ABSTRACT
We describe an efficient synthetic route to differentially protected diester, 1-(tert-butyl) 4-methyl (1R,2S,4R)-2-methylcyclohexane-1,4-dicarboxylate (+)-1, via palladium-catalyzed methoxycarbonylation of an enol triflate derived from a Hagemann's ester derivative followed by a stereoselective Crabtree hydrogenation. Diester 1 is a novel chiral synthon useful in drug discovery and was instrumental in the generation of useful SAR during a RORγt inverse agonist program. In addition, we describe a second-generation synthesis of the clinical candidate BMS-986251, using diester 1 as a critical component.
Subject(s)
Carboxylic Acids , Esters , Cyclohexanes , StereoisomerismABSTRACT
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
In order to rapidly develop C6 and C8 SAR of our reported tricyclic sulfone series of RORγt inverse agonists, a late-stage bromination was employed. Although not regioselective, the bromination protocol allowed us to explore new substitution patterns/vectors that otherwise would have to be incorporated at the very beginning of the synthesis. Based on the SAR obtained from this exercise, compound 15 bearing a C8 fluorine was developed as a very potent and selective RORγt inverse agonist. This analog's in vitro profile, pharmacokinetic (PK) data and efficacy in an IL-23 induced mouse acanthosis model will be discussed.
Subject(s)
Heterocyclic Compounds, 3-Ring/therapeutic use , Melanosis/drug therapy , Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & inhibitors , Sulfones/therapeutic use , Animals , Crystallography, X-Ray , Drug Inverse Agonism , Female , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Interleukin-18 , Male , Melanosis/chemically induced , Mice, Inbred BALB C , Mice, Inbred C57BL , Molecular Structure , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Protein Binding , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/pharmacokineticsABSTRACT
Incorporation of a suitably-placed electrophilic group transformed a series of reversible BTK inhibitors based on carbazole-1-carboxamide and tetrahydrocarbazole-1-carboxamide into potent, irreversible inhibitors. Removal of one ring from the core of these compounds provided a potent irreversible series of 2,3-dimethylindole-7-carboxamides having excellent potency and improved selectivity, with the additional advantages of reduced lipophilicity and molecular weight.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Carbazoles/pharmacology , Indoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Agammaglobulinaemia Tyrosine Kinase/metabolism , Carbazoles/chemical synthesis , Carbazoles/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Indoles/chemical synthesis , Indoles/chemistry , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model.
Subject(s)
Amines/chemistry , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/chemistry , Amines/metabolism , Amines/therapeutic use , Animals , Autoimmune Diseases/drug therapy , Binding Sites , Class I Phosphatidylinositol 3-Kinases , Crystallography, X-Ray , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , Mice , Microsomes, Liver/metabolism , Molecular Docking Simulation , Phosphatidylinositol 3-Kinases/metabolism , Piperazine , Piperazines/chemistry , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/therapeutic use , Structure-Activity Relationship , Triazines/chemistryABSTRACT
Four series of disubstituted carbazole-1-carboxamides were designed and synthesised as inhibitors of Bruton's tyrosine kinase (BTK). 4,7- and 4,6-disubstituted carbazole-1-carboxamides were potent and selective inhibitors of BTK, while 3,7- and 3,6-disubstituted carbazole-1-carboxamides were potent and selective inhibitors of Janus kinase 2 (JAK2).
Subject(s)
Amides/pharmacology , Carbazoles/pharmacology , Drug Design , Janus Kinase 2/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Carbazoles/chemistry , Dose-Response Relationship, Drug , Humans , Janus Kinase 2/metabolism , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein-Tyrosine Kinases/metabolism , Structure-Activity RelationshipABSTRACT
Glucokinase (GK) is a key regulator of glucose homeostasis, and its small-molecule activators represent a promising opportunity for the treatment of type 2 diabetes. Several GK activators have been advanced into clinical trials and have demonstrated promising efficacy; however, hypoglycemia represents a key risk for this mechanism. In an effort to mitigate this hypoglycemia risk while maintaining the efficacy of the GK mechanism, we have investigated a series of amino heteroaryl phosphonate benzamides as ''partial" GK activators. The structure-activity relationship studies starting from a "full GK activator" 11, which culminated in the discovery of the "partial GK activator" 31 (BMS-820132), are discussed. The synthesis and in vitro and in vivo preclinical pharmacology profiles of 31 and its pharmacokinetics (PK) are described. Based on its promising in vivo efficacy and preclinical ADME and safety profiles, 31 was advanced into human clinical trials.
Subject(s)
Azetidines , Diabetes Mellitus, Type 2 , Hypoglycemia , Organophosphonates , Azetidines/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Glucokinase , Humans , Hypoglycemia/drug therapy , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Organophosphonates/pharmacology , Organophosphonates/therapeutic useABSTRACT
The synthesis and follow-up SAR studies of our development candidate 1 by incorporating 2-aryl-4-oxazolylmethoxy and 2-aryl-4-thiazolylmethoxy moieties into the oxybenzylglycine framework of the PPARalpha/gamma dual agonist muraglitazar is described. SAR studies indicate that different substituents on the aryloxazole/thiazole moieties as well as the choice of carbamate substituent on the glycine moiety can significantly modulate the selectivity of PPARalpha versus PPARgamma. Potent, highly selective PPARalpha activators 2a and 2l, as well as PPARalpha activators with significant PPARgamma activity, such as 2s, were identified. The in vivo pharmacology of these compounds in preclinical animal models as well as their ADME profiles are discussed.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Glycine/analogs & derivatives , PPAR alpha/agonists , PPAR gamma/agonists , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacokinetics , Binding Sites , Cricetinae , Crystallography, X-Ray , Glycine/chemical synthesis , Glycine/pharmacokinetics , Humans , Male , PPAR alpha/metabolism , PPAR gamma/metabolism , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Employing a virtual screening approach, we identified the pyroglutamide moiety as a nonacid replacement for the cyclohexanecarboxylic acid group which, when coupled to our previously reported conformationally locked tricyclic core, provided potent and selective RORγt inverse agonists. Structure-activity relationship optimization of the pyroglutamide moiety led to the identification of compound 18 as a potent and selective RORγt inverse agonist, albeit with poor aqueous solubility. We took advantage of the tertiary carbinol group in 18 to synthesize a phosphate prodrug, which provided good solubility, excellent exposures in mouse PK studies, and significant efficacy in a mouse model of psoriasis.
ABSTRACT
Novel tricyclic analogues were designed, synthesized, and evaluated as RORγt inverse agonists. Several of these compounds were potent in an IL-17 human whole blood assay and exhibited excellent oral bioavailability in mouse pharmacokinetic studies. This led to the identification of compound 5, which displayed dose-dependent inhibition of IL-17F production in a mouse IL-2/IL-23 stimulated pharmacodynamic model. In addition, compound 5 was studied in mouse acanthosis and imiquimod-induced models of skin inflammation, where it demonstrated robust efficacy comparable to a positive control. As a result of this excellent overall profile, compound 5 (BMS-986251) was selected as a clinically viable developmental candidate.
ABSTRACT
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
The orexigenic peptide ghrelin has been shown to have prokinetic activity in the gastrointestinal (GI) system of several species, including humans. In this series of experiments, we have evaluated the prokinetic activity of novel, small-molecule ghrelin receptor (GhrR) agonists after parenteral and peroral dosing in mice and rats. Gastric emptying, small intestinal transport, and fecal output were determined after intraperitoneal and intracerebroventricular dosing of GhrR agonists, using ghrelin as a positive control. These same parameters were evaluated after oral gavage dosing of the synthetic agonists. Regardless of dose route, GhrR agonist treatment increased gastric emptying, small intestinal transit, and fecal output. However, fecal output was only increased by GhrR agonist treatment if mice were able to feed during the stimulatory period. Thus, GhrR agonists can stimulate upper GI motility, and the orexigenic action of the compounds can indirectly contribute to prokinetic activity along the entire GI tract. The orexigenic and prokinetic effects of either ghrelin or small-molecule GhrR agonists were selective for the GhrR because they were absent when evaluated in GhrR knockout mice. We next evaluated the efficacy of the synthetic GhrR agonists dosed in a model of opiate-induced bowel dysfunction induced by a single injection of morphine. Oral dosing of a GhrR agonist normalized GI motility in opiate-induced dysmotility. These data demonstrate the potential utility of GhrR agonists for treating gastrointestinal hypomotility disorders.
Subject(s)
Gastrointestinal Motility/drug effects , Ghrelin/administration & dosage , Ghrelin/pharmacology , Peptide Hormones/administration & dosage , Peptide Hormones/pharmacology , Receptors, Ghrelin/agonists , Administration, Oral , Animals , Body Weight/drug effects , Bowen's Disease/chemically induced , Bowen's Disease/drug therapy , Bowen's Disease/physiopathology , Central Nervous System/drug effects , Defecation/drug effects , Eating/drug effects , Gastric Emptying/drug effects , Gastrointestinal Transit/drug effects , Intestine, Small/drug effects , Intestine, Small/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Morphine/pharmacology , Peptide Hormones/blood , Rats , Rats, Sprague-Dawley , Receptors, Ghrelin/genetics , Receptors, Ghrelin/metabolismABSTRACT
Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Drug Discovery , Indoles/pharmacology , Piperidines/pharmacology , Protein Kinase Inhibitors/pharmacology , Animals , Arthritis, Rheumatoid/drug therapy , Dose-Response Relationship, Drug , Humans , Indoles/pharmacokinetics , Indoles/therapeutic use , Inhibitory Concentration 50 , Lupus Erythematosus, Systemic/drug therapy , Macaca fascicularis , Mice , Piperidines/pharmacokinetics , Piperidines/therapeutic use , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic useABSTRACT
RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.
Subject(s)
Drug Design , Drug Inverse Agonism , Nuclear Receptor Subfamily 1, Group F, Member 3/agonists , Pyrrolidines/pharmacology , Animals , Humans , Jurkat Cells , Mice , Models, Molecular , Nuclear Receptor Subfamily 1, Group F, Member 3/chemistry , Protein Conformation , Pyrrolidines/chemistry , Pyrrolidines/pharmacokinetics , Structure-Activity Relationship , Tissue DistributionABSTRACT
The first enantioselective synthesis of (D)-2-tert-butoxycarbonylamino-5,5-difluoro-5-phenyl-pentanoic acid 3 was achieved. The incorporation of the titled compound into growth hormone secretagogue (GHS) compounds resulted in new analogs 10 and 16, both of which had significantly increased in vitro potency. The compound 10 also showed improved in vivo efficacy as well as pharmacokinetic properties in rat models.
Subject(s)
Growth Hormone/metabolism , Pentanoic Acids/chemical synthesis , Administration, Oral , Animals , Area Under Curve , Biological Availability , Carbamates/pharmacology , Chemistry, Pharmaceutical/methods , Drug Design , Indoles/pharmacology , Models, Chemical , Pentanoic Acids/chemistry , Pentanoic Acids/pharmacology , Peptide Hormones/chemistry , Rats , Spiro Compounds/pharmacology , Stereoisomerism , Tetrazoles/pharmacologyABSTRACT
The discovery and optimization of a novel series of prolinol-derived GHSR agonists is described. This series emerged from a 11,520-member solid-phase library targeting the GPCR protein superfamily, and the rapid optimization of low micromolar hits into single-digit nanomolar leads can be attributed to the solid-phase synthesis of matrix libraries, which revealed multiple non-additive structure-activity relationships. In addition, the separation of potent diastereomers highlighted the influence of the alpha-methyl stereochemistry of the phenoxyacetamide sidechain on GHSR activity.
Subject(s)
Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Receptors, G-Protein-Coupled/drug effects , Receptors, Ghrelin/agonists , Combinatorial Chemistry Techniques , Molecular Structure , Pyrrolidines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
1H-tetrazole-1-alkanenitrile SR-9g exhibits a >10-fold in vivo potency enhancement over the lead nitrile 1 and has acceptable oral bioavailability in rats and dogs. An enantiospecific synthesis of 1H-tetrazole-1-alkanenitrile nitriles 9 has been developed.
Subject(s)
Growth Hormone/metabolism , Nitriles/pharmacology , Tetrazoles/pharmacology , Administration, Oral , Animals , Biological Availability , Cytochrome P-450 Enzyme System/metabolism , Dogs , Magnetic Resonance Spectroscopy , Molecular Structure , Nitriles/chemical synthesis , Nitriles/pharmacokinetics , Pituitary Gland , Rats , Structure-Activity Relationship , Tetrazoles/chemical synthesis , Tetrazoles/pharmacokineticsABSTRACT
A novel series of N1 substituted tetrazole amides were prepared and showed to be potent growth hormone (GH) secretagogues. Among them, hydroxyl containing analog 31 displayed excellent in vivo activity by increasing plasma GH 10-fold in an anesthetized IV rat model.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Growth Hormone/metabolism , Tetrazoles/chemistry , Amides/chemistry , Animals , Cell Line , Glioma/metabolism , Growth Hormone/blood , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
The structure-activity relationship of the O-benzyl serine side chain was investigated based on the tetrazole-based growth hormone secretagogue BMS-317180 (2). The ortho position of the benzyl moiety was found to be favorable for introduction of substituents. A series of ortho-substituted compounds were synthesized with improved in-vitro and in-vivo activity. Among them, the biphenyl compound 2p shows twofold improvement in potency compared to its parent compound BMS-317180 (2).
Subject(s)
Drug Design , Growth Hormone/metabolism , Serine/analogs & derivatives , Tetrazoles/chemistry , Tetrazoles/pharmacology , Animals , Carbamates/pharmacology , Molecular Structure , Rats , Serine/chemistry , Structure-Activity Relationship , Tetrazoles/chemical synthesisABSTRACT
A tetrazole-based peptidomimetic 2 (BMS-317180) was discovered as a human growth hormone secretagogue (GHS). Compound 2 is a potent, novel, orally effective GHS that shows an excellent safety profile in preclinical studies. The compound was advanced into clinical development.