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1.
J Med Chem ; 67(10): 8122-8140, 2024 May 23.
Article in English | MEDLINE | ID: mdl-38712838

ABSTRACT

Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase and member of the TEC family of kinases, is involved in the regulation, migration, and functional activation of B cells and myeloid cells in the periphery and the central nervous system (CNS), cell types which are deemed central to the pathology contributing to disease progression in MS patients. Herein, we describe the discovery of BIIB129 (25), a structurally distinct and brain-penetrant targeted covalent inhibitor (TCI) of BTK with an unprecedented binding mode responsible for its high kinome selectivity. BIIB129 (25) demonstrated efficacy in disease-relevant preclinical in vivo models of B cell proliferation in the CNS, exhibits a favorable safety profile suitable for clinical development as an immunomodulating therapy for MS, and has a low projected total human daily dose.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase , Brain , Multiple Sclerosis , Protein Kinase Inhibitors , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Agammaglobulinaemia Tyrosine Kinase/metabolism , Multiple Sclerosis/drug therapy , Humans , Animals , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/chemistry , Brain/metabolism , Mice , Drug Discovery , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Rats , Structure-Activity Relationship , Cell Proliferation/drug effects , Female
2.
ACS Med Chem Lett ; 13(4): 665-673, 2022 Apr 14.
Article in English | MEDLINE | ID: mdl-35450377

ABSTRACT

Phospholipase D (PLD) is a phospholipase enzyme responsible for hydrolyzing phosphatidylcholine into the lipid signaling molecule, phosphatidic acid, and choline. From a therapeutic perspective, PLD has been implicated in human cancer progression as well as a target for neurodegenerative diseases, including Alzheimer's. Moreover, knockdown of PLD rescues the ALS phenotype in multiple Drosophila models of ALS (amyotrophic lateral sclerosis) and displays modest motor benefits in an SOD1 ALS mouse model. To further validate whether inhibiting PLD is beneficial for the treatment of ALS, a brain penetrant small molecule inhibitor with suitable PK properties to test in an ALS animal model is needed. Using a combination of ligand-based drug discovery and structure-based design, a dual PLD1/PLD2 inhibitor was discovered that is single digit nanomolar in the Calu-1 cell assay and has suitable PK properties for in vivo studies. To capture the in vivo measurement of PLD inhibition, a transphosphatidylation pharmacodynamic LC-MS assay was developed, in which a dual PLD1/PLD2 inhibitor was found to reduce PLD activity by 15-20-fold.

3.
J Med Chem ; 65(2): 1206-1224, 2022 01 27.
Article in English | MEDLINE | ID: mdl-34734694

ABSTRACT

Multiple Sclerosis is a chronic autoimmune neurodegenerative disorder of the central nervous system (CNS) that is characterized by inflammation, demyelination, and axonal injury leading to permeant disability. In the early stage of MS, inflammation is the primary driver of the disease progression. There remains an unmet need to develop high efficacy therapies with superior safety profiles to prevent the inflammation processes leading to disability. Herein, we describe the discovery of BIIB091, a structurally distinct orthosteric ATP competitive, reversible inhibitor that binds the BTK protein in a DFG-in confirmation designed to sequester Tyr-551, an important phosphorylation site on BTK, into an inactive conformation with excellent affinity. Preclinical studies demonstrated BIB091 to be a high potency molecule with good drug-like properties and a safety/tolerability profile suitable for clinical development as a highly selective, reversible BTKi for treating autoimmune diseases such as MS.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase , Drug Discovery , Multiple Sclerosis , Protein Kinase Inhibitors , Animals , Male , Rats , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Macaca fascicularis , Multiple Sclerosis/drug therapy , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Rats, Sprague-Dawley , Tissue Distribution
4.
Bioorg Med Chem ; 44: 116275, 2021 08 15.
Article in English | MEDLINE | ID: mdl-34314938

ABSTRACT

Bruton's tyrosine kinase (BTK) is an essential node on the BCR signaling in B cells, which are clinically validated to play a critical role in B-cell lymphomas and various auto-immune diseases such as Multiple Sclerosis (MS), Pemphigus, and rheumatoid arthritis (RA). Although non-selective irreversible BTK inhibitors have been approved for oncology, due to the emergence of drug resistance in B-cell lymphoma associated with covalent inhibitor, there an unmet medical need to identify reversible, selective, potent BTK inhibitor as viable therapeutics for patients. Herein, we describe the identification of Hits and subsequence optimization to improve the physicochemical properties, potency and kinome selectivity leading to the discovery of a novel class of BTK inhibitors. Utilizing Met ID and structure base design inhibitors were synthesized with increased in vivo metabolic stability and oral exposure in rodents suitable for advancing to lead optimization.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Drug Discovery , Protein Kinase Inhibitors/pharmacokinetics , Agammaglobulinaemia Tyrosine Kinase/metabolism , Dose-Response Relationship, Drug , Humans , Molecular Structure , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Structure-Activity Relationship
5.
Clin Transl Immunology ; 10(6): e1295, 2021.
Article in English | MEDLINE | ID: mdl-34141433

ABSTRACT

OBJECTIVES: Bruton's tyrosine kinase (BTK) plays a non-redundant signaling role downstream of the B-cell receptor (BCR) in B cells and the receptors for the Fc region of immunoglobulins (FcR) in myeloid cells. Here, we characterise BIIB091, a novel, potent, selective and reversible small-molecule inhibitor of BTK. METHODS: BIIB091 was evaluated in vitro and in vivo in preclinical models and in phase 1 clinical trial. RESULTS: In vitro, BIIB091 potently inhibited BTK-dependent proximal signaling and distal functional responses in both B cells and myeloid cells with IC50s ranging from 3 to 106 nm, including antigen presentation to T cells, a key mechanism of action thought to be underlying the efficacy of B cell-targeted therapeutics in multiple sclerosis. BIIB091 effectively sequestered tyrosine 551 in the kinase pocket by forming long-lived complexes with BTK with t 1/2 of more than 40 min, thereby preventing its phosphorylation by upstream kinases. As a key differentiating feature of BIIB091, this property explains the very potent whole blood IC50s of 87 and 106 nm observed with stimulated B cells and myeloid cells, respectively. In vivo, BIIB091 blocked B-cell activation, antibody production and germinal center differentiation. In phase 1 healthy volunteer trial, BIIB091 inhibited naïve and unswitched memory B-cell activation, with an in vivo IC50 of 55 nm and without significant impact on lymphoid or myeloid cell survival after 14 days of dosing. CONCLUSION: Pharmacodynamic results obtained in preclinical and early clinical settings support the advancement of BIIB091 in phase 2 clinical trials.

6.
J Org Chem ; 84(12): 7936-7949, 2019 06 21.
Article in English | MEDLINE | ID: mdl-31117567

ABSTRACT

An operationally simple protocol has been discovered that couples primary or secondary amines with N-aryl-substituted lactams to deliver differentiated diamines in moderate to high yields. The process allows for the partial reduction of a lactam in the presence of Cp2ZrHCl (Schwartz's reagent), followed by a reductive amination between the resulting hemiaminal and primary or secondary amine. These reactions can be telescoped in a one-pot fashion to significantly simplify the operation. The scope of amines and substituted lactams of various ring sizes was demonstrated through the formation of a range of differentiated diamine products. Furthermore, this methodology was expanded to include N-aryl pyrrolidinone substrates with an enantiopure ester group at the 5-position, and α-amino piperidinones were prepared with complete retention of stereochemical information. The development of this chemistry has enabled the consideration of lactams as useful synthons.

7.
Bioorg Med Chem Lett ; 27(15): 3477-3485, 2017 08 01.
Article in English | MEDLINE | ID: mdl-28629594

ABSTRACT

The voltage-gated sodium channel NaV1.7 has received much attention from the scientific community due to compelling human genetic data linking gain- and loss-of-function mutations to pain phenotypes. Despite this genetic validation of NaV1.7 as a target for pain, high quality pharmacological tools facilitate further understanding of target biology, establishment of target coverage requirements and subsequent progression into the clinic. Within the sulfonamide class of inhibitors, reduced potency on rat NaV1.7 versus human NaV1.7 was observed, rendering in vivo rat pharmacology studies challenging. Herein, we report the discovery and optimization of novel benzoxazine sulfonamide inhibitors of human, rat and mouse NaV1.7 which enabled pharmacological assessment in traditional behavioral rodent models of pain and in turn, established a connection between formalin-induced pain and histamine-induced pruritus in mice. The latter represents a simple and efficient means of measuring target engagement.


Subject(s)
Benzoxazines/chemistry , Benzoxazines/pharmacology , NAV1.7 Voltage-Gated Sodium Channel/metabolism , Sulfonamides/chemistry , Sulfonamides/pharmacology , Voltage-Gated Sodium Channel Blockers/chemistry , Voltage-Gated Sodium Channel Blockers/pharmacology , Analgesics/chemistry , Analgesics/pharmacokinetics , Analgesics/pharmacology , Analgesics/therapeutic use , Animals , Benzoxazines/pharmacokinetics , Benzoxazines/therapeutic use , Humans , Male , Mice , Mice, Inbred C57BL , Molecular Docking Simulation , Pain/drug therapy , Pain/metabolism , Rats , Rats, Sprague-Dawley , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic use , Voltage-Gated Sodium Channel Blockers/pharmacokinetics , Voltage-Gated Sodium Channel Blockers/therapeutic use
9.
J Med Chem ; 60(14): 5990-6017, 2017 07 27.
Article in English | MEDLINE | ID: mdl-28324649

ABSTRACT

Because of its strong genetic validation, NaV1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaV isoforms. Herein, we report the discovery and optimization of a series of atropisomeric quinolinone sulfonamide inhibitors [ Bicyclic sulfonamide compounds as sodium channel inhibitors and their preparation . WO 2014201206, 2014 ] of NaV1.7, which demonstrate nanomolar inhibition of NaV1.7 and exhibit high levels of selectivity over other sodium channel isoforms. After optimization of metabolic and pharmacokinetic properties, including PXR activation, CYP2C9 inhibition, and CYP3A4 TDI, several compounds were advanced into in vivo target engagement and efficacy models. When tested in mice, compound 39 (AM-0466) demonstrated robust pharmacodynamic activity in a NaV1.7-dependent model of histamine-induced pruritus (itch) and additionally in a capsaicin-induced nociception model of pain without any confounding effect in open-field activity.


Subject(s)
NAV1.7 Voltage-Gated Sodium Channel/metabolism , Quinolones/chemistry , Sulfonamides/chemistry , Voltage-Gated Sodium Channel Blockers/chemistry , Analgesics/chemistry , Analgesics/pharmacokinetics , Analgesics/pharmacology , Animals , Capsaicin , Cell Line , Dogs , Histamine , Mice, Inbred C57BL , Molecular Docking Simulation , Pain/chemically induced , Pain/prevention & control , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Pruritus/chemically induced , Pruritus/prevention & control , Quinolones/administration & dosage , Quinolones/chemical synthesis , Quinolones/pharmacokinetics , Quinolones/pharmacology , Rats , Structure-Activity Relationship , Sulfonamides/administration & dosage , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , Voltage-Gated Sodium Channel Blockers/pharmacokinetics , Voltage-Gated Sodium Channel Blockers/pharmacology
10.
J Med Chem ; 60(14): 5969-5989, 2017 07 27.
Article in English | MEDLINE | ID: mdl-28287723

ABSTRACT

Several reports have recently emerged regarding the identification of heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaV isoforms. The optimization of a series of internal NaV1.7 leads that address a number of metabolic liabilities including bioactivation, PXR activation, as well as CYP3A4 induction and inhibition led to the identification of potent and selective inhibitors that demonstrated favorable pharmacokinetic profiles and were devoid of the aforementioned liabilities. The key to achieving this within a series prone to transporter-mediated clearance was the identification of a small range of optimal cLogD values and the discovery of subtle PXR SAR that was not lipophilicity dependent. This enabled the identification of compound 20, which was advanced into a target engagement pharmacodynamic model where it exhibited robust reversal of histamine-induced scratching bouts in mice.


Subject(s)
Isoquinolines/chemistry , NAV1.7 Voltage-Gated Sodium Channel/metabolism , Sulfonamides/chemistry , Voltage-Gated Sodium Channel Blockers/chemistry , Animals , Cell Line , Cytochrome P-450 CYP3A/biosynthesis , Cytochrome P-450 CYP3A Inhibitors/chemistry , Cytochrome P-450 CYP3A Inhibitors/pharmacokinetics , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Dogs , Enzyme Induction , Histamine , Humans , Isoquinolines/administration & dosage , Isoquinolines/pharmacokinetics , Male , Mice, Inbred C57BL , Pregnane X Receptor , Pruritus/chemically induced , Pruritus/prevention & control , Rats , Receptors, Steroid/agonists , Structure-Activity Relationship , Sulfonamides/administration & dosage , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , Voltage-Gated Sodium Channel Blockers/pharmacokinetics , Voltage-Gated Sodium Channel Blockers/pharmacology
11.
ACS Med Chem Lett ; 7(12): 1062-1067, 2016 Dec 08.
Article in English | MEDLINE | ID: mdl-27994738

ABSTRACT

Human genetic evidence has identified the voltage-gated sodium channel NaV1.7 as an attractive target for the treatment of pain. We initially identified naphthalene sulfonamide 3 as a potent and selective inhibitor of NaV1.7. Optimization to reduce biliary clearance by balancing hydrophilicity and hydrophobicity (Log D) while maintaining NaV1.7 potency led to the identification of quinazoline 16 (AM-2099). Compound 16 demonstrated a favorable pharmacokinetic profile in rat and dog and demonstrated dose-dependent reduction of histamine-induced scratching bouts in a mouse behavioral model following oral dosing.

12.
Bioorg Med Chem Lett ; 25(4): 767-74, 2015 Feb 15.
Article in English | MEDLINE | ID: mdl-25613679

ABSTRACT

The ß-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of the most hotly pursued targets for the treatment of Alzheimer's disease. We used a structure- and property-based drug design approach to identify 2-aminooxazoline 3-azaxanthenes as potent BACE1 inhibitors which significantly reduced CSF and brain Aß levels in a rat pharmacodynamic model. Compared to the initial lead 2, compound 28 exhibited reduced potential for QTc prolongation in a non-human primate cardiovascular safety model.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Xanthenes/chemistry , Xanthenes/pharmacology , Alzheimer Disease/drug therapy , Animals , Cell Line , HEK293 Cells , Humans , Protease Inhibitors/chemical synthesis , Rats , Xanthenes/chemical synthesis
13.
J Med Chem ; 57(23): 9796-810, 2014 Dec 11.
Article in English | MEDLINE | ID: mdl-25389560

ABSTRACT

The optimization of a series of aminooxazoline xanthene inhibitors of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Aß lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust Aß reduction in a rat pharmacodynamic model (78% Aß reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , Oxazolone/analogs & derivatives , Protease Inhibitors/chemical synthesis , Xanthenes/chemical synthesis , Animals , Crystallography, X-Ray , HEK293 Cells , Humans , Inhibitory Concentration 50 , Male , Microsomes, Liver/metabolism , Oxazolone/chemical synthesis , Oxazolone/pharmacology , Rats, Sprague-Dawley , Structure-Activity Relationship , Xanthenes/pharmacology
14.
J Med Chem ; 57(23): 9811-31, 2014 Dec 11.
Article in English | MEDLINE | ID: mdl-25363711

ABSTRACT

We have previously shown that the aminooxazoline xanthene scaffold can generate potent and orally efficacious BACE1 inhibitors although certain of these compounds exhibited potential hERG liabilities. In this article, we describe 4-aza substitution on the xanthene core as a means to increase BACE1 potency while reducing hERG binding affinity. Further optimization of the P3 and P2' side chains resulted in the identification of 42 (AMG-8718), a compound with a balanced profile of BACE1 potency, hERG binding affinity, and Pgp recognition. This compound produced robust and sustained reductions of CSF and brain Aß levels in a rat pharmacodynamic model and exhibited significantly reduced potential for QTc elongation in a cardiovascular safety model.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Benzopyrans/chemical synthesis , Protease Inhibitors/chemical synthesis , Pyridines/chemical synthesis , Spiro Compounds/chemical synthesis , Amyloid beta-Peptides/metabolism , Animals , Benzopyrans/pharmacology , Ether-A-Go-Go Potassium Channels/drug effects , HEK293 Cells , Humans , Inhibitory Concentration 50 , Microsomes, Liver/metabolism , Pyridines/pharmacology , Rats, Sprague-Dawley , Spiro Compounds/pharmacology , Structure-Activity Relationship
15.
Bioorg Med Chem Lett ; 19(1): 31-5, 2009 Jan 01.
Article in English | MEDLINE | ID: mdl-19062274

ABSTRACT

A series of alpha-amidosulfones were found to be potent and selective agonists of CB(2). The discovery, synthesis, and structure-activity relationships of this series of agonists are reported. In addition, the pharmacokinetic properties of the most promising compounds are profiled.


Subject(s)
Receptor, Cannabinoid, CB2/agonists , Sulfones/chemistry , Amides/chemistry , Amides/pharmacology , Animals , Humans , Microsomes, Liver , Pharmacokinetics , Rats , Structure-Activity Relationship , Sulfones/pharmacology
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