ABSTRACT
Efforts directed at improving potency and preparing structurally different TYK2 JH2 inhibitors from the first generation of compounds such as 1a led to the SAR study of new central pyridyl based analogs 2-4. The current SAR study resulted in the identification of 4h as a potent and selective TYK2 JH2 inhibitor with distinct structural differences from 1a. In this manuscript, the in vitro and in vivo profiles of 4h are described. The hWB IC50 of 4h was shown as 41 nM with 94% bioavailability in the mouse PK study.
Subject(s)
Pyridines , TYK2 Kinase , Mice , Animals , Structure-Activity Relationship , Pyridines/pharmacologyABSTRACT
GPR40 AgoPAMs are highly effective antidiabetic agents that have a dual mechanism of action, stimulating both glucose-dependent insulin and GLP-1 secretion. The early lipophilic, aromatic pyrrolidine and dihydropyrazole GPR40 AgoPAMs from our laboratory were highly efficacious in lowering plasma glucose levels in rodents but possessed off-target activities and triggered rebound hyperglycemia in rats at high doses. A focus on increasing molecular complexity through saturation and chirality in combination with reducing polarity for the pyrrolidine AgoPAM chemotype resulted in the discovery of compound 46, which shows significantly reduced off-target activities as well as improved aqueous solubility, rapid absorption, and linear PK. In vivo, compound 46 significantly lowers plasma glucose levels in rats during an oral glucose challenge yet does not demonstrate the reactive hyperglycemia effect at high doses that was observed with earlier GPR40 AgoPAMs.
Subject(s)
Blood Glucose , Hyperglycemia , Rats , Animals , Receptors, G-Protein-Coupled , Glucagon-Like Peptide 1 , Hypoglycemic Agents/pharmacology , Pyrrolidines/pharmacology , Pyrrolidines/chemistry , InsulinABSTRACT
BMS-813160 is a pharmaceutical entity currently in development at Bristol Myers Squibb. Its defining structural feature is a unique chiral all cis triamino cyclohexane core. Medicinal and process chemistry groups at BMS have previously published synthesis strategies for chemotypes similar to the target molecule, but a streamlined approach amenable for longer-term supply was necessary. A new synthetic route was conceptualized, experimentally investigated, and determined to meet the criteria for efficiency that addressed key limitations of previous approaches. Adopting/optimizing the Trost asymmetric allylic amination desymmetrization methodology was a key tool used to produce a synthesis intermediate with high optical purity. In addition, developing a tandem Mannich-aza-Michael reaction to obviate the need for a Curtis/acylation sequence and a novel reductive amination/thermal lactamization to circumvent Freidinger-type pyrrolidone preparation are some of the synthesis improvements that enabled access to the target molecule to fulfill long-term supply requirements.
Subject(s)
Catalysis , Amination , Pyrazoles , Stereoisomerism , TriazinesABSTRACT
Heart failure (HF) treatment remains a critical unmet medical need. Studies in normal healthy volunteers and HF patients have shown that [Pyr1]apelin-13, the endogenous ligand for the APJ receptor, improves cardiac function. However, the short half-life of [Pyr1]apelin-13 and the need for intravenous administration have limited the therapeutic potential for chronic use. We sought to identify potent, small-molecule APJ agonists with improved pharmaceutical properties to enable oral dosing in clinical studies. In this manuscript, we describe the identification of a series of pyrimidinone sulfones as a structurally differentiated series to the clinical lead (compound 1). Optimization of the sulfone series for potency, metabolic stability and oral bioavailability led to the identification of compound 22, which showed comparable APJ potency to [Pyr1]apelin-13 and exhibited an acceptable pharmacokinetic profile to advance to the acute hemodynamic rat model.
