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.
Bruton’s tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous autoimmune diseases. This article ...will detail the structure–activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl-9H-carbazole-1-carboxamide 6 (BMS-935177) was selected to advance into clinical development.
This report describes the biological activity, characterization, and SAR leading to 9d (BMS-754807) a small molecule IGF-1R kinase inhibitor in clinical development.
Compound 3 (BMS-536924), a novel small-molecule inhibitor of the insulin-like growth factor receptor kinase with equal potency against the insulin receptor is described. The in vitro and in vivo ...biological activity of this interesting compound is also reported.
Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or αLβ2, belongs to the β2 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-4.4nonan-7-yl)nicotinic acid (2e) was selected to advance into clinical trials.
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.
The crystal structure of BMX reveals a typical kinase protein fold that includes an extended activation loop and a stabilized DFG motif rendering the kinase in an inactive conformation. Dasatinib and PP2 bind to BMX in the ATP binding pocket and display similar binding modes to that observed in other Tec and Src protein kinases. The BMX structures identify DFG‐motif conformational elements that could potentially be utilized to design potent and/or selective BMX inhibitors.
Tau‐tubulin kinase 1 (TTBK1) is a dual‐specificity (serine/threonine and tyrosine) kinase belonging to the casein kinase 1 superfamily. TTBK1 is a neuron‐specific kinase that regulates tau ...phosphorylation. Hyperphosphorylation of tau is implicated in the pathogenesis of Alzheimer's disease. Two kinase‐domain constructs of TTBK1 were expressed in a baculovirus‐infected insect‐cell system and purified. The purified TTBK1 kinase‐domain proteins were crystallized using the hanging‐drop vapor‐diffusion method. X‐ray diffraction data were collected and the structure of TTBK1 was determined by molecular replacement both as an apo structure and in complex with a kinase inhibitor.
Analogs utilizing proline isosteres in IGF-1R/IR inhibitors are disclosed. X-ray co-crystallography of selected analogs reveals information key to target potency.
Pyrrolidine, pyrrolidinone, ...carbocyclic, and acyclic groups were used as isosteric proline replacements in a series of insulin-like growth factor I receptor kinase/insulin receptor kinase inhibitors. Examples that were similar in potency to proline-containing reference compounds were shown to project a key fluoropyridine amide into a common space, while less potent compounds were not able to do so for reasons of stereochemistry or structural rigidity.
An effective process for screening, imaging, and optimizing crystallization trials using a combination of external and internal hardware and software has been deployed. The combination of this ...infrastructure with a vast annotated crystallization database enables the creation of custom crystallization screening strategies. Because of the strong chemotype-dependent crystallization observed with HCV NS3 protease (HCVPr), this strategy was applied to a chemotype resistant to all prior crystallization efforts. The crystallization database was mined for ingredients used to generate earlier HCVPr/inhibitor co-crystals. A random screen was created from the most prolific ingredients. A previously untested combination of proven ingredients was identified that led to a successful crystallization condition for the resistant chemotype.
The discovery and synthesis of 3-(1
H-benzo
dimidazol-2-yl)pyridin-2(1
H)-one inhibitors of insulin-like growth factor receptor-1 (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 are presented.
The discovery and synthesis of 3-(1
H-benzo
dimidazol-2-yl)pyridin-2(1
H)-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.
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