ABSTRACT
A series of novel (4-piperidin-1-yl)-phenyl sulfonamides was prepared and evaluated for their biological activity on the human beta(3)-adrenergic receptor (AR). Replacement of the 3,4-dihydroxyl group of the catechol moiety with 4-hydroxyl-3-methyl sulfonamide on the left-hand side of the compounds resulted in a number of potent full agonists at the beta(3) receptor. Modification of the right-hand side of the compounds by incorporation of a free carboxylic acid resulted in a few potent human beta(3) agonists with low affinities for beta(1)- and beta(2)-ARs. N-Alkyl substitution on the 4-piperidin-1-yl-phenylamine further increased the beta(3) potency while maintaining the selectivity. For example, sulfonamide 48 is a potent full beta(3) agonist (EC(50)=0.004 microM, IA=1.0) with > 500-fold selectivity over beta(1)- and beta(2)-ARs.
Subject(s)
Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Agonists/chemical synthesis , Piperidines/chemical synthesis , Sulfonamides/chemical synthesis , Adrenergic beta-Agonists/chemistry , Adrenergic beta-Agonists/pharmacology , Animals , CHO Cells , Cricetinae , Humans , Piperidines/chemistry , Piperidines/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
As part of our investigation into the development of potent and selective human beta3 agonists, a series of thiazolidinedione analogues was prepared and evaluated for their biological activity on the human beta3-adrenergic receptor. The oxadiazolidinedione derivative 17 was found to be the most potent and selective compound in this study, with an EC50 value of 0.02 microM at the beta3 receptor, 259-fold selectivity over the beta1 receptor, and 745-fold selectivity over the beta2 receptor.
Subject(s)
Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Agonists/pharmacology , Cyclic AMP/agonists , Thiazolidinediones , Adrenergic beta-Agonists/chemical synthesis , Animals , CHO Cells , Cricetinae , Humans , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacology , Protein Binding/physiology , Sensitivity and Specificity , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacologyABSTRACT
In search of potent and selective human beta(3) agonists as potential drugs for the treatment of human obesity and type II diabetes, a series of (4-piperidin-1-yl)phenyl amides was prepared and evaluated for their biological activity on the human beta(3)-adrenergic receptor. The leucine derivative 26e and the reverse amide 33b were found to be the two most potent and selective compounds in this study. With EC(50) values of 0.008 and 0.009 microM, respectively, at the beta(3) receptor, nearly completely abolished intrinsic activity at either the beta(1) or beta(2) receptor, and significant thermogenesis effects on human beta(3)-adrenergic receptor transgenic mice, 26e and33b are among the most potent and selective human beta(3) agonists known to date.
Subject(s)
Adrenergic beta-Agonists/chemical synthesis , Leucine/chemical synthesis , Piperidines/chemical synthesis , Receptors, Adrenergic, beta-3/metabolism , Sulfonamides/chemical synthesis , Adrenergic beta-Agonists/chemistry , Adrenergic beta-Agonists/metabolism , Adrenergic beta-Agonists/pharmacology , Animals , Body Temperature/drug effects , CHO Cells , Cricetinae , Cyclic AMP/metabolism , Energy Metabolism/drug effects , Female , Humans , Leucine/analogs & derivatives , Leucine/chemistry , Leucine/metabolism , Leucine/pharmacology , Mice , Mice, Transgenic , Piperidines/chemistry , Piperidines/metabolism , Piperidines/pharmacology , Radioligand Assay , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/metabolism , Sulfonamides/pharmacology , TransfectionABSTRACT
Methylsulfonamide substituted 2,4-thiazolidinedione 22c is a potent (EC50=0.01 microM, IA=1.19) and selective (more than 110-fold over beta1 and beta2 agonist activity) beta3 agonist. This compound has also been proven to be active and selective in an in vivo mode.
Subject(s)
Adrenergic beta-3 Receptor Agonists , Thiazoles/pharmacology , Thiazolidinediones , Animals , Diabetes Mellitus, Type 2/drug therapy , Disease Models, Animal , Humans , Mice , Mice, Knockout , Mice, Transgenic , Obesity/drug therapy , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistry , Thiazoles/therapeutic useABSTRACT
A combinatorial approach for rapid optimization of a vitronectin receptor (alphavbeta3) inhibitor lead was accomplished by solid-phase synthesis. Orthogonally bis protected 2,3-diaminopropionic acid was used to immobilize the C-terminus of the molecule. Selective deprotection and functionalization of the alpha-amino group followed by acyl resorcinol scaffold attachment and N-terminus diversification was used to explore structure activity relationship (SAR).
Subject(s)
Receptors, Vitronectin/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
A series of xanthine sulfonamides is presented as a class of calcitonin (CT) inducers - a potentially new method for treating diseases associated with postmenopausal bone loss such as osteoporosis. We have found that certain di-n-butylxanthine sulfonamides 4 upregulate CT transcription in a CT-luciferase reporter gene assay (CT-luci) and increase the production and release of CT in a CT secretion/RIA assay (CTS). In addition, these compounds do not have potent PDE4 inhibitory activity as do the related xanthine methylene ketones such as denbufyllene (2). One compound in particular (9) shows a transcription activation ratio (TAR) of 2.1 in CT-luci, a CTS increase of 3.6-fold, and a PDE4 (phosphodiesterase type IV) IC(50) = 4.1 microM. In addition, this compound showed a statistically significant 47% trabecular bone protection in ovariectomized-induced osteopenia (OVX) rats as determined by assay when administered for 4 weeks at 30 mg/kg/day, i. p. by quantitative computed tomography (QCT). When administered p.o., compound 9 shows 50% trabecular bone protection when administered for 3 weeks at 50 mg/kg/day, i.p. This compared with salmon CT which shows 62% trabecular bone protection when administered at 50 IU/kg/day for 4 weeks.
Subject(s)
Calcitonin/biosynthesis , Sulfonamides/chemical synthesis , Xanthines/chemical synthesis , 3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Animals , Bone Density/drug effects , Bone Diseases, Metabolic/drug therapy , Bone Diseases, Metabolic/pathology , Calcitonin/genetics , Cyclic Nucleotide Phosphodiesterases, Type 4 , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Female , Genes, Reporter , Humans , Luciferases/genetics , Ovariectomy , Radioimmunoassay , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Transcription, Genetic , Xanthines/chemistry , Xanthines/pharmacologyABSTRACT
CL316243 is a highly selective and potent beta3-adrenergic receptor agonist, and has been shown in rodent models to be an effective agent for treating obesity and Type II diabetes. To improve the oral absorption and pharmacokinetic profiles of CL316243, a number of prodrugs have been synthesized and evaluated. Several ester-type prodrugs show significant improvements in oral bioavailability in both rodent and primate models.
Subject(s)
Adrenergic beta-Agonists/pharmacology , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Dioxoles/pharmacology , Hypoglycemic Agents/pharmacology , Obesity/drug therapy , Prodrugs/pharmacology , Adrenergic beta-Agonists/chemistry , Adrenergic beta-Agonists/metabolism , Animals , Biological Availability , Esters/chemistry , Esters/metabolism , Fatty Acids/blood , Half-Life , Haplorhini , Humans , Hydrolysis , Mice , Prodrugs/chemistry , Prodrugs/metabolism , RatsABSTRACT
Solid-phase synthesis is a valuable tool for drug discovery research. The value is particularly evident in lead optimization work where it contributes to the rapid and thorough identification of the optimal drug candidate within a lead series. Solid-phase synthesis methods continue to be developed at a rapid pace, and these methods will eventually become standard tools for medicinal chemists. This review is focused on papers published since the beginning of 1998, which describe the use of solid-phase synthesis in lead optimization.
ABSTRACT
Described in this paper is the synthesis and pharmacological activity of five metabolites of the angiotensin II antagonist tasosartan (1). Of particular interest is the effect of the additional acidic group of the enol metabolite (8) on activity. As suggested by the structural-activity relationship of other angiotensin II antagonist series, a second acidic group can improve receptor binding activity but decrease in vivo activity after oral dosing. The metabolic introduction of a second acidic group in tasosartan bypasses this problem and contributes to the excellent profile of the compound. A molecular modeling study provides a rationale for the role of the enol group of 8 in AT1 receptor binding.
Subject(s)
Angiotensin II/antagonists & inhibitors , Models, Molecular , Pyridones/chemical synthesis , Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Tetrazoles/metabolism , Administration, Oral , Adrenal Glands/drug effects , Adrenal Glands/metabolism , Angiotensin II/metabolism , Angiotensin II Type 1 Receptor Blockers , Angiotensin II Type 2 Receptor Blockers , Angiotensin Receptor Antagonists , Animals , Blood Pressure/drug effects , Heart Rate/drug effects , Hypertension/physiopathology , In Vitro Techniques , Injections, Intravenous , Liver/drug effects , Liver/metabolism , Molecular Conformation , Pyridones/administration & dosage , Pyridones/chemistry , Pyridones/pharmacology , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Angiotensin, Type 1 , Receptor, Angiotensin, Type 2 , Receptors, Angiotensin/metabolism , Structure-Activity RelationshipABSTRACT
S(+)-aporphines are partial agonists at D2 dopamine receptors. High selectivity of anti-dopaminergic action in limbic vs. extrapyr amidal regions of rat brain and lack of induction of dopaminergic supersensitivity have suggested their potential as atypical antipsychotic drugs. Now, in testing for effects on circulating prolactin, a typical D2 antagonist haloperidol elevated, and potent agonist R(-)-11-hydroxy-N-propylnoraporphine lowered, serum prolactin levels in gentled male rats, while S(+)-N-propylnorapomorphine and its 11-monohydroxy analog had little or no effect, even at high doses. Lack of hyperprolactinemia adds to characteristics of S(+)-aporphines that are desirable in improved antipsychotics.
Subject(s)
Aporphines/pharmacology , Prolactin/blood , Animals , Apomorphine/analogs & derivatives , Apomorphine/pharmacology , Dopamine Agonists/pharmacology , Haloperidol/pharmacology , Male , Radioimmunoassay , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D2/agonists , StereoisomerismABSTRACT
A series of pyrido[2,3-d]pyrimidine angiotensin II (A II) antagonists was synthesized and tested for antagonism of A II. Compounds with a biphenylyltetrazole pharmacophore and small alkyl groups at the 2- and 4-positions of the pyridopyrimidine ring were found to be the most potent in an AT1 receptor binding assay and in blocking the A II pressor response in anesthetized, ganglion-blocked A II-infused rats. 5,8-Dihydro-2,4-dimethyl-8-[(2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl)methyl]pyrido[2,3-d]pyrimidin-7(6H)-one (4a) was one of the more potent compounds in the binding assay and was the most efficacious compound in the A II-infused rat model. Further study of 4a in Goldblatt (2K-1C) rats showed the compound to have oral bioavailability and to be an efficacious and potent compound in a high renin form of hypertension.
Subject(s)
Pyridines/chemical synthesis , Pyridines/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Tetrazoles/chemical synthesis , Tetrazoles/pharmacology , Animals , Blood Pressure/drug effects , Liver/drug effects , Liver/metabolism , Male , Pressoreceptors/drug effects , Pyridines/pharmacokinetics , Pyrimidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Tetrazoles/pharmacokineticsABSTRACT
PURPOSE: Characteristic changes of platelet membrane monoamine oxidase and adenylate cyclase activities have been described in men with alcoholism. We studied the occurrence of these changes in abstinent alcoholic women and in nonalcoholic female control subjects with and without family histories of alcoholism. METHODS: Blood samples were collected from 23 female alcoholics and 39 nonalcoholic female social drinkers. Platelet membrane assays were performed for monoamine oxidase and adenylate cyclase activities. RESULTS: Alcoholic women had lower basal adenylate cyclase (p < 0.01) and adenylate cyclase activities stimulated by cesium fluoride (p < 0.001), by the guanine nucleotide analog 5'-guanylylimidodiphosphate (p < 0.02), and by prostaglandin E1 (p < 0.01). Female control subjects with family histories of alcoholism also had lower basal adenylate cyclase (p < 0.01) and adenylate cyclase activities enhanced by incubation with cesium fluoride (p < 0.005) and 5'-guanylylimidodiphosphate (p < 0.001). Monoamine oxidase activity levels measured with (p < 0.001) and without ethanol (p < 0.01) were higher for alcoholic women. No significant differences were found between female control subjects with and without family histories of alcoholism for monoamine oxidase in the absence or presence of ethanol. DISCUSSION: In vitro platelet adenylate cyclase activity may facilitate a diagnosis of alcoholism in women and may be a biologic indicator of vulnerability in the offspring of alcoholics.
Subject(s)
Adenylyl Cyclases/blood , Alcoholism/genetics , Blood Platelets/enzymology , Monoamine Oxidase/blood , Adult , Alcoholism/diagnosis , Alcoholism/psychology , Biomarkers/blood , Female , Humans , Male , Middle Aged , Reference Values , Sex FactorsABSTRACT
A series of naphthalenyl 3H-1,2,3,5-oxathiadiazole 2-oxides was prepared and tested for antihyperglycemic activity in the db/db mouse, a model for type 2 (non-insulin dependent) diabetes mellitus. Substitution at the 1-, 5-, or 8-positions of the naphthalene ring with a halogen was found to be beneficial to antihyperglycemic activity. 4-[(5-Chloronaphthalen-2-yl)methyl]-3H-1,2,3,5-oxathiadiazole++ + 2-oxide (45), one of the most potent compounds in this series, was selected for further pharmacological evaluation.
Subject(s)
Hypoglycemic Agents/chemical synthesis , Naphthalenes/chemical synthesis , Thiadiazoles/chemical synthesis , Animals , Blood Glucose/drug effects , Female , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Male , Mice , Mice, Obese , Naphthalenes/chemistry , Naphthalenes/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thiadiazoles/chemistry , Thiadiazoles/pharmacologyABSTRACT
Acute cocaine administration alters secretion of anterior pituitary hormones in experimental animals, and cocaine abuse may compromise neuroendocrine function in humans. The goal of this study was to examine cocaine's acute effects on neuroendocrine hormones in cocaine-dependent men. Plasma adrenocorticotropic hormone (ACTH), luteinizing hormone and prolactin levels were measured in 18 men before and after i.v. administration of cocaine (30 mg) or placebo. Each subject served as his own control during the i.v. placebo and cocaine administration conditions. Plasma cocaine levels peaked at 260 ng/ml within 5 min after the i.v. injection. Plasma ACTH levels increased significantly above base-line levels at 5, 15, 30 (P < .01) and 45 min (P < .05) after i.v. cocaine. Plasma luteinizing hormone levels increased significantly above base-line levels at 5 (P < .05) and at 15 min (P < .01) after i.v. cocaine. No changes in plasma ACTH or luteinizing hormone levels were found after i.v. placebo injection. Plasma prolactin levels decreased significantly at 30, 45, 60, 90 and 120 min (P < .01) after both i.v. cocaine and placebo administration. Cocaine-induced increases in plasma ACTH levels may be due to its effects on dopaminergic systems which modulate corticotropin-releasing factor release in brain.
Subject(s)
Adrenocorticotropic Hormone/blood , Cocaine , Luteinizing Hormone/blood , Prolactin/blood , Substance-Related Disorders/blood , Adult , Body Weight , Cocaine/administration & dosage , Cocaine/blood , Humans , Male , Time FactorsABSTRACT
Adrenocorticotropin (ACTH) levels in plasma increased rapidly to 105% above baseline within 5 minutes after intravenous injection of cocaine (30 mg) in cocaine-dependent men. The time course of ACTH stimulation paralleled increases in plasma cocaine levels and self-reports of salient drug effects on mood states and did not occur after placebo administration. An opioid mixed agonist-antagonist, buprenorphine (4 mg/day sublingually), suppressed the acute cocaine-induced stimulation of both ACTH and euphoria. Buprenorphine's suppression of postcocaine ACTH and euphoria were not related to differences in plasma cocaine levels or cocaine-induced alterations of cardiovascular function.
Subject(s)
Adrenocorticotropic Hormone/metabolism , Affect/drug effects , Buprenorphine/pharmacology , Cocaine/antagonists & inhibitors , Adult , Buprenorphine/blood , Cocaine/blood , Euphoria/drug effects , Hemodynamics/drug effects , Humans , Male , Substance-Related Disorders/psychologyABSTRACT
The synthesis and Class III antiarrhythmic activity of a series of 4-[(methylsulfonyl)amino]benzamides and sulfonamides are described. Selected compounds show a potent Class III activity and are devoid of effects on conduction both in vitro (dog Purkinje fibers) and in vivo (anesthetized dogs). Compounds having a 2-aminobenzimidazole group were found to be the most potent, and one compound having this heterocycle (5, WAY-123,398) was selected for further characterization. Compound 5 was shown to have good oral bioavailability and a favorable hemodynamic profile to produce a 3-fold increase of the ventricular fibrillation threshold and to terminate ventricular fibrillation, restoring sinus rhythm in anesthetized dogs. Voltage-clamp studies in isolated myocytes show that 5 is a potent and specific blocker of the delayed rectifier potassium current (IK) at concentrations that cause significant prolongation of action potential duration.
Subject(s)
Anti-Arrhythmia Agents/chemical synthesis , Benzamides/chemistry , Benzimidazoles/pharmacology , Sulfanilamides/pharmacology , Sulfonamides/chemistry , Action Potentials/drug effects , Anti-Arrhythmia Agents/pharmacology , Anti-Arrhythmia Agents/therapeutic use , Atrial Function , Benzamides/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/therapeutic use , Biological Availability , Electric Conductivity , Heart Atria/drug effects , Heart Conduction System/drug effects , Heart Conduction System/physiology , Heart Ventricles/drug effects , Membrane Potentials/drug effects , Molecular Structure , Myocardial Contraction/drug effects , Purkinje Fibers/drug effects , Purkinje Fibers/physiology , Structure-Activity Relationship , Sulfanilamides/chemical synthesis , Sulfanilamides/therapeutic use , Sulfonamides/pharmacology , Ventricular Fibrillation/drug therapy , Ventricular FunctionSubject(s)
Alcoholism/physiopathology , Gonadal Steroid Hormones/physiology , Hypothalamo-Hypophyseal System/drug effects , Hypothalamo-Hypophyseal System/physiopathology , Pituitary-Adrenal System/drug effects , Pituitary-Adrenal System/physiopathology , Reinforcement, Psychology , Alcohol Drinking/adverse effects , Alcohol Drinking/physiopathology , Alcoholism/psychology , Female , Gonadotropin-Releasing Hormone/physiology , Humans , Libido/drug effects , Libido/physiology , MaleABSTRACT
In a pilot study 5 matched pairs of female social drinkers received both 0.56 g/kg alcohol and placebo in a double-blind crossover design. Family history positive (FHP) women had biological fathers who met criteria for alcohol dependence, and FHN women had no relatives who met these criteria. FHP and FHN women had BALs about 70 mg/dl 60 min after alcohol. FHP subjects had significantly lower prolactin levels 40, 60 and 80 min following alcohol, but higher cortisol levels 130 and 150 min following alcohol. No significant differences in hormone levels occurred after placebo.
Subject(s)
Alcoholism/genetics , Ethanol/pharmacology , Hydrocortisone/blood , Prolactin/blood , Adult , Alcoholism/blood , Double-Blind Method , Ethanol/administration & dosage , Female , Humans , Kinetics , Male , Reference ValuesABSTRACT
Pyrimidineacetic acids and (pyrimidinyloxy)acetic acids were synthesized by alkylation, with methyl bromoacetate or tert-butyl bromoacetate as alkylating agents. Alkylation reaction at the nitrogen or oxygen atom for different substrates was found to be solvent dependent. N-Alkylation was favored in ethereal solvent, e.g., tetrahydrofuran and dimethoxyethane, whereas O-alkylation was predominant in dimethylformamide. These compounds were tested in vitro to determine their ability to inhibit bovine lens aldose reductase. Selected compounds were assayed in vivo, in a 4-day galactose-fed rat model. The decrease in galactitol from the control was determined in lens, nerve, and diaphragm. Several of the 6-oxopyrimidine-1-acetic acids and (pyrimidinyl-4-oxy)acetic acids were found to be potent inhibitors of bovine lens aldose reductase. A study was also undertaken to determine in vitro the transport behavior of selected compounds in the isolated rat sciatic nerve. A discussion of the structure-activity relationship of this class of compounds with reference to their intrinsic biochemical activity is reported. It is concluded, in general, that ability of a compound to penetrate the tissue membrane plays an important role in the genesis of in vivo lens aldose reductase (LAR) inhibitory activity.
Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Pyrimidines/chemical synthesis , Acetates , Administration, Oral , Alkylation , Animals , Cattle , Chemical Phenomena , Chemistry, Physical , Crystallography , Galactosemias/drug therapy , In Vitro Techniques , Lens, Crystalline/enzymology , Molecular Structure , Pyrimidines/pharmacology , Rats , Structure-Activity Relationship , X-Ray DiffractionABSTRACT
Chronic alcohol abuse is associated with derangements of reproductive function in women. The mechanism of increased risk for alcohol-related abortions and fetal alcohol syndrome is unknown. The goal of this study was to determine if acute alcohol administration affected gonadal steroid hormone levels after administration of human chorionic gonadotropin (hCG) to normal healthy women. hCG was used to simulate the hormonal milieu during the first trimester of pregnancy. Ten women were studied during the mid-luteal phase (between days 17 and 23) of their menstrual cycle. Plasma estradiol, progesterone and prolactin were measured before and after simultaneous administration of 5000 I.U. of hCG (Profasi) and alcohol or placebo solution under double-blind conditions. There was a significant increase in plasma estradiol (P less than .001) and prolactin levels (P less than .01) after hCG and alcohol administration but not after hCG and placebo administration. Plasma progesterone increased significantly (P less than .001) above base line after hCG and placebo administration but this was not observed after hCG and alcohol administration. Since progesterone is essential for the maintenance of pregnancy, alcohol's attenuation of the expected progesterone response to hCG stimulation could increase the risk of spontaneous abortion. An alcohol-induced increase in estradiol after hCG administration could contribute to risk for fetal dysmorphology during the first trimester of pregnancy.