Subject(s)
Apelin Receptors/agonists , Cardiovascular Agents/pharmacology , Cardiovascular Agents/pharmacokinetics , Intercellular Signaling Peptides and Proteins/pharmacology , Animals , Area Under Curve , Cardiovascular Agents/chemical synthesis , Drug Design , Half-Life , Humans , Intercellular Signaling Peptides and Proteins/chemistry , Macaca fascicularis , Molecular Structure , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
RORγt is the master regulator of the IL-23/IL-17 axis, a pathway that is clinically validated for the treatment of various immunological disorders. Over the last few years, our group has reported different chemotypes that potently act as inverse agonists of RORγt. One of them, the tricyclic pyrrolidine chemotype, has demonstrated biologic-like preclinical efficacy and has led to our clinical candidate BMS-986251. In this letter, we discuss the invention of an annulation reaction which enabled the synthesis of a tricyclic exocyclic amide chemotype and the identification of compounds with RORγt inverse agonist activity. Preliminary structure activity relationships are disclosed.
Subject(s)
Amides/chemistry , Hydrocarbons, Cyclic/chemistry , Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & inhibitors , Sulfones/chemistry , Amides/chemical synthesis , Amides/metabolism , Animals , Cyclization , Drug Inverse Agonism , Humans , Hydrocarbons, Cyclic/chemical synthesis , Hydrocarbons, Cyclic/metabolism , Mice , Microsomes, Liver/metabolism , Molecular Docking Simulation , Molecular Structure , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/metabolismABSTRACT
A novel series of cis-3,4-diphenylpyrrolidines were designed as RORγt inverse agonists based on the binding conformation of previously reported bicyclic sulfonamide 1. Preliminary synthesis and structure-activity relationship (SAR) study established (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidine as the most effective scaffold. Subsequent SAR optimization led to identification of a piperidinyl carboxamide 31, which was potent against RORγt (EC50 of 61 nM in an inverse agonist assay), selective relative to RORα, RORß, LXRα and LXRß, and stable in human and mouse liver microsomes. Furthermore, compound 31 exhibited considerably lower PXR Ymax (46%) and emerged as a promising lead. The binding mode of the diphenylpyrrolidine series was established with an X-ray co-crystal structure of 10A/RORγt.
Subject(s)
Drug Design , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Pyrrolidines/chemistry , Animals , Binding Sites , Crystallography, X-Ray , Drug Inverse Agonism , Humans , Mice , Microsomes, Liver/metabolism , Molecular Dynamics Simulation , Nuclear Receptor Subfamily 1, Group F, Member 3/agonists , Pregnane X Receptor/agonists , Pregnane X Receptor/metabolism , Pyrrolidines/chemical synthesis , Pyrrolidines/metabolism , Structure-Activity RelationshipABSTRACT
Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides. Several compounds were advanced to PK evaluation. Among them, compound 4a was one of the most potent with measurable ELHDL hSerum potency and compound 3g demonstrated the best overall pharmacokinetic parameters.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Lipase/antagonists & inhibitors , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Animals , Cholesterol, HDL/blood , Cholesterol, HDL/metabolism , Enzyme Inhibitors/blood , Enzyme Inhibitors/chemical synthesis , Humans , Lipase/blood , Lipase/metabolism , Mice , Models, Molecular , Pyrimidinones/blood , Pyrimidinones/chemical synthesis , Structure-Activity RelationshipABSTRACT
We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies.
Subject(s)
Bridged Bicyclo Compounds/pharmacology , Drug Design , Propanols/pharmacology , Receptors, Retinoic Acid/agonists , Receptors, Steroid/agonists , Sulfonamides/pharmacology , Animals , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Liver X Receptors/agonists , Male , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Structure , Pregnane X Receptor , Propanols/chemical synthesis , Propanols/chemistry , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Retinoic Acid Receptor gammaABSTRACT
This letter describes the discovery, synthesis, SAR, and biological activity of [2.2.1]-bicyclic sultams as potent antagonists of the androgen receptor. Optimization of the series led to the identification of compound 25, which displayed robust pharmacodynamic effects in rats after oral dosing.
Subject(s)
Androgen Receptor Antagonists/chemistry , Androgen Receptor Antagonists/pharmacology , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacology , Naphthalenesulfonates/chemistry , Naphthalenesulfonates/pharmacology , Administration, Oral , Androgen Receptor Antagonists/pharmacokinetics , Animals , Bridged Bicyclo Compounds/administration & dosage , Bridged Bicyclo Compounds/pharmacokinetics , Cell Line, Tumor , Humans , Models, Molecular , Naphthalenesulfonates/administration & dosage , Naphthalenesulfonates/pharmacokinetics , Rats , Receptors, Androgen/metabolism , Structure-Activity RelationshipABSTRACT
A novel cyclohexenyl series of CCR2 antagonists has been discovered. This series of small, rigid compounds exhibits submicromolar binding affinity for CCR2. Modification of the substituents on the cyclohexene ring led to the identification of potent CCR2 antagonists. Progress from initial lead 5 (IC50=700nM) to (-)-38 (IC50=9.0nM) is discussed.
Subject(s)
Cyclohexenes/chemistry , Cyclohexenes/pharmacology , Receptors, CCR2/antagonists & inhibitors , Cyclohexenes/chemical synthesis , Drug Discovery , Humans , Models, Molecular , Receptors, CCR2/metabolism , Structure-Activity RelationshipABSTRACT
PURPOSE: Precipitation of weakly basic drugs in intestinal fluids can affect oral drug absorption. In this study, the implications of self-association of brivanib alaninate in acidic aqueous solution, leading to supersaturation at basic pH condition, on its solubility and oral absorption were investigated. METHODS: Self-association of brivanib alaninate was investigated by proton NMR spectroscopy, surface tension measurement, dynamic light scattering, isothermal titration calorimetry, and molecular modeling. Drug solubility was determined in various pH media, and its tendency to supersaturate upon pH shift was investigated in buffered and biorelevant aqueous solutions. Pharmacokinetic modeling of human oral drug absorption was utilized for parameter sensitivity analyses of input variables. RESULTS: Brivanib alaninate exhibited continuous, and pH- and concentration-dependent self-association. This phenomenon resulted in positive deviation of drug solubility at acidic pH and the formation of a stable supersaturated drug solution in pH-shift assays. Consistent with the supersaturation phenomenon observed in vitro, oral absorption simulations necessitated invoking long precipitation time in the intestine to successfully predict in vivo data. CONCLUSIONS: Self-association of a weakly basic drug in acidic aqueous solution can increase its oral absorption by supersaturation and precipitation resistance at the intestinal pH. This consideration is important to the selection of parameters for oral absorption simulation.
Subject(s)
Alanine/analogs & derivatives , Triazines/chemistry , Triazines/pharmacokinetics , Administration, Oral , Alanine/chemistry , Alanine/pharmacokinetics , Buffers , Calorimetry , Chemistry, Pharmaceutical , Colloids , Computer Simulation , Humans , Hydrogen-Ion Concentration , Intestinal Absorption , Magnetic Resonance Spectroscopy , Models, Molecular , Particle Size , Solubility , Surface TensionABSTRACT
A series of carbamoylmethylene linked prodrugs of 1 (BMS-582949), a clinical p38α inhibitor, were synthesized and evaluated. Though the phosphoryloxymethylene carbamates (3, 4, and 5) and α-aminoacyloxymethylene carbamates (22, 23, and 26) were found unstable at neutral pH values, fumaric acid derived acyloxymethylene carbamates (2, 28, and 31) were highly stable under both acidic and neutral conditions. Prodrugs 2 and 31 were also highly soluble at both acidic and neutral pH values. At a solution dose of 14.2mpk (equivalent to 10mpk of 1), 2 gave essentially the same exposure of 1 compared to dosing 10mpk of 1 itself. At a suspension dose of 142mpk (equivalent to 100mpk of 1), 2 demonstrated that it could overcome the solubility issue associated with 1 and provide a much higher exposure of 1. To our knowledge, the unique type of prodrugs like 2, 28, and 31 was not reported in the past and could represent a novel prodrug approach for secondary amides, a class of molecules frequently identified as drug candidates.
Subject(s)
Dacarbazine/analogs & derivatives , Prodrugs/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyrroles/pharmacology , Triazines/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Crystallography, X-Ray , Dacarbazine/chemistry , Dose-Response Relationship, Drug , Hydrogen-Ion Concentration , Models, Molecular , Molecular Structure , Prodrugs/administration & dosage , Prodrugs/chemical synthesis , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemical synthesis , Pyrroles/administration & dosage , Pyrroles/chemical synthesis , Rats , Solubility , Structure-Activity Relationship , Temperature , Triazines/administration & dosage , Triazines/chemical synthesis , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Formyl peptide receptor 2 (FPR2) agonists have shown efficacy in inflammatory-driven animal disease models and have the potential to treat a range of diseases. Many reported synthetic agonists contain a phenylurea, which appears to be necessary for activity in the reported chemotypes. We set out to find isosteres for the phenylurea and focused our efforts on heteroaryl rings. The wide range of potencies with heterocyclic isosteres demonstrates how electronic effects of the heteroatom placement impact molecular recognition. Herein, we report our discovery of benzimidazole and aminophenyloxadiazole FPR2 agonists with low nanomolar activity.
ABSTRACT
Factor XIa (FXIa) is an enzyme in the coagulation cascade thought to amplify thrombin generation but has a limited role in hemostasis. From preclinical models and human genetics, an inhibitor of FXIa has the potential to be an antithrombotic agent with superior efficacy and safety. Reversible and irreversible inhibitors of FXIa have demonstrated excellent antithrombotic efficacy without increased bleeding time in animal models (Weitz, J. I., Chan, N. C. Arterioscler. Thromb. Vasc. Biol. 2019, 39 (1), 7-12). Herein, we report the discovery of a novel series of macrocyclic FXIa inhibitors containing a pyrazole P2' moiety. Optimization of the series for (pharmacokinetic) PK properties, free fraction, and solubility resulted in the identification of milvexian (BMS-986177/JNJ-70033093, 17, FXIa Ki = 0.11 nM) as a clinical candidate for the prevention and treatment of thromboembolic disorders, suitable for oral administration.
Subject(s)
Carotid Artery Thrombosis , Factor XIa , Fibrinolytic Agents , Pyrimidines , Triazoles , Animals , Mice , Rabbits , Administration, Oral , Carotid Artery Thrombosis/drug therapy , Factor XIa/antagonists & inhibitors , Fibrinolytic Agents/administration & dosage , Fibrinolytic Agents/chemical synthesis , Fibrinolytic Agents/pharmacokinetics , Fibrinolytic Agents/therapeutic use , Macaca fascicularis , Molecular Structure , Pyrazoles/administration & dosage , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Pyrazoles/therapeutic use , Pyrimidines/administration & dosage , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Pyrimidines/therapeutic use , Rats, Sprague-Dawley , Structure-Activity Relationship , Triazoles/administration & dosage , Triazoles/chemical synthesis , Triazoles/pharmacokinetics , Triazoles/therapeutic useABSTRACT
The synthesis, structure-activity relationships (SAR), and biological results of pyridyl-substituted azaindole based tricyclic inhibitors of IKK2 are described. Compound 4m demonstrated potent in vitro potency, acceptable pharmacokinetic and physicochemical properties, and efficacy when dosed orally in a mouse model of inflammatory bowel disease.
Subject(s)
Acetamides/chemistry , Drug Discovery , Enzyme Inhibitors/chemistry , Heterocyclic Compounds, 3-Ring/chemistry , I-kappa B Kinase/antagonists & inhibitors , Acetamides/chemical synthesis , Acetamides/pharmacology , Administration, Oral , Animals , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Inflammatory Bowel Diseases/drug therapy , Inhibitory Concentration 50 , Mice , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
Apelin-13 is an endogenous peptidic agonist of the apelin receptor (APJ) receptor with the potential for improving cardiac function in heart failure patients. However, the low plasma stability of apelin-13 necessitates continuous intravenous infusion for therapeutic use. There are several approaches to increase the stability of apelin-13 including attachment of pharmacokinetic enhancing groups, stabilized peptides, and Fc-fusion approaches. We sought a small-molecule APJ receptor agonist approach to target a compound with a pharmacokinetic profile amenable for chronic oral administration. This manuscript describes sequential optimization of the pyrimidinone series, leading to pyridinone 14, with in vitro potency equivalent to the endogenous ligand apelin-13 and with an excellent oral bioavailability and PK profile in multiple preclinical species. Compound 14 exhibited robust pharmacodynamic effects similar to apelin-13 in an acute rat pressure-volume loop model and was advanced as a clinical candidate.
Subject(s)
Apelin Receptors/agonists , Pyridones/chemistry , Pyridones/pharmacology , Animals , Apelin Receptors/metabolism , Dogs , Drug Discovery , Haplorhini , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Male , Models, Molecular , Pyridones/pharmacokinetics , Rats , Rats, Sprague-DawleyABSTRACT
Bruton's tyrosine kinase (BTK) has been shown to play a key role in the pathogenesis of autoimmunity. Therefore, the inhibition of the kinase activity of BTK with a small molecule inhibitor could offer a breakthrough in the clinical treatment of many autoimmune diseases. This Letter describes the discovery of BMS-986143 through systematic structure-activity relationship (SAR) development. This compound benefits from defined chirality derived from two rotationally stable atropisomeric axes, providing a potent and selective single atropisomer with desirable efficacy and tolerability profiles.
ABSTRACT
This communication highlights the use of chiral sulfinamides as nitrogen nucleophiles in intermolecular aza-Michael reactions. When chiral sulfinamides are coupled to a chloroethyl group, the corresponding novel annulating reagents can be used to streamline the stereoselective synthesis of complex pyrrolidine-containing molecules. As a result, it has enabled a medicinal chemistry campaign for the synthesis of biologically active RORγt inverse agonists.
ABSTRACT
The APJ receptor and its endogenous peptidic ligand apelin have been implicated as important modulators of cardiovascular function, and APJ receptor agonists may be beneficial in the treatment of heart failure. In this article, we describe the discovery of a series of biphenyl acid derivatives as potent APJ receptor agonists. Following the identification of initial high-throughput screen lead 2, successive optimization led to the discovery of lead compound 15a. Compound 15a demonstrated comparable in vitro potency to apelin-13, the endogenous peptidic ligand for the APJ receptor. In vivo, compound 15a demonstrated a dose-dependent improvement in the cardiac output in male Sprague Dawley rats with no significant changes in either mean arterial blood pressure or heart rate, consistent with the hemodynamic profile of apelin-13 in an acute pressure volume loop model.
Subject(s)
Apelin Receptors/agonists , Cardiovascular Agents/chemistry , Cardiovascular Agents/pharmacology , Small Molecule Libraries/pharmacology , Animals , Apelin Receptors/chemistry , Apelin Receptors/metabolism , Biphenyl Compounds/chemistry , Blood Pressure/drug effects , Dose-Response Relationship, Drug , HEK293 Cells , Heart Rate/drug effects , High-Throughput Screening Assays/methods , Humans , Intercellular Signaling Peptides and Proteins/pharmacology , Male , Rats, Sprague-Dawley , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Structure-Activity RelationshipABSTRACT
The four members of the Janus family of nonreceptor tyrosine kinases play a significant role in immune function. The JAK family kinase inhibitor, tofacitinib 1, has been approved in the United States for use in rheumatoid arthritis (RA) patients. A number of JAK inhibitors with a variety of JAK family selectivity profiles are currently in clinical trials. Our goal was to identify inhibitors that were functionally selective for JAK1 and JAK3. Compound 22 was prepared with the desired functional selectivity profile, but it suffered from poor absorption related to physical properties. Use of the phosphate prodrug 32 enabled progression to a murine collagen induced arthritis (CIA) model. The demonstration of a robust efficacy in the CIA model suggests that use of phosphate prodrugs may resolve issues with progressing this chemotype for the treatment of autoimmune diseases such as RA.