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1.
ACS Med Chem Lett ; 9(12): 1193-1198, 2018 Dec 13.
Article in English | MEDLINE | ID: mdl-30613325

ABSTRACT

We report herein the design and synthesis of a series of orally active, liver-targeted hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors for the treatment of anemia. In order to mitigate the concerns for potential systemic side effects, we pursued liver-targeted HIF-PHD inhibitors relying on uptake via organic anion transporting polypeptides (OATPs). Starting from a systemic HIF-PHD inhibitor (1), medicinal chemistry efforts directed toward reducing permeability and, at the same time, maintaining oral absorption led to the synthesis of an array of structurally diverse hydroxypyridone analogues. Compound 28a was chosen for further profiling, because of its excellent in vitro profile and liver selectivity. This compound significantly increased hemoglobin levels in rats, following chronic QD oral administration, and displayed selectivity over systemic effects.

2.
J Med Chem ; 60(23): 9676-9690, 2017 12 14.
Article in English | MEDLINE | ID: mdl-29156136

ABSTRACT

The discovery of a potent selective low dose Janus kinase 1 (JAK1) inhibitor suitable for clinical evaluation is described. As part of an overall goal to minimize dose, we pursued a medicinal chemistry strategy focused on optimization of key parameters that influence dose size, including lowering human Clint and increasing intrinsic potency, bioavailability, and solubility. To impact these multiple parameters simultaneously, we used lipophilic ligand efficiency as a key metric to track changes in the physicochemical properties of our analogs, which led to improvements in overall compound quality. In parallel, structural information guided advancements in JAK1 selectivity by informing on new vector space, which enabled the discovery of a unique key amino acid difference between JAK1 (Glu966) and JAK2 (Asp939). This difference was exploited to consistently produce analogs with the best balance of JAK1 selectivity, efficacy, and projected human dose, ultimately culminating in the discovery of compound 28.


Subject(s)
Janus Kinase 1/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Animals , Dogs , Drug Discovery , Halogenation , Humans , Janus Kinase 1/chemistry , Janus Kinase 1/metabolism , Molecular Docking Simulation , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacokinetics , Pyrazoles/administration & dosage , Pyrazoles/pharmacokinetics , Rats , Structure-Activity Relationship
3.
J Pharmacol Exp Ther ; 361(2): 229-244, 2017 05.
Article in English | MEDLINE | ID: mdl-28193636

ABSTRACT

Reversible janus associated kinase (JAK) inhibitors such as tofacitinib and decernotinib block cytokine signaling and are efficacious in treating autoimmune diseases. However, therapeutic doses are limited due to inhibition of other JAK/signal transducer and activator of transcription pathways associated with hematopoiesis, lipid biogenesis, infection, and immune responses. A selective JAK3 inhibitor may have a better therapeutic index; however, until recently, no compounds have been described that maintain JAK3 selectivity in cells, as well as against the kinome, with good physicochemical properties to test the JAK3 hypothesis in vivo. To quantify the biochemical basis for JAK isozyme selectivity, we determined that the apparent Km value for each JAK isozyme ranged from 31.8 to 2.9 µM for JAK1 and JAK3, respectively. To confirm compound activity in cells, we developed a novel enzyme complementation assay that read activity of single JAK isozymes in a cellular context. Reversible JAK3 inhibitors cannot achieve sufficient selectivity against other isozymes in the cellular context due to inherent differences in enzyme ATP Km values. Therefore, we developed irreversible JAK3 compounds that are potent and highly selective in vitro in cells and against the kinome. Compound 2, a potent inhibitor of JAK3 (0.15 nM) was 4300-fold selective for JAK3 over JAK1 in enzyme assays, 67-fold [interleukin (IL)-2 versus IL-6] or 140-fold [IL-2 versus erythropoietin or granulocyte-macrophage colony-stimulating factor (GMCSF)] selective in cellular reporter assays and >35-fold selective in human peripheral blood mononuclear cell assays (IL-7 versus IL-6 or GMCSF). In vivo, selective JAK3 inhibition was sufficient to block the development of inflammation in a rat model of rheumatoid arthritis, while sparing hematopoiesis.


Subject(s)
Autoimmune Diseases , Janus Kinase 1 , Janus Kinase 3 , Piperidines/pharmacology , Pyrimidines/pharmacology , Pyrroles/pharmacology , Animals , Arthritis, Experimental/drug therapy , Autoimmune Diseases/drug therapy , Autoimmune Diseases/metabolism , Dose-Response Relationship, Drug , Drug Monitoring/methods , Humans , Isoenzymes , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 1/chemistry , Janus Kinase 1/metabolism , Janus Kinase 3/antagonists & inhibitors , Janus Kinase 3/chemistry , Janus Kinase 3/metabolism , Monitoring, Immunologic/methods , Protein Kinase Inhibitors/pharmacology , Rats
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