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1.
J Med Chem ; 64(16): 11886-11903, 2021 08 26.
Article in English | MEDLINE | ID: mdl-34355886

ABSTRACT

The PKC-θ isoform of protein kinase C is selectively expressed in T lymphocytes and plays an important role in the T cell antigen receptor (TCR)-triggered activation of mature T cells, T cell proliferation, and the subsequent release of cytokines such as interleukin-2 (IL-2). Herein, we report the synthesis and structure-activity relationship (SAR) of a novel series of PKC-θ inhibitors. Through a combination of structure-guided design and exploratory SAR, suitable replacements for the basic C4 amine of the original lead (3) were identified. Property-guided design enabled the identification of appropriately substituted C2 groups to afford potent analogs with metabolic stability and permeability to support in vivo testing. With exquisite general kinase selectivity, cellular inhibition of T cell activation as assessed by IL-2 expression, a favorable safety profile, and demonstrated in vivo efficacy in models of acute and chronic T cell activation with oral dosing, CC-90005 (57) was selected for clinical development.


Subject(s)
Cyclohexanols/therapeutic use , Graft vs Host Disease/drug therapy , Immunologic Factors/therapeutic use , Protein Kinase C-theta/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Animals , Caco-2 Cells , Cell Proliferation/drug effects , Cyclohexanols/chemical synthesis , Cyclohexanols/metabolism , Humans , Immunologic Factors/chemical synthesis , Immunologic Factors/metabolism , Lymphocyte Activation/drug effects , Male , Mice, Inbred C57BL , Molecular Docking Simulation , Molecular Structure , Protein Binding , Protein Kinase C-delta/antagonists & inhibitors , Protein Kinase C-delta/metabolism , Protein Kinase C-theta/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Structure-Activity Relationship , T-Lymphocytes/drug effects
2.
PLoS One ; 11(1): e0145705, 2016.
Article in English | MEDLINE | ID: mdl-26756335

ABSTRACT

Autoantibodies and the immunoreceptors to which they bind can contribute to the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA). Spleen Tyrosine Kinase (Syk) is a non-receptor tyrosine kinase with a central role in immunoreceptor (FcR) signaling and immune cell functionality. Syk kinase inhibitors have activity in antibody-dependent immune cell activation assays, in preclinical models of arthritis, and have progressed into clinical trials for RA and other autoimmune diseases. Here we describe the characterization of a novel triazolopyridine-based Syk kinase inhibitor, CC-509. This compound is a potent inhibitor of purified Syk enzyme, FcR-dependent and FcR-independent signaling in primary immune cells, and basophil activation in human whole blood. CC-509 is moderately selective across the kinome and against other non-kinase enzymes or receptors. Importantly, CC-509 was optimized away from and has modest activity against cellular KDR and Jak2, kinases that when inhibited in a preclinical and clinical setting may promote hypertension and neutropenia, respectively. In addition, CC-509 is orally bioavailable and displays dose-dependent efficacy in two rodent models of immune-inflammatory disease. In passive cutaneous anaphylaxis (PCA), CC-509 significantly inhibited skin edema. Moreover, CC-509 significantly reduced paw swelling and the tissue levels of pro-inflammatory cytokines RANTES and MIP-1α in the collagen-induced arthritis (CIA) model. In summary, CC-509 is a potent, moderately selective, and efficacious inhibitor of Syk that has a differentiated profile when compared to other Syk compounds that have progressed into the clinic for RA.


Subject(s)
Indazoles/chemistry , Inflammation/drug therapy , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyridines/chemistry , Triazoles/chemistry , Animals , Arthritis, Experimental/drug therapy , Arthritis, Experimental/physiopathology , Basophils/cytology , Cell Line , Collagen/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Edema/pathology , Eosinophils/cytology , Female , HEK293 Cells , Humans , Hypertension/drug therapy , Inflammation/physiopathology , Inhibitory Concentration 50 , Janus Kinase 2/antagonists & inhibitors , Male , Neutropenia/drug therapy , Neutrophils/cytology , Rats , Rats, Inbred Lew , Rats, Sprague-Dawley , Receptors, Fc/chemistry , Skin/pathology , Syk Kinase , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors
3.
J Bone Miner Res ; 24(2): 231-40, 2009 Feb.
Article in English | MEDLINE | ID: mdl-18847323

ABSTRACT

Recent clinical trials with bisphosphonates and PTH have not supported the hypothesis that combination treatments with antiresorptive and anabolic agents would lead to synergistic activity. We hypothesized that combination treatment with a selective androgen receptor modulator (SARM), LGD-3303, and a bisphosphonate would be beneficial. In vitro competitive binding and transcriptional activity assays were used to characterize LGD-3303. LGD-3303 is a potent nonsteroidal androgen that shows little or no cross-reactivity with related nuclear receptors. Tissue selective activity of LGD-3303 was assessed in orchidectomized male rats orally administered LGD-3303 for 14 days. LGD-3303 increased the levator ani muscle weight above eugonadal levels but had greatly reduced activity on the prostate, never increasing the ventral prostate weight to >50% of eugonadal levels even at high doses. Ovariectomized female rats were treated with LGD-3303, alendronate, or combination treatment to study the effects on bone. DXA scans, histomorphometry, and biomechanics were performed. LGD-3303 increased muscle weight in females rats. In addition, LGD-3303 increased BMD and BMC at both cortical and cancellous bone sites. At cortical sites, the effects were caused in part by anabolic activity on the periosteal surface. At every measured site, combination treatment was as effective as either single agent and in some cases showed significant added benefit. LGD-3303 is a novel SARM with anabolic effects on muscle and cortical bone not observed with bisphosphonates. Combination therapy with LGD-3303 and alendronate had additive effects and may potentially be a useful therapy for osteoporosis and frailty.


Subject(s)
Androgen Antagonists/therapeutic use , Bone Diseases, Metabolic/drug therapy , Diphosphonates/therapeutic use , Absorptiometry, Photon , Androgen Antagonists/pharmacology , Animals , Biomechanical Phenomena/drug effects , Body Weight/drug effects , Bone Density/drug effects , Bone Diseases, Metabolic/blood , Bone Diseases, Metabolic/physiopathology , Diphosphonates/pharmacology , Drug Synergism , Drug Therapy, Combination , Estrogens/deficiency , Female , Femur/drug effects , Femur/pathology , Femur/physiopathology , Lumbar Vertebrae/drug effects , Lumbar Vertebrae/pathology , Lumbar Vertebrae/physiopathology , Male , Orchiectomy , Organ Size/drug effects , Osteocalcin/blood , Ovariectomy , Pyrroles/pharmacology , Pyrroles/therapeutic use , Quinolones/pharmacology , Quinolones/therapeutic use , Rats , Rats, Sprague-Dawley , Transcription, Genetic/drug effects
4.
Endocrinology ; 149(3): 1103-12, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18063690

ABSTRACT

Although it is evident that androgens increase muscle mass and strength, little is known about the critical molecular targets of androgens in skeletal muscle. In rodents, the skeletal alpha-actin gene is a tissue-specific gene expressed only in the levator ani and other skeletal muscles but not in the prostate or preputial gland, the well-known androgen target tissue. We identified tissue-specific androgen-regulated genes in the skeletal muscle in rats after oral administration of androgens and focused on androgen-dependent up-regulation of the skeletal alpha-actin gene. To investigate the mechanism of action, an in vitro system with various cell lines and a series of deletion mutants of the alpha-actin promoter were used. The human skeletal alpha-actin promoter was activated by androgens in the muscle cell line C2C12 but not in the liver, prostate, or breast cancer cell lines in which exogenous human androgen receptor is expressed. The sequence of the promoter is sufficient for cell-specific androgen response, providing a model for the tissue specificity demonstrated in vivo. Using a series of deletion mutants, the androgen response can be maintained using just the proximal promoter region. The importance of androgen regulation of this small portion of the human skeletal alpha-actin promoter was demonstrated by the correlation between muscle and the alpha-actin promoter activity for an array of selective androgen receptor modulators (SARMs), including an orally active SARM LGD2226. Taken together, the results suggest that the regulation of skeletal alpha-actin by androgens/SARMs may represent an important model system for understanding androgen anabolic action in the muscle.


Subject(s)
Actins/metabolism , Androgens/physiology , Muscle, Skeletal/metabolism , Actins/genetics , Aminoquinolines/pharmacology , Animals , Base Sequence , Cell Line , Cell Line, Tumor , Dihydrotestosterone/pharmacology , Gene Expression Regulation , Humans , Male , Mice , Models, Animal , Molecular Sequence Data , Promoter Regions, Genetic , Quinolones/pharmacology , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Androgen/metabolism , Transfection
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