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1.
J Med Chem ; 53(22): 8104-15, 2010 Nov 25.
Article in English | MEDLINE | ID: mdl-20973483

ABSTRACT

The in vivo characterization of a dual adenosine A(2A)/A(1) receptor antagonist in several animal models of Parkinson's disease is described. Discovery and scale-up syntheses of compound 1 are described in detail, highlighting optimization steps that increased the overall yield of 1 from 10.0% to 30.5%. Compound 1 is a potent A(2A)/A(1) receptor antagonist in vitro (A(2A) K(i) = 4.1 nM; A(1) K(i) = 17.0 nM) that has excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse model of reserpine-induced akinesia, rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation, and MPTP-treated non-human primate model.


Subject(s)
Adenosine A1 Receptor Antagonists/chemical synthesis , Adenosine A2 Receptor Antagonists/chemical synthesis , Antiparkinson Agents/chemical synthesis , Indenes/chemical synthesis , Parkinson Disease/metabolism , Pyrimidines/chemical synthesis , Receptor, Adenosine A2A/physiology , Adenosine A1 Receptor Antagonists/pharmacokinetics , Adenosine A1 Receptor Antagonists/pharmacology , Adenosine A2 Receptor Antagonists/pharmacokinetics , Adenosine A2 Receptor Antagonists/pharmacology , Administration, Oral , Animals , Antiparkinson Agents/pharmacokinetics , Antiparkinson Agents/pharmacology , Callithrix , Disease Models, Animal , Female , Indenes/pharmacokinetics , Indenes/pharmacology , Macaca fascicularis , Male , Mice , Mice, Inbred BALB C , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley
2.
Metabolism ; 54(7): 848-55, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15988691

ABSTRACT

Abstract Specific blockade of glucocorticoid receptor (GCCR) action in the liver without affecting the hypothalamus-pituitary-adrenal axis could be a novel pharmaceutical approach to treat type 2 diabetes. In the present study, we applied an antisense oligonucleotide (ASO) against GCCR (ASO-GCCR) to reduce the expression of liver GCCR and examined its impact on the diabetic syndrome in ob / ob and db / db mice. A 3-week treatment regimen of ASO-GCCR (25 mg/kg IP, twice per week) markedly reduced liver GCCR messenger RNA and protein expression with no alteration of GCCR messenger RNA expression in the hypothalamus, pituitary, or adrenal gland. The ASO-GCCR treatment lowered blood glucose levels by 45% and 23% in ob / ob and db / db mice, respectively, compared with those observed in the control group. The ASO-GCCR-treated mice also showed significant enhancement of insulin-mediated inhibition of hepatic glucose production during a euglycemic-hyperinsulinemic clamp as well as marked reduction of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase activity compared with control mice. The ASO-GCCR treatment did not change peripheral insulin sensitivity during the clamp. The ob / ob mice treated with ASO-GCCR had no significant difference in the plasma corticosterone and corticotropin levels compared with control mice. Lean mice receiving a similar treatment regimen of ASO-GCCR exhibited no change in blood glucose levels, oral glucose tolerance tests, or insulin tolerance tests. Our results demonstrate that selective inhibition of GCCR expression in the liver by the ASO-GCCR treatment reduced hepatic glucose production and improved blood glucose control under diabetic conditions.


Subject(s)
Diabetes Mellitus, Experimental/metabolism , Gluconeogenesis/drug effects , Hyperglycemia/prevention & control , Liver/metabolism , Oligonucleotides, Antisense/pharmacology , Receptors, Glucocorticoid/drug effects , Animals , Blotting, Western , Diabetes Mellitus, Experimental/blood , Female , Glucose Tolerance Test , Mice
3.
Diabetes ; 53(2): 410-7, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14747292

ABSTRACT

Excess glucagon levels contribute to the hyperglycemia associated with type 2 diabetes. Reducing glucagon receptor expression may thus ameliorate the consequences of hyperglucagonemia and improve blood glucose control in diabetic patients. This study describes the antidiabetic effects of a specific glucagon receptor antisense oligonucleotide (GR-ASO) in db/db mice. The ability of GR-ASOs to inhibit glucagon receptor mRNA expression was demonstrated in primary mouse hepatocytes by quantitative real-time RT-PCR. Intraperitoneal administration of GR-ASO at a dosage of 25 mg/kg twice a week in db/db mice for 3 weeks resulted in 1) decreased glucagon receptor mRNA expression in liver; 2) decreased glucagon-stimulated cAMP production in hepatocytes isolated from GR-ASO-treated db/db mice; 3) significantly reduced blood levels of glucose, triglyceride, and free fatty acids; 4) improved glucose tolerance; and 5) a diminished hyperglycemic response to glucagon challenge. Neither lean nor db/db mice treated with GR-ASO exhibited hypoglycemia. Suppression of GR expression was also associated with increased ( approximately 10-fold) levels of plasma glucagon. No changes were observed in pancreatic islet cytoarchitecture, islet size, or alpha-cell number. However, alpha-cell glucagon levels were increased significantly. Our studies support the concept that antagonism of glucagon receptors could be an effective approach for controlling blood glucose in diabetes.


Subject(s)
Diabetes Mellitus/genetics , Diabetes Mellitus/prevention & control , Down-Regulation/drug effects , Hepatocytes/metabolism , Oligonucleotides, Antisense/pharmacology , Receptors, Glucagon/genetics , Animals , Blood Glucose/metabolism , Cyclic AMP/metabolism , Disease Models, Animal , Female , Gluconeogenesis , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Oligonucleotides, Antisense/therapeutic use , Transcription, Genetic
4.
J Med Chem ; 47(1): 196-209, 2004 Jan 01.
Article in English | MEDLINE | ID: mdl-14695833

ABSTRACT

A series of benzoxazinones has been synthesized and tested for PPARgamma agonist activity. Synthetic approaches were developed to provide either racemic or chiral compounds. In vitro functional potency could be measured through induction of the aP2 gene, a target of PPARgamma. These studies revealed that compounds with large aliphatic chains at the nitrogen of the benzoxazinone were the most potent. Substitution of the chain was tolerated and in many cases enhanced the in vitro potency of the compound. Select compounds were further tested for metabolic stability, oral bioavailability in rats, and efficacy in db/db mice after 11 days of dosing. In vivo analysis with 13 and 57 demonstrated that the series has potential for the treatment of type 2 diabetes.


Subject(s)
Amides/chemical synthesis , Diabetes Mellitus, Type 2/drug therapy , Oxazines/chemical synthesis , Receptors, Cytoplasmic and Nuclear/agonists , Transcription Factors/agonists , Amides/chemistry , Amides/pharmacology , Animals , Biological Availability , Cytochrome P-450 Enzyme System/metabolism , Drug Stability , Female , Humans , In Vitro Techniques , Mice , Microsomes, Liver/metabolism , Oxazines/chemistry , Oxazines/pharmacology , Rats , Stereoisomerism , Structure-Activity Relationship
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