ABSTRACT
Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFα). Structure-activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic-pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed.
Subject(s)
Naphthyridines/pharmacology , Quinolines/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Animals , Arthritis, Experimental/drug therapy , Arthritis, Rheumatoid/drug therapy , Drug Design , Female , Humans , Mice, Inbred C57BL , Microsomes, Liver/metabolism , Molecular Structure , Naphthyridines/chemical synthesis , Naphthyridines/pharmacokinetics , Naphthyridines/therapeutic use , Proof of Concept Study , Quinolines/chemical synthesis , Quinolines/pharmacokinetics , Quinolines/therapeutic use , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolismABSTRACT
The potent MCHR1 in vitro and in vivo antagonist activity of a series of cyclic tertiary alcohols derived from compound 2b is described. Subsequent pharmacokinetic and pharmacodynamic studies identified BMS-814580 (compound 10) as a highly efficacious antiobesity agent with a relatively clean in vitro and in vivo safety profile.
Subject(s)
Anti-Obesity Agents/chemistry , Anti-Obesity Agents/therapeutic use , Obesity/drug therapy , Pyrimidines/chemistry , Pyrimidines/therapeutic use , Receptors, Somatostatin/antagonists & inhibitors , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/pharmacology , Dogs , Halogenation , Humans , Macaca fascicularis , Male , Mice , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Receptors, Somatostatin/metabolism , Structure-Activity RelationshipABSTRACT
Identification of MCHR1 antagonists with a preclinical safety profile to support clinical evaluation as antiobesity agents has been a challenge. Our finding that a basic moiety is not required for MCHR1 antagonists to achieve high affinity allowed us to explore structures less prone to off-target activities such as hERG inhibition. We report the SAR evolution of hydroxylated thienopyrimidinone ethers culminating in the identification of 27 (BMS-819881), which entered obesity clinical trials as the phosphate ester prodrug 35 (BMS-830216).
Subject(s)
Anti-Obesity Agents/pharmacology , Drug Discovery , Obesity/drug therapy , Receptors, Somatostatin/antagonists & inhibitors , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/therapeutic use , Dogs , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Male , RatsABSTRACT
A series of inhibitors of mammalian 15-lipoxygenase (15-LO) based on a 3,4,5-tri-substituted pyrazole scaffold is described. Replacement of a sulfonamide functionality in the lead series with a sulfamide group resulted in improved physicochemical properties generating analogs with enhanced inhibition in cell-based and whole blood assays.
Subject(s)
Amides/chemistry , Arachidonate 15-Lipoxygenase/chemistry , Lipoxygenase Inhibitors/chemistry , Pyrazoles/chemistry , Amides/chemical synthesis , Amides/pharmacology , Animals , Arachidonate 15-Lipoxygenase/metabolism , CHO Cells , Cricetinae , Cricetulus , Humans , Hydroxyeicosatetraenoic Acids/blood , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/pharmacology , Rabbits , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
Agonists of the 5-HT(2C) receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT(2B) receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT(2C) agonists with no detectable agonism of the 5-HT(2B) receptor is described. Among these, compounds (+)-2a and (+)-3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing.
Subject(s)
Anti-Obesity Agents/chemistry , Obesity/drug therapy , Quinazolinones/chemistry , Serotonin 5-HT2 Receptor Agonists , Serotonin Receptor Agonists/chemistry , Administration, Oral , Animals , Anti-Obesity Agents/administration & dosage , Anti-Obesity Agents/metabolism , Eating/drug effects , Eating/physiology , Humans , Male , Obesity/metabolism , Protein Binding/physiology , Quinazolinones/administration & dosage , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin Receptor Agonists/administration & dosage , Serotonin Receptor Agonists/metabolismABSTRACT
3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded as generally safe, they are known to cause myopathy and, in rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids are mediated through the inhibition of HMGR in the hepatocyte, whereas evidence suggests that myotoxicity is due to inhibition of HMGR within the myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could potentially result in an improved therapeutic window. Implementation of a strategy that focused on in vitro potency, compound polarity, cell selectivity, and oral absorption, followed by extensive efficacy and safety modeling in guinea pig and rat, resulted in the identification of compound 1b (BMS-644950). Using this discovery pathway, we compared 1b to other marketed statins to demonstrate its outstanding efficacy and safety profile. With the potential to generate an excellent therapeutic window, 1b was advanced into clinical development.
Subject(s)
Hydroxymethylglutaryl CoA Reductases/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Triazoles/chemical synthesis , Administration, Oral , Animals , Biological Availability , Chemical and Drug Induced Liver Injury/etiology , Cholesterol/biosynthesis , Cholesterol/blood , Crystallography, X-Ray , Dogs , Female , Guinea Pigs , Haplorhini , Humans , Hydroxymethylglutaryl CoA Reductases/chemistry , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/toxicity , In Vitro Techniques , Liver/drug effects , Liver/metabolism , Models, Molecular , Muscle Cells/cytology , Muscle Cells/drug effects , Muscle Cells/metabolism , Pyrimidines/pharmacology , Pyrimidines/toxicity , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Triazoles/pharmacology , Triazoles/toxicityABSTRACT
A series of 2,4,5-tri-substituted imidazoles has proven to be highly potent in inhibiting mammalian 15-lipoxygenase (15-LO) with excellent selectivity over human isozymes 5- and P-12-LO. Non-symmetrical sulfamides (e.g., 21a-n) were found to be suitable replacements for the earlier arylsulfonamide-containing members of this series (e.g., 2, 14a-p). Several members of these series also demonstrated potent inhibition of human 15-LO in a cell-based assay.
Subject(s)
Imidazoles/pharmacology , Lipoxygenase Inhibitors , Lipoxygenase Inhibitors/pharmacology , Animals , CHO Cells , Cricetinae , Cricetulus , Humans , Imidazoles/chemistry , Lipoxygenase Inhibitors/chemistry , Male , Rats , Rats, Sprague-DawleyABSTRACT
A series of inhibitors of mammalian 15-lipoxygenase based on tryptamine and homotryptamine scaffolds is described. Compounds with aryl substituents at C-2 of the indole core of tryptamine and homotryptamine sulfonamides (e.g., 37a-p) proved to be potent inhibitors of the isolated enzyme. Selected compounds also demonstrated desirable inhibition selectivities over isozymes 5- and P-12-LO.
Subject(s)
Enzyme Inhibitors/pharmacology , Lipoxygenase Inhibitors , Sulfonamides/pharmacology , Tryptamines/chemistry , Animals , Enzyme Inhibitors/chemistry , Molecular Structure , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
Inhibition of the sodium hydrogen exchanger isoform-1 (NHE-1) has been shown to limit damage to the myocardium under ischemic conditions in animals. While most known NHE-1 inhibitors are acylguanidines, this report describes the design and synthesis of a series of heterocyclic inhibitors of NHE-1 including aminoimidazoles with undiminished in vitro activity and oral bioavailability.