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1.
Bioorg Med Chem Lett ; 26(6): 1605-1611, 2016 Mar 15.
Article in English | MEDLINE | ID: mdl-26876931

ABSTRACT

The discovery of non-basic N'-(arylsulfonyl)pyrazoline-1-carboxamidines as 5-HT6 antagonists with unique structural features was recently disclosed. Here we describe how this structural class was further developed by addressing an unexplored interaction site of the 5-HT6 receptor. Compound 13 resulting from this effort is a highly potent and selective 5-HT6 antagonist with improved metabolic stability. It is furthermore devoid of hERG affinity. Despite its modest CNS/plasma ratio, a high brain free fraction ensured substantial exposure to allow for rodent cognition studies.


Subject(s)
Pyrazoles/pharmacology , Receptors, Serotonin/metabolism , Serotonin Antagonists/pharmacology , Sulfonamides/pharmacology , Binding Sites/drug effects , Dose-Response Relationship, Drug , Humans , Molecular Docking Simulation , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/chemistry , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry
2.
Eur J Med Chem ; 46(10): 5086-98, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21885167

ABSTRACT

The discovery, synthesis and structure-activity relationship (SAR) of a novel series of cannabinoid 1 (CB(1)) and cannabinoid 2 (CB(2)) receptor ligands are reported. Based on the aminoalkylindole class of cannabinoid receptor agonists, a biphenyl moiety was introduced as novel lipophilic indole 3-acyl substituent in 11-16. Furthermore, the 3-carbonyl tether was replaced with a carboxamide linker in 17-20 and the azaindole (pyrrolopyridine) nucleus was designed as indole bioisostere with improved physicochemical properties in 21-25. Through these SAR efforts, several high affinity CB(1)/CB(2) dual cannabinoid receptor ligands were identified. Indole-3-carboxamide 17 displayed single-digit nanomolar affinity and ~80 fold selectivity for CB(1) over the CB(2) receptor. The azaindoles displayed substantially improved physicochemical properties (lipophilicity; aqueous solubility). Azaindole 21 elicited potent cannabinoid activity. Cannabinoid receptor agonists 17 and 21 potently modulated excitatory synaptic transmission in an acute rat brain slice model of cannabinoid receptor-modulated neurotransmission.


Subject(s)
Cannabinoid Receptor Agonists , Indoles/chemistry , Indoles/pharmacology , Receptors, Cannabinoid/metabolism , Animals , Brain/drug effects , Brain/metabolism , CHO Cells , Cricetinae , Humans , Indoles/chemical synthesis , Ligands , Male , Rats , Rats, Wistar , Receptor, Cannabinoid, CB2/agonists , Structure-Activity Relationship
3.
J Med Chem ; 54(20): 7030-54, 2011 Oct 27.
Article in English | MEDLINE | ID: mdl-21866910

ABSTRACT

The 5-HT(6) receptor (5-HT(6)R) has been in the spotlight for several years regarding CNS-related diseases. We set out to discover novel, neutral 5-HT(6)R antagonists to improve off-target selectivity compared to basic amine-containing scaffolds dominating the field. High-throughput screening identified the N'-(sulfonyl)pyrazoline-1-carboxamidine scaffold as a promising neutral core for starting hit-to-lead. Medicinal chemistry, molecular modeling, small molecule NMR and X-ray crystallography were subsequently applied to optimize the leads into antagonists (compounds 1-49) displaying high 5-HT(6)R affinity with optimal off-target selectivity. Unique structural features include a pseudoaromatic system and an internal hydrogen bond freezing the bioactive conformation. While physicochemical properties and CNS availability were generally favorable, significant efforts had to be made to improve metabolic stability. The optimized structure 42 is an extremely selective, hERG-free, high-affinity 5-HT(6)R antagonist showing good human in vitro metabolic stability. Rat pharmacokinetic data were sufficiently good to enable further in vivo profiling.


Subject(s)
Amidines/chemical synthesis , Pyrazoles/chemical synthesis , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemical synthesis , Sulfonamides/chemical synthesis , Amidines/chemistry , Amidines/pharmacology , Animals , CHO Cells , Cricetinae , Cricetulus , Crystallography, X-Ray , Guinea Pigs , Hepatocytes/metabolism , Humans , In Vitro Techniques , Ligands , Magnetic Resonance Spectroscopy , Male , Models, Molecular , Protein Binding , Pyrazoles/chemistry , Pyrazoles/pharmacology , Rats , Rats, Wistar , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacology , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology
4.
Bioorg Med Chem Lett ; 20(17): 4992-8, 2010 Sep 01.
Article in English | MEDLINE | ID: mdl-20688519

ABSTRACT

The synthesis and SAR of 3-alkyl-4-aryl-4,5-dihydropyrazole-1-carboxamides 1-23 and 1-alkyl-5-aryl-4,5-dihydropyrazole-3-carboxamides 24-27 as two novel cannabinoid CB(1) receptor agonist classes were described. The target compounds elicited high affinities to the CB(1) as well as the CB(2) receptor and were found to act as CB(1) receptor agonists. The key compound 19 elicited potent CB(1) agonistic and CB(2) inverse agonistic properties in vitro and showed in vivo activity in a rodent model for multiple sclerosis after oral administration.


Subject(s)
Pyrazoles/pharmacology , Receptor, Cannabinoid, CB1/agonists , Pyrazoles/chemistry
5.
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
6.
Bioorg Med Chem Lett ; 20(9): 2983-6, 2010 May 01.
Article in English | MEDLINE | ID: mdl-20347298

ABSTRACT

A dihydroquinolinone moiety was found to be a potent serotonin reuptake inhibitor pharmacophore when combined with certain amines. This fragment was coupled with selected D(2) ligands to prepare a series of dual acting compounds with attractive in vitro profiles as dopamine D(2) partial agonists and serotonin reuptake inhibitors. Structure-activity studies revealed that the linker plays a key role in contributing to D(2) affinity, function, and SRI activity.


Subject(s)
Antipsychotic Agents/chemistry , Dopamine Agonists/chemistry , Quinolones/chemistry , Schizophrenia/drug therapy , Selective Serotonin Reuptake Inhibitors/chemistry , Animals , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/therapeutic use , Disease Models, Animal , Dopamine Agonists/chemical synthesis , Dopamine Agonists/therapeutic use , Quinolones/chemical synthesis , Quinolones/therapeutic use , Receptor, Serotonin, 5-HT1A/chemistry , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Dopamine D2/agonists , Receptors, Dopamine D2/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/therapeutic use , Structure-Activity Relationship
7.
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
8.
J Med Chem ; 53(3): 1338-46, 2010 Feb 11.
Article in English | MEDLINE | ID: mdl-20047331

ABSTRACT

Pyrazolines 7-10 were designed as novel CB(1) receptor antagonists, which exhibited improved turbidimetric aqueous solubilities. On the basis of their extended CB(1) antagonist pharmacophore, hybrid molecules exhibiting cannabinoid CB(1) receptor antagonistic as well as acetylcholinesterase (AChE) inhibiting activities were designed. The target compounds 12, 13, 20, and 21 are based on 1 (tacrine) as the AChE inhibitor (AChEI) pharmacophore and two different CB(1) antagonistic pharmacophores. The imidazole-based 20 showed high CB(1) receptor affinity (48 nM) in combination with high CB(1)/CB(2) receptor subtype selectivity (>20-fold) and elicited equipotent AChE inhibitory activity as 1. Molecular modeling studies revealed the presence of a binding pocket in the AChE enzyme which nicely accommodates the CB(1) pharmacophores of the target compounds 12, 13, 20, and 21.


Subject(s)
Acetylcholinesterase/chemistry , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/pharmacology , Drug Design , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Receptor, Cannabinoid, CB2/antagonists & inhibitors , Tacrine/analogs & derivatives , Tacrine/chemistry , Animals , CHO Cells , Cannabinoids/metabolism , Cells, Cultured , Cholinesterase Inhibitors/chemistry , Cricetinae , Cricetulus , Crystallography, X-Ray , Humans , Kidney/cytology , Kidney/drug effects , Models, Molecular , Molecular Structure , Protein Conformation , Structure-Activity Relationship , Tacrine/chemical synthesis , Tacrine/pharmacology
9.
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
10.
Bioorg Med Chem Lett ; 19(19): 5675-8, 2009 Oct 01.
Article in English | MEDLINE | ID: mdl-19699640

ABSTRACT

The synthesis and structure-activity relationship studies of 1,4,5,6-tetrahydropyridazines are described. The target compounds 3-5 represent a novel class of potent and selective CB1 receptor antagonists.


Subject(s)
Pyridazines/chemical synthesis , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Animals , CHO Cells , Cricetinae , Cricetulus , Humans , Pyridazines/chemistry , Pyridazines/pharmacology , Receptor, Cannabinoid, CB1/metabolism , Structure-Activity Relationship
11.
Bioorg Med Chem Lett ; 18(1): 188-93, 2008 Jan 01.
Article in English | MEDLINE | ID: mdl-18006307

ABSTRACT

We have investigated a series of 7-azaindoles as potential partial agonists of the alpha4beta2 nicotinic acetylcholine receptor (nAChR). Three series of 7-azaindole derivatives have been synthesized and evaluated for rat brain neuronal nicotinic receptor affinity and functional activity. Compound (+)-51 exhibited the most potent nAChR binding (Ki = 10 nM). Compound 30A demonstrated both moderate binding affinity and partial agonist potency, thus representing a promising lead for the indications of cognition and smoking cessation.


Subject(s)
Indoles/chemistry , Indoles/pharmacology , Nicotinic Agonists/chemistry , Nicotinic Agonists/pharmacology , Alkaloids/chemistry , Alkaloids/metabolism , Animals , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Aza Compounds/pharmacokinetics , Aza Compounds/pharmacology , Azocines/chemistry , Azocines/metabolism , Brain/metabolism , Indoles/chemical synthesis , Indoles/pharmacokinetics , Kinetics , Neurons/metabolism , Nicotinic Agonists/chemical synthesis , Nicotinic Agonists/pharmacokinetics , Quinolizines/chemistry , Quinolizines/metabolism , Radioligand Assay , Rats , Receptors, Nicotinic/chemistry , Receptors, Nicotinic/metabolism
12.
Synapse ; 60(8): 599-608, 2006 Dec 15.
Article in English | MEDLINE | ID: mdl-17001660

ABSTRACT

Present Parkinson's disease treatment strategies are far from ideal for a variety of reasons; it has therefore been suggested that partial dopamine receptor agonism might be a potential therapeutic approach with potentially fewer side effects. In the present study, we describe the in vitro characterization of the nonergot ligand SLV308 (7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolonemonohydrochloride). SLV308 binds to dopamine D(2), D(3), and D(4) receptors and 5-HT(1) (A) receptors and is a partial agonist at dopamine D(2) and D(3) receptors and a full agonist at serotonin 5-HT(1) (A) receptors. At cloned human dopamine D(2,L) receptors, SLV308 acted as a potent but partial D(2) receptor agonist (pEC(50) = 8.0 and pA(2) = 8.4) with an efficacy of 50% on forskolin stimulated cAMP accumulation. At human recombinant dopamine D(3) receptors, SLV308 acted as a partial agonist in the induction of [(35)S]GTPgammaS binding (intrinsic activity of 67%; pEC(50) = 9.2) and antagonized the dopamine induction of [(35)S]GTPgammaS binding (pA(2) = 9.0). SLV308 acted as a full 5-HT(1) (A) receptor agonist on forskolin induced cAMP accumulation at cloned human 5-HT(1) (A) receptors but with low potency (pEC(50) = 6.3). In rat striatal slices SLV308 concentration-dependently attenuated forskolin stimulated accumulation of cAMP, as expected for a dopamine D(2) and D(3) receptor agonist. SLV308 antagonized the inhibitory effect of quinpirole on K(+)-stimulated [(3)H]-dopamine release from rat striatal slices (pA(2) = 8.5). In the same paradigm, SLV308 had antagonist properties in the presence of quinpirole (pA(2) = 8.5), but the partial D(2) agonist terguride had much stronger antagonistic properties. In conclusion, SLV308 combines high potency partial agonism at dopamine D(2) and D(3) receptors with full efficacy low potency serotonin 5-HT(1) (A) receptor agonism and is worthy of profiling in in vivo models of Parkinson's disease.


Subject(s)
Benzoxazoles/chemistry , Benzoxazoles/pharmacology , Dopamine Agonists/pharmacology , Parkinson Disease/drug therapy , Piperazines/pharmacology , Receptors, Dopamine D2/agonists , Serotonin 5-HT1 Receptor Agonists , Serotonin Receptor Agonists/pharmacology , Animals , Benzoxazoles/isolation & purification , Binding, Competitive/drug effects , Binding, Competitive/physiology , Brain/drug effects , Brain/metabolism , Brain/physiopathology , CHO Cells , Colforsin/pharmacology , Cricetinae , Cyclic AMP/metabolism , Dopamine Agonists/chemistry , Dopamine Agonists/isolation & purification , Dose-Response Relationship, Drug , Drug Interactions/physiology , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Humans , Lisuride/analogs & derivatives , Lisuride/pharmacology , Male , Molecular Structure , Parkinson Disease/metabolism , Parkinson Disease/physiopathology , Piperazines/chemistry , Piperazines/isolation & purification , Quinpirole/pharmacology , Radioligand Assay , Rats , Rats, Wistar , Receptor, Serotonin, 5-HT1A/genetics , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Dopamine D2/genetics , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3/agonists , Receptors, Dopamine D3/genetics , Receptors, Dopamine D3/metabolism , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/isolation & purification
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