Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 10 de 10
Filter
Add more filters










Publication year range
1.
Bioorg Med Chem Lett ; 20(9): 2770-5, 2010 May 01.
Article in English | MEDLINE | ID: mdl-20363132

ABSTRACT

The cannabinoid CB(1)/CB(2) receptor subtype selectivity in the 1,2-diarylimidazole-4-carboxamide series was boosted by fine-tuning its 5-substitution pattern. The presence of the 5-methylsulfonyl group in 11 led to a greater than approximately 840-fold CB(1)/CB(2) subtype selectivity. The compounds 10, 18 and 19 were found more active than rimonabant (1) in a CB(1)-mediated rodent hypotension model after oral administration. Our findings suggest a limited brain exposure of the P-glycoprotein substrates 11, 12 and 21.


Subject(s)
Aminoimidazole Carboxamide/analogs & derivatives , Imidazoles/chemistry , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Receptor, Cannabinoid, CB2/antagonists & inhibitors , Sulfones/chemistry , Administration, Oral , Aminoimidazole Carboxamide/chemical synthesis , Aminoimidazole Carboxamide/chemistry , Aminoimidazole Carboxamide/therapeutic use , Animals , Disease Models, Animal , Drug Inverse Agonism , Hypotension/drug therapy , Imidazoles/chemical synthesis , Imidazoles/therapeutic use , Mice , Rats , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/therapeutic use
2.
Bioorg Med Chem Lett ; 20(5): 1752-7, 2010 Mar 01.
Article in English | MEDLINE | ID: mdl-20137935

ABSTRACT

The synthesis, structure-activity relationship (SAR) studies and intramolecular hydrogen bonding pattern of 1,3,5-trisubstituted 4,5-dihydropyrazoles are described. The target compounds 6-18 represent a novel class of potent and selective CB(1) receptor antagonists. Based on X-ray diffraction data, the orally active 17 is shown to elicit a different intramolecular H-bonding mode as compared to ibipinabant (3) and SLV330 (4).


Subject(s)
Anti-Obesity Agents/chemical synthesis , Pyrazoles/chemical synthesis , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Sulfonamides/chemical synthesis , Administration, Oral , Animals , Anti-Obesity Agents/chemistry , Anti-Obesity Agents/pharmacology , Binding Sites , Crystallography, X-Ray , Humans , Hydrogen Bonding , Molecular Conformation , Pyrazoles/chemistry , Pyrazoles/pharmacology , Rats , Receptor, Cannabinoid, CB1/metabolism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology
3.
Bioorg Med Chem Lett ; 20(3): 1084-9, 2010 Feb 01.
Article in English | MEDLINE | ID: mdl-20031412

ABSTRACT

The synthesis and structure-activity relationship studies of imidazoles are described. The target compounds 6-20 represent a novel chemotype of potent and CB(2)/CB(1) selective cannabinoid CB(2) receptor antagonists/inverse agonists with very high binding efficiencies in combination with favourable logP and calculated polar surface area values. Compound 12 exhibited the highest CB(2) receptor affinity (K(i)=1.03 nM) in this series, as well as the highest CB(2)/CB(1) subtype selectivity (>9708-fold).


Subject(s)
Imidazoles/chemical synthesis , Imidazoles/metabolism , Receptor, Cannabinoid, CB2/antagonists & inhibitors , Receptor, Cannabinoid, CB2/metabolism , Animals , CHO Cells , Cannabinoids/antagonists & inhibitors , Cannabinoids/metabolism , Cricetinae , Cricetulus , Dose-Response Relationship, Drug , Humans , Protein Binding/physiology , Structure-Activity Relationship
4.
Neuropsychopharmacology ; 32(1): 78-94, 2007 Jan.
Article in English | MEDLINE | ID: mdl-16710314

ABSTRACT

Combined dopamine D(2) receptor antagonism and serotonin (5-HT)(1A) receptor agonism may improve efficacy and alleviate some side effects associated with classical antipsychotics. The present study describes the in vitro and in vivo characterization of 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluoro-phenyl)-pyridin-3-ylmethyl]-piperazine monohydrochloride (SLV313), a D(2/3) antagonist and 5-HT(1A) agonist. SLV313 possessed high affinity at human recombinant D(2), D(3), D(4), 5-HT(2B), and 5-HT(1A) receptors, moderate affinity at 5-HT(7) and weak affinity at 5-HT(2A) receptors, with little-no affinity at 5-HT(4), 5-HT(6), alpha(1), and alpha(2) (rat), H(1) (guinea pig), M(1), M(4), 5-HT(3) receptors, and the 5-HT transporter. SLV313 had full agonist activity at cloned h5-HT(1A) receptors (pEC(50)=9.0) and full antagonist activity at hD(2) (pA(2)=9.3) and hD(3) (pA(2)=8.9) receptors. In vivo, SLV313 antagonized apomorphine-induced climbing and induced 5-HT(1A) syndrome behaviors and hypothermia, the latter behaviors being antagonized by the 5-HT(1A) antagonist WAY100635. In a drug discrimination procedure SLV313 induced full generalization to the training drug flesinoxan and was also antagonized by WAY100635. In the nucleus accumbens SLV313 reduced extracellular 5-HT and increased dopamine levels in the same dose range. Acetylcholine and dopamine were elevated in the hippocampus and mPFCx, the latter antagonized by WAY100635, suggesting possible 5-HT(1A)-dependent efficacy for the treatment of cognitive and attentional processes. SLV313 did not possess cataleptogenic potential (up to 60 mg/kg p.o.). The number of spontaneously active dopamine cells in the ventral tegmental area was reduced by SLV313 and clozapine, while no such changes were seen in the substantia nigra zona compacta following chronic administration. These results suggest that SLV313 is a full 5-HT(1A) receptor agonist and full D(2/3) receptor antagonist possessing characteristics of an atypical antipsychotic, representing a potential novel treatment for schizophrenia.


Subject(s)
Antipsychotic Agents/pharmacology , Dopamine D2 Receptor Antagonists , Piperazines/pharmacology , Serotonin 5-HT1 Receptor Agonists , Analysis of Variance , Animals , Behavior, Animal/drug effects , Binding, Competitive/drug effects , Brain Chemistry/drug effects , CHO Cells , Catalepsy/drug therapy , Columbidae , Cricetinae , Cricetulus , Discrimination, Psychological/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Interactions , Humans , Male , Piperazines/chemistry , Rats , Rats, Wistar , Serotonin Receptor Agonists/pharmacology , Transfection
5.
Chem Pharm Bull (Tokyo) ; 54(9): 1326-30, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16946546

ABSTRACT

The syntheses of several 1-aryl-4-(arylpyridylmethyl)piperazines (4) and their affinities for dopamine D(2) and serotonin 5-HT(1A) receptors are described. The compounds were evaluated both in vitro and in vivo, resulting in the identification of the drug candidate SLV313 (4e) with equipotent and full D(2) receptor antagonism and 5-HT(1A) receptor agonism. Minor structural modifications in SLV313 revealed the possibility of designing compounds possessing varying degrees of partial agonism on one or both target receptors.


Subject(s)
Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacology , Dopamine D2 Receptor Antagonists , Piperazines/chemistry , Piperazines/pharmacology , Serotonin 5-HT1 Receptor Antagonists , Administration, Oral , Animals , Antipsychotic Agents/administration & dosage , Dogs , Drug Design , Drug Evaluation, Preclinical , Female , Injections, Intravenous , Ligands , Male , Molecular Structure , Piperazines/administration & dosage , Rats , Stereoisomerism , Structure-Activity Relationship
6.
Bioorg Med Chem Lett ; 16(4): 1045-8, 2006 Feb 15.
Article in English | MEDLINE | ID: mdl-16289817
7.
J Med Chem ; 48(22): 6855-69, 2005 Nov 03.
Article in English | MEDLINE | ID: mdl-16250644

ABSTRACT

A series of novel bicyclic 1-heteroaryl-4-[omega-(1H-indol-3-yl)alkyl]piperazines was synthesized and evaluated on binding to dopamine D(2) receptors and serotonin reuptake sites. This class of compounds proved to be potent in vitro dopamine D(2) receptor antagonists and in addition were highly active as serotonin reuptake inhibitors. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both the antagonism of apomorphine-induced climbing and the potentiation of 5-HTP-induced behavior in mice. On the basis of the preclinical data, 8-{4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazin-1-yl}-4H-benzo[1,4]oxazin-(R)-2-methyl-3-one (45c, SLV314) was selected for clinical development. In vitro and in vivo studies revealed that 45c has favorable pharmacokinetic properties and a high CNS-plasma ratio. Molecular modeling studies showed that the bifunctional activity of 45c can be explained by its ability to adopt two different conformations fitting either the dopamine D(2) receptor pharmacophore or the serotonin transporter pharmacophore.


Subject(s)
Antipsychotic Agents/chemical synthesis , Benzoxazines/chemical synthesis , Dopamine D2 Receptor Antagonists , Indoles/chemical synthesis , Piperazines/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemical synthesis , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Antipsychotic Agents/pharmacokinetics , Antipsychotic Agents/pharmacology , Benzoxazines/pharmacokinetics , Benzoxazines/pharmacology , Biological Transport , CHO Cells , Cell Line , Cricetinae , Cricetulus , Indoles/pharmacokinetics , Indoles/pharmacology , Male , Models, Molecular , Piperazines/pharmacokinetics , Piperazines/pharmacology , Rats , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity Relationship
8.
Bioorg Med Chem Lett ; 15(21): 4794-8, 2005 Nov 01.
Article in English | MEDLINE | ID: mdl-16140010

ABSTRACT

Novel 3,4-diarylpyrazolines 1 as potent CB1 receptor antagonists with lipophilicity lower than that of SLV319 are described. The key change is the replacement of the arylsulfonyl group in the original series by a dialkylaminosulfonyl moiety. The absolute configuration (4S) of eutomer 24 was established by X-ray diffraction analysis and 24 showed a close molecular fit with rimonabant in a CB1 receptor-based model. Compound 17 exhibited the highest CB1 receptor affinity (Ki = 24 nM) in this series, as well as very potent CB1 antagonistic activity (pA2 = 8.8) and a high CB1/CB2 subtype selectivity (approximately 147-fold).


Subject(s)
Pyrazoles/chemical synthesis , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Cannabinoids/antagonists & inhibitors , Humans , Hydrophobic and Hydrophilic Interactions , Molecular Structure , Pyrazoles/pharmacology , Stereoisomerism , Structure-Activity Relationship , Sulfonamides , X-Ray Diffraction
9.
J Med Chem ; 48(6): 1823-38, 2005 Mar 24.
Article in English | MEDLINE | ID: mdl-15771428

ABSTRACT

Series of thiazoles, triazoles, and imidazoles were designed as bioisosteres, based on the 1,5-diarylpyrazole motif that is present in the potent CB(1) receptor antagonist rimonabant (SR141716A, 1). A number of target compounds was synthesized and evaluated in cannabinoid (hCB(1) and hCB(2)) receptor assays. The thiazoles, triazoles, and imidazoles elicited in vitro( )()CB(1) antagonistic activities and in general exhibited considerable CB(1) vs CB(2) receptor subtype selectivities, thereby demonstrating to be cannabinoid bioisosteres of the original diarylpyrazole class. Some key representatives in the imidazole series showed potent pharmacological in vivo activities after oral administration in both a CB agonist-induced hypotension model and a CB agonist-induced hypothermia model. Molecular modeling studies showed a close three-dimensional structural overlap between the key compound 62 and rimonabant. A structure-activity relationship (SAR) study revealed a close correlation between the biological results in the imidazole and pyrazole series.


Subject(s)
Imidazoles/chemical synthesis , Piperidines/chemistry , Piperidines/chemical synthesis , Pyrazoles/chemistry , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Thiazoles/chemical synthesis , Triazoles/chemical synthesis , Administration, Oral , Animals , CHO Cells , Cricetinae , Cricetulus , Cyclohexanols/antagonists & inhibitors , Hypotension/chemically induced , Hypothermia/chemically induced , Imidazoles/chemistry , Imidazoles/pharmacology , Mice , Models, Molecular , Molecular Conformation , Piperidines/pharmacology , Pyrazoles/pharmacology , Radioligand Assay , Rats , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB2/drug effects , Rimonabant , Stereoisomerism , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacology , Triazoles/chemistry , Triazoles/pharmacology
10.
J Med Chem ; 47(3): 627-43, 2004 Jan 29.
Article in English | MEDLINE | ID: mdl-14736243

ABSTRACT

A series of novel 3,4-diarylpyrazolines was synthesized and evaluated in cannabinoid (hCB(1) and hCB(2)) receptor assays. The 3,4-diarylpyrazolines elicited potent in vitro CB(1) antagonistic activities and in general exhibited high CB(1) vs CB(2) receptor subtype selectivities. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both a CB agonist-induced blood pressure model and a CB agonist-induced hypothermia model. Chiral separation of racemic 67, followed by crystallization and an X-ray diffraction study, elucidated the absolute configuration of the eutomer 80 (SLV319) at its C(4) position as 4S. Bioanalytical studies revealed a high CNS-plasma ratio for the development candidate 80. Molecular modeling studies showed a relatively close three-dimensional structural overlap between 80 and the known CB(1) receptor antagonist rimonabant (SR141716A). Further analysis of the X-ray diffraction data of 80 revealed the presence of an intramolecular hydrogen bond that was confirmed by computational methods. Computational models and X-ray diffraction data indicated a different intramolecular hydrogen bonding pattern in the in vivo inactive compound 6. In addition, X-ray diffraction studies of 6 revealed a tighter intermolecular packing than 80, which also may contribute to its poorer absorption in vivo. Replacement of the amidine -NH(2) moiety with a -NHCH(3) group proved to be the key change for gaining oral biovailability in this series of compounds leading to the identification of 80.


Subject(s)
Pyrazoles/chemical synthesis , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Sulfonamides/chemical synthesis , Administration, Oral , Animals , Arachidonic Acid/metabolism , Binding, Competitive , Biological Availability , CHO Cells , Cricetinae , Crystallography, X-Ray , Fever/chemically induced , Fever/physiopathology , Humans , Hypotension/chemically induced , Hypotension/physiopathology , Male , Mice , Models, Molecular , Molecular Conformation , Pyrazoles/chemistry , Pyrazoles/pharmacology , Radioligand Assay , Rats , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology
SELECTION OF CITATIONS
SEARCH DETAIL
...