyte Function-Associated Antigen-1/chemistry , Lymphocyte Function-Associated Antigen-1/immunology , Nicotinic Acids/toxicity , Structure-Activity RelationshipABSTRACT
The discovery and synthesis of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor 1-receptor (IGF-1R) are presented. Installing amine containing side chains at the 4-position of pyridone ring significantly improved the enzyme potency. SAR and biological activity of these compounds is presented.
Subject(s)
Pyridines/chemical synthesis , Pyridines/pharmacology , Receptor, IGF Type 1/antagonists & inhibitors , Benzimidazoles , Cell Line , Humans , Inhibitory Concentration 50 , Pyridones , Structure-Activity RelationshipABSTRACT
A series of structurally novel small molecule inhibitors of human alpha-thrombin was prepared to elucidate their structure-activity relationships (SARs), selectivity and activity in vivo. BMS-189664 (3) is identified as a potent, selective, and orally active reversible inhibitor of human alpha-thrombin which is efficacious in vivo in a mouse lethality model, and at inhibiting both arterial and venous thrombosis in cynomolgus monkey models.
