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1.
Bioorg Med Chem Lett ; 22(13): 4273-80, 2012 Jul 01.
Article in English | MEDLINE | ID: mdl-22664127

ABSTRACT

Synthesis and biological evaluation of a new series of structurally unrestricted and intramolecular hydrogen bond restricted derivatives of 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines (angular tricyclics) and 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines (linear tricyclics) are described. Structurally restricted derivatives are highly potent and selective blockers of 5-HT(6) receptors with little difference between angular or linear shape of the tricyclic core, the angular species being only slightly more potent. The angular representative of 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines, 5, can be considered as more favorable candidate for further development as it shows only weak 5-HT(2B) blocking activity (IC(50)=6.16 µM as compared with IC(50)=1.8 nM for 5-HT(6) receptors) and very low hERG potassium channel blocking potency (IC(50)=54.2 µM). The linear analog, 11, is less favorable as while showing no binding to the 5-HT(2B) receptor at concentrations of up to 10 µM, it exhibits quite a high potency to block the hERG channel (IC(50)=0.5 µM).


Subject(s)
Pyrazoles/chemistry , Pyrimidines/chemistry , Receptors, Serotonin/chemistry , Crystallography, X-Ray , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , Hydrogen Bonding , Isomerism , Molecular Conformation , Protein Binding , Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemistry , Structure-Activity Relationship
2.
J Med Chem ; 54(23): 8161-73, 2011 Dec 08.
Article in English | MEDLINE | ID: mdl-22029285

ABSTRACT

Syntheses, biological evaluation as 5-HT(6) receptor (5-HT(6)R) antagonists, and structure-activity relationships for a series of novel 5,7-disubstituted (3-arylsulfonyl-pyrazolo[1,5-a]pyrimidins are disclosed. The molecule conformational flexibility in the series is restricted by formation of the intramolecular hydrogen bond between 3-sulfo and 2-methylamino groups, which renders high potency and high selectivity to block serotonin-induced responses in HEK-293 cells stably expressing human 5-HT(6)R. In this work, we tested the hypothesis if addition of a positively ionizable group (PI) to the pyrimidine ring of the scaffold members in positions 5, 6, or 7 could further increase their 5HT(6)R blocking potency. We show that the presence of the PI group with small substituents does not substantially affect either potency or selectivity of the ligands while causing substantial changes in their cLogP values. This provides a possibility for designing of the 5HT(6)R ligands with modified ADME characteristics without grossly affecting efficiency of their interaction with the receptor. In respect to the structure-activity relationship (SAR), among other physiochemical parameters, only the molecule size and shape (described by gyration radii) showed a clear tendency for more compact molecules to be more potent antagonists of this receptor.


Subject(s)
Methylamines/chemical synthesis , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemical synthesis , Sulfones/chemical synthesis , HEK293 Cells , Humans , Methylamines/chemistry , Methylamines/pharmacology , Models, Molecular , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacology , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacology
3.
Bioorg Med Chem ; 19(4): 1482-91, 2011 Feb 15.
Article in English | MEDLINE | ID: mdl-21277782

ABSTRACT

Syntheses of a series of novel 3-sulfonyl-pyrazolo[1,5-a]pyrimidines and their 5-HT(6) receptor antagonistic structure-activity relationship are disclosed. The nature and position of substituents, which affect their receptor antagonistic activity, are analyzed. Among all synthesized derivatives, {3-(3-chlorophenylsulfonyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl}-methyl-amine 33 (K(i)=190 pM), (3-phenylsulfonyl-7-methyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 44 (K(i)=240 pM), (3-phenylsulfonyl-5-metoxymethyl-7-methyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 50 (K(i)=270 pM), and (3-phenylsulfonyl-5-methyl-7-metoxymethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 52 (K(i)=280 pM) are the most potent antagonists of the 5-HT(6) receptors.


Subject(s)
Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacology , Cell Line , Humans , Models, Molecular , Molecular Structure , Pyrazoles/chemistry , Structure-Activity Relationship , Sulfur Compounds/chemistry
4.
Eur J Med Chem ; 46(4): 1189-97, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21333408

ABSTRACT

Syntheses, biological evaluation, and structure-activity relationships for a series of novel 2-substituted 3-benzenesulfonyl-5,6-dimethyl-pyrazolo[1,5-a]pyrimidines are disclosed. In spite of a wide, four orders of magnitude, SAR range (K(i) varied from 260 pM to 2.96 µM), no significant correlation of 5-HT(6)R antagonistic potency was observed with major physiochemical characteristics, such as molecular weight, surface polar area, cLogP, or number of rotatable bonds. Statistically significant trend was only observed for size of substitute group, which was not enough to explain the deep SAR trend. Besides with the substitute group size, another factor that presumably plays a role in defining the compound potencies is a relative position of the heterocycle and sulfophenyl moieties. Among all synthesized derivatives, (3-benzenesulfonyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methyl-amine 18 is the most potent (K(i) = 260 pM) and extremely selective, 5000 to >50,000-fold relative to 55 therapeutic targets, antagonist of the 5-HT(6) receptor.


Subject(s)
Drug Design , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacology , Sulfones/chemistry , Sulfones/pharmacology , HEK293 Cells , Humans , Models, Molecular , Molecular Conformation , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Receptors, Serotonin/chemistry , Serotonin Antagonists/chemical synthesis , Substrate Specificity , Sulfones/chemical synthesis
5.
J Med Chem ; 53(14): 5186-96, 2010 Jul 22.
Article in English | MEDLINE | ID: mdl-20560595

ABSTRACT

5-HT(6) receptors are exclusively localized in the CNS and have high affinity with many psychotropic agents. Though the role of this receptor in many CNS diseases is widely anticipated, lack of definite progress in the development of 5-HT(6) receptor-oriented drugs indicates a need for further discoveries of novel chemotypes with high potency and high selectivity to the receptor. Here we present preparations and biological evaluation of a series of (3-phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines. Phenylsulfonylcyclopentapyrazolopyrimidine 7 was found to be a highly selective 5-HT(6) receptor antagonist with high affinity (low picomolar range) and potency. 7 and a few of its analogues were further tested for biological effect on 5-HT(2B) receptors and hERG potassium channels, potential liability targets. Such liability appears to be minimal, based on the in vitro data.


Subject(s)
Amines/chemical synthesis , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemical synthesis , Sulfones/chemical synthesis , Amines/chemistry , Amines/pharmacology , Cell Line , Crystallography, X-Ray , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Models, Molecular , Molecular Structure , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Radioligand Assay , Serotonin 5-HT2 Receptor Antagonists , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacology , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacology
6.
Bioorg Med Chem Lett ; 20(7): 2133-6, 2010 Apr 01.
Article in English | MEDLINE | ID: mdl-20207539

ABSTRACT

Synthesis and biological evaluation of 1 ('angular') and 2 ('linear') cycloalkane-annelated 3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidines as novel ligands of the 5-HT(6) receptors are disclosed. The new compounds 1 and 2 are highly selective antagonists of the receptor with sub-nanomolar affinities (K(i)<1 nM). In its structure, this new chemotype lacks a basic ionizable side chain, which is considered as the characteristic feature of the 5-HT(6) receptor antagonists pharmacophore model.


Subject(s)
Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacology , Animals , CHO Cells , Cell Line , Cricetinae , Cricetulus , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Pyrimidines/chemical synthesis , Serotonin Antagonists/chemical synthesis
7.
Eur J Med Chem ; 45(2): 782-9, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19939513

ABSTRACT

A series of novel 8-sulfonyl-substituted 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles (THPI) has been synthesized and their ability to interact with 5-HT(6) receptors evaluated in cell-based and radioligand binding assays. Amongst evaluated THPIs, compounds 9.HCl and 20.HCl have been identified as the most potent 5-HT(6) receptor antagonists with K(i) values equal to 2.1 nM and 5.7 nM and IC(50) values (functional assay) equal to 15 nM and 78 nM, respectively. Affinities of these two compounds for several serotonin receptors in the competitive radioligand binding assays as well as their specificity profiles against a panel of therapeutic targets have been determined.


Subject(s)
Indoles/chemistry , Indoles/pharmacology , