ABSTRACT
Pan proviral insertion site of Moloney murine leukemia (PIM) 1, 2, and 3 kinase inhibitors have recently begun to be tested in humans to assess whether pan PIM kinase inhibition may provide benefit to cancer patients. Herein, the synthesis, in vitro activity, in vivo activity in an acute myeloid leukemia xenograft model, and preclinical profile of the potent and selective pan PIM kinase inhibitor compound 8 (PIM447) are described. Starting from the reported aminopiperidyl pan PIM kinase inhibitor compound 3, a strategy to improve the microsomal stability was pursued resulting in the identification of potent aminocyclohexyl pan PIM inhibitors with high metabolic stability. From this aminocyclohexyl series, compound 8 entered the clinic in 2012 in multiple myeloma patients and is currently in several phase 1 trials of cancer patients with hematological malignancies.
Subject(s)
Leukemia, Myeloid, Acute/drug therapy , Picolinic Acids/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Amides/therapeutic use , Animals , Cell Line, Tumor , Halogenation , Humans , Leukemia, Myeloid, Acute/metabolism , Mice , Models, Molecular , Picolinic Acids/chemical synthesis , Picolinic Acids/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-pim-1/metabolismABSTRACT
Proviral insertion of Moloney virus (PIM) 1, 2, and 3 kinases are serine/threonine kinases that normally function in survival and proliferation of hematopoietic cells. As high expression of PIM1, 2, and 3 is frequently observed in many human malignancies, including multiple myeloma, non-Hodgkins lymphoma, and myeloid leukemias, there is interest in determining whether selective PIM inhibition can improve outcomes of these human cancers. Herein, we describe our efforts toward this goal. The structure guided optimization of a singleton high throughput screening hit in which the potency against all three PIM isoforms was increased >10,000-fold to yield compounds with pan PIM K is < 10 pM, nanomolar cellular potency, and in vivo activity in an acute myeloid leukemia Pim-dependent tumor model is described.
ABSTRACT
An SAR campaign designed to increase polarity in the 'tail' region of benzothiazole 1 resulted in two series of structurally novel 5-and 6-substituted S1P(1) agonists. Structural optimization for potency ultimately delivered carboxamide (+)-11f, which in addition to possessing improved physicochemical properties relative to starting benzothiazole 1, also displayed good S1P(3) selectivity and acceptable in vivo lymphocyte-depleting activity.
Subject(s)
Benzothiazoles/chemistry , Lymphocytes/drug effects , Receptors, Lysosphingolipid/agonists , Receptors, Lysosphingolipid/chemistry , Animals , CHO Cells , Cell Line, Tumor , Chemistry, Pharmaceutical/methods , Chemistry, Physical/methods , Cricetinae , Cricetulus , Drug Design , Female , Green Fluorescent Proteins/metabolism , Humans , Ketones , Lymphocytes/cytology , Models, Chemical , Rats , Rats, Inbred Lew , Receptors, G-Protein-Coupled/metabolismABSTRACT
Optimization of a benzofuranyl S1P1 agonist lead compound (3) led to the discovery of 1-(3-fluoro-4-(5-(2-fluorobenzyl)benzo[d]thiazol-2-yl)benzyl)azetidine-3-carboxylic acid (14), a potent S1P1 agonist with minimal activity at S1P3. Dosed orally at 0.3 mg/kg, 14 significantly reduced blood lymphocyte counts 24 h postdose and attenuated a delayed type hypersensitivity (DTH) response to antigen challenge.
ABSTRACT
The optimization of a series of thiazolopyridine S1P1 agonists with limited activity at the S1P3 receptor is reported. These efforts resulted in the discovery of 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo-[5,4-b]pyridin-2-yl)benzyl)azetidine-3-carboxylic acid (5d, AMG 369), a potent dual S1P1/S1P5 agonist with limited activity at S1P3 and no activity at S1P2/S1P4. Dosed orally at 0.1 mg/kg, 5d is shown to reduce blood lymphocyte counts 24 h postdose and delay the onset and reduce the severity of experimental autoimmune encephalomyelitis in rat.
ABSTRACT
We report the structure-based design and synthesis of a novel series of aza-benzimidazoles as PHD2 inhibitors. These efforts resulted in compound 22, which displayed highly potent inhibition of PHD2 function in vitro.
Subject(s)
Aza Compounds/chemical synthesis , Aza Compounds/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Procollagen-Proline Dioxygenase/antagonists & inhibitors , Aza Compounds/chemistry , Basic Helix-Loop-Helix Transcription Factors , Benzimidazoles/chemistry , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Humans , Hypoxia-Inducible Factor-Proline Dioxygenases , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
We report the discovery of potent agonists for the human formyl-peptide-like 1 receptor (hFPRL1). These compounds did not act at a closely related receptor denoted human formyl peptide receptor (hFPR) up to 10 microM concentration. Recent studies have indicated that agonizing this receptor may promote resolution of inflammation. In an exploratory study, a novel hFPRL1 agonist showed efficacy in a mouse ear inflammation model following oral administration.
