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1.
J Med Chem ; 49(8): 2600-10, 2006 Apr 20.
Article in English | MEDLINE | ID: mdl-16610803

ABSTRACT

The development of a series of GABA(A) alpha2/alpha3 subtype selective pyridazine based benzodiazepine site agonists as anxiolytic agents with reduced sedative/ataxic potential is described, including the discovery of 16, a remarkably alpha3-selective compound ideal for in vivo study. These ligands are antagonists at the alpha1 subtype, with good CNS penetration and receptor occupancy, and excellent oral bioavailability.


Subject(s)
Anti-Anxiety Agents/pharmacology , Anxiety/drug therapy , GABA Agonists/pharmacology , GABA-A Receptor Agonists , Pyridazines/pharmacology , Animals , Anti-Anxiety Agents/administration & dosage , Anti-Anxiety Agents/chemical synthesis , Binding Sites , GABA Agonists/administration & dosage , GABA Agonists/chemical synthesis , Humans , Ligands , Molecular Structure , Pyridazines/administration & dosage , Pyridazines/chemical synthesis , Rats , Recombinant Proteins/agonists , Stereoisomerism , Structure-Activity Relationship
2.
J Med Chem ; 49(1): 35-8, 2006 Jan 12.
Article in English | MEDLINE | ID: mdl-16392789

ABSTRACT

A series of high-affinity GABA(A) agonists with good oral bioavailability in rat and dog and functional selectivity for the GABA(A)alpha2 and -alpha3 subtypes is reported. The 7-trifluoromethylimidazopyrimidine 14g and the 7-propan-2-olimidazopyrimidine 14k are anxiolytic in both conditioned and unconditioned animal models of anxiety with minimal sedation observed at full BZ binding site occupancy.


Subject(s)
Anxiety Disorders/drug therapy , GABA-A Receptor Agonists , Pyrimidines/pharmacology , Administration, Oral , Animals , Binding Sites , Biological Availability , Cell Line , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Humans , Molecular Structure , Patch-Clamp Techniques , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats , Receptors, GABA-A , Structure-Activity Relationship
3.
J Med Chem ; 48(23): 7089-92, 2005 Nov 17.
Article in English | MEDLINE | ID: mdl-16279764

ABSTRACT

There is increasing evidence that compounds with selectivity for gamma-aminobutyric acid(A) (GABA(A)) alpha2- and/or alpha3-subtypes may retain the desirable anxiolytic activity of nonselective benzodiazepines but possess an improved side effect profile. Herein we describe a novel series of GABA(A) alpha2/alpha3 subtype-selective agonists leading to the identification of the development candidate 17, a nonsedating anxiolytic in preclinical animal assays.


Subject(s)
Anti-Anxiety Agents/chemical synthesis , GABA-A Receptor Agonists , Hypnotics and Sedatives/chemical synthesis , Pyridazines/chemical synthesis , Triazoles/chemical synthesis , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Binding, Competitive , Cell Line , Dogs , GABA-A Receptor Antagonists , Half-Life , Humans , Hypnotics and Sedatives/chemistry , Hypnotics and Sedatives/pharmacology , Mice , Oocytes/drug effects , Oocytes/physiology , Patch-Clamp Techniques , Primates , Pyridazines/chemistry , Pyridazines/pharmacology , Radioligand Assay , Rats , Receptors, GABA-A/physiology , Recombinant Proteins/agonists , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacology , Xenopus
4.
J Med Chem ; 47(7): 1807-22, 2004 Mar 25.
Article in English | MEDLINE | ID: mdl-15027873

ABSTRACT

Studies with our screening lead 5 and the literature compound 6 led to the identification of 6-benzyloxy-3-(4-methoxy)phenyl-1,2,4-triazolo[3,4-a]phthalazine 8 as a ligand with binding selectivity for the gamma-aminobutyric acid-A (GABA-A) alpha 3- and alpha 5-containing receptor subtypes over the GABA-A alpha 1 subtype (K(i): alpha 2 = 850 nM, alpha 3 = 170 nM, alpha 5 = 72 nM, alpha 1 = 1400 nM). Early optimization studies identified the close analogue 10 (K(i): alpha 2 = 16 nM, alpha 3 = 41 nM, alpha 5 = 38 nM, alpha 1 = 280 nM) as a suitable lead for further study. High-affinity ligands were identified by replacing the 6-benzyloxy group of compound 10 with 2-pyridylmethoxy (compound 29), but binding selectivity was not enhanced (K(i): alpha 2 = 1.7 nM, alpha 3 = 0.71 nM, alpha 5 = 0.33 nM, alpha 1 = 2.7 nM). Furthermore, on evaluation in xenopus oocytes,(22) 29 was discovered to be a weak to moderate inverse agonist at all four receptor subtypes (alpha 1, -7%; alpha 2, -5%; alpha 3, -16%; alpha 5, -5%). Replacement of the 3-phenyl group of 29 with alternatives led to reduced affinity, and smaller 3-substituents led to reduced efficacy. Methyl substitution of the benzo-fused ring of 29 at the 7-, 8-, and 10-positions resulted in increased efficacy although selectivity was abolished. Increased efficacy and retention of selectivity for alpha 3 over alpha 1 was achieved with the 7,8,9,10-tetrahydro-(7,10-ethano)-phthalazine 62. Compound 62 is currently one of the most binding selective GABA-A alpha 3-benzodiazepine-site partial agonists known, and although its selectivity is limited, its good pharmacokinetic profile in the rat (33% oral bioavailability after a 3 mg/kg dose, reaching a peak plasma concentration of 179 ng/mL; half-life of 1 h) made it a useful pharmacological tool to explore the effect of a GABA-A alpha 2/alpha 3 agonist in vivo.


Subject(s)
GABA-A Receptor Agonists , Phthalazines/chemical synthesis , Triazoles/chemical synthesis , Animals , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Binding, Competitive , Biological Availability , Cell Line , Humans , Magnetic Resonance Spectroscopy , Maze Learning/drug effects , Oocytes/drug effects , Oocytes/metabolism , Patch-Clamp Techniques , Phthalazines/chemistry , Phthalazines/pharmacology , Radioligand Assay , Rats , Receptors, GABA-A/metabolism , Receptors, GABA-A/physiology , Recombinant Proteins/metabolism , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacology , Xenopus
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