ABSTRACT
We describe the synthesis of triazole-containing carboline derivatives and their utility as bromodomain and extra-terminal (BET) inhibitors. A convergent synthetic route permitted the detailed investigation of deuteration and fluorination strategies to reduce clearance while maintaining a favorable in vitro profile. This work led to the identification of a potent BET inhibitor, 2-{8-fluoro-3-[4-(2H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol (15), which demonstrated reduced clearance and an improved pharmacokinetic (PK) profile across preclinical species. Importantly, no major metabolite was observed when 15 was incubated with human hepatocytes (hHEP) for 2 h. This study culminated with the evaluation of 15 in a mouse triple-negative breast cancer (TNBC) tumor model where it demonstrated robust efficacy at low doses.
ABSTRACT
The identification of agonists of the stimulator of interferon genes (STING) pathway has been an area of intense research due to their potential to enhance innate immune response and tumor immunogenicity in the context of immuno-oncology therapy. Initial efforts to identify STING agonists focused on the modification of 2',3'-cGAMP (1) (an endogenous STING activator ligand) and other closely related cyclic dinucleotides (CDNs). While these efforts have successfully identified novel CDNs that have progressed into the clinic, their utility is currently limited to patients with solid tumors that STING agonists can be delivered to intratumorally. Herein, we report the discovery of a unique class of non-nucleotide small-molecule STING agonists that demonstrate antitumor activity when dosed intratumorally in a syngeneic mouse model.
Subject(s)
Membrane Proteins/agonists , Animals , Crystallography, X-Ray , Cyclic AMP/chemistry , Cyclic AMP/pharmacology , Cyclic GMP/chemistry , Cyclic GMP/pharmacology , Female , Humans , Immunity, Innate/drug effects , Immunotherapy/methods , Membrane Proteins/chemistry , Mice , Mice, Inbred BALB C , Models, Molecular , Neoplasms/immunology , Signal Transduction/drug effects , Small Molecule LibrariesABSTRACT
Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit 1, a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole 9 with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of 18 (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation.
Subject(s)
Antineoplastic Agents/pharmacology , Carbazoles/pharmacology , Drug Discovery , Phenylalanine/pharmacology , Proline/pharmacology , Tryptophan/pharmacology , Administration, Oral , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Carbazoles/administration & dosage , Carbazoles/chemistry , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/metabolism , Dose-Response Relationship, Drug , Humans , Molecular Structure , Phenylalanine/administration & dosage , Phenylalanine/chemistry , Proline/administration & dosage , Proline/chemistry , Structure-Activity Relationship , Transcription Factors/antagonists & inhibitors , Transcription Factors/metabolism , Tryptophan/administration & dosage , Tryptophan/chemistryABSTRACT
We describe our efforts to introduce structural diversity to a previously described triazole-containing N1-carboline series of bromodomain and extra-terminal (BET) inhibitors. N9 carbolines were designed to retain favorable binding interactions that the N1-carbolines possess. A convergent synthetic route enabled modifications to reduce clearance, enhance physicochemical properties, and improve the overall in vitro profile. This work led to the identification of a potent BET inhibitor, (S)-2-{8-fluoro-5-[(3-fluoropyridin-2-yl)(oxan-4-yl)methyl]-7-[4-(2H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-3-yl}propan-2-ol (10), a compound with enhanced oral exposure in mice. Subsequent evaluation in a mouse triple-negative breast cancer tumor model revealed efficacy at 4 mg/kg of N9-carboline 10.
Subject(s)
Antineoplastic Agents/pharmacology , Carbolines/pharmacology , Drug Development , Proteins/antagonists & inhibitors , Triple Negative Breast Neoplasms/drug therapy , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Carbolines/administration & dosage , Carbolines/chemistry , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/pathology , Mice , Molecular Structure , Proteins/metabolism , Structure-Activity Relationship , Triple Negative Breast Neoplasms/pathologyABSTRACT
Structure-activity relationships in a series of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides identified highly potent inhibitors of γ-secretase mediated signaling of Notch1/2/3/4 receptors. On the basis of its robust in vivo efficacy at tolerated doses in Notch driven leukemia and solid tumor xenograft models, 12 (BMS-906024) was selected as a candidate for clinical evaluation.
ABSTRACT
This Letter describes synthesis, SAR, and biological activity of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides as inhibitors of γ-secretase mediated signaling of Notch receptors. Optimization of this series led to the identification of BMS-871 (compound 30) which displayed robust in vivo efficacy in Notch-dependent leukemia and solid tumor xenograft models.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Benzodiazepinones/administration & dosage , Benzodiazepinones/pharmacology , Receptors, Notch/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemistry , Benzodiazepinones/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Receptors, Notch/metabolism , Structure-Activity RelationshipABSTRACT
The synthesis, structure-activity relationships (SAR) and biological evaluation of thiazole based tricyclic inhibitors of IKK2 are described. Compound 9 was determined to be orally efficacious in a murine model of rheumatoid arthritis.
Subject(s)
Arthritis, Rheumatoid/drug therapy , I-kappa B Kinase/antagonists & inhibitors , Imidazoles/chemistry , Protein Kinase Inhibitors/chemistry , Pyridines/chemistry , Thiazoles/chemistry , Animals , Disease Models, Animal , Dogs , Drug Evaluation, Preclinical , Female , I-kappa B Kinase/metabolism , Mice , Mice, Inbred BALB C , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Pyridines/pharmacokinetics , Pyridines/therapeutic use , Rats , Structure-Activity RelationshipABSTRACT
The design and synthesis of a novel series of oxazole-, thiazole-, and imidazole-based inhibitors of IkappaB kinase (IKK) are reported. Biological activity was improved compared to the pyrazolopurine lead, and the expedient synthesis of the new tricyclic systems allowed for efficient exploration of structure-activity relationships. This, combined with an iterative rat cassette dosing strategy, was used to identify compounds with improved pharmacokinetic (PK) profiles to advance for in vivo evaluation.
Subject(s)
Heterocyclic Compounds, 3-Ring/chemical synthesis , I-kappa B Kinase/antagonists & inhibitors , Imidazoles/chemical synthesis , Oxazoles/chemical synthesis , Thiazoles/chemical synthesis , Animals , Crystallography, X-Ray , Female , Glutathione Transferase/genetics , Glutathione Transferase/metabolism , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , I-kappa B Kinase/genetics , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , In Vitro Techniques , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred BALB C , Microsomes, Liver/metabolism , Oxazoles/pharmacokinetics , Oxazoles/pharmacology , Rats , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Structure-Activity Relationship , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
In an era of increasing resistance to classical antibacterial agents, the synthetic oxazolidinone series of antibiotics has attracted much interest. Zyvoxtrade mark was the first oxazolidinone to be approved for clinical use against infections caused by multi-drug resistant Gram-positive bacteria. In the course of studies directed toward the discovery of novel antibacterial agents, a new series of synthetic phenyl-isoxazolinone agents that displayed potent activity against Gram-positive bacterial strains was recently discovered at Bristol-Myers Squibb. Extensive investigation of various substitutions on the phenyl ring was then undertaken. We report here, the synthesis and antibacterial activity of a series of biaryl isoxazolinone compounds.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Isoxazoles/chemistry , Isoxazoles/pharmacology , Animals , Haemophilus influenzae/drug effects , Rats , Structure-Activity RelationshipABSTRACT
A series of potential antimicrobial derivatives possessing bioisosteric replacements for the central oxazolidinone ring found in oxazolidinone antibacterials have been prepared. The design concept involved replacement of the requisite sp(3)-hybridized stereogenic center found at the 5-position of the oxazolidinone with a nitrogen atom. The synthesis and antibacterial activity of three such ring systems, the benzisoxazolinones, pyrroles, and isoxazolinones is described.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Isoxazoles/chemistry , Nitrogen/chemistry , Oxazolidinones/chemistry , Oxazolone/analogs & derivatives , Oxazolone/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Isoxazoles/chemical synthesis , Isoxazoles/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Oxazolone/chemical synthesis , Oxazolone/pharmacology , Pyrroles/chemical synthesis , Pyrroles/chemistry , Pyrroles/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The synthesis and antifungal activity of 5'- and 5'-6'-substituted azasordarin derivatives are described. Modification of the 5'-position led to the discovery of the spirocyclopentyl analogue 7g, which is the first azasordarin to register single-digit MIC values versus Aspergillus spp. Further investigation identified the 5'-i-Pr derivative 7b, which displays superior pharmacokinetic properties compared to other azasordarins.
Subject(s)
Antifungal Agents/chemistry , Antifungal Agents/pharmacokinetics , Aza Compounds/chemical synthesis , Aza Compounds/pharmacokinetics , Administration, Oral , Animals , Antifungal Agents/pharmacology , Aspergillus/drug effects , Aza Compounds/chemistry , Aza Compounds/pharmacology , Glycosides/chemistry , Indenes , Injections, Intravenous , Mice , Microbial Sensitivity Tests , Spiro Compounds/chemistry , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Compounds based on sordaricin were prepared via organometallic addition onto a fully protected sordaricin aldehyde. The fungal growth inhibition profiles for these compounds were established and the results are presented here. The synthesis of homologated sordaricin as well as ether and ester derivatives is presented, and structural rearrangement products upon oxidation. These compounds were evaluated as agents to inhibit fungal growth.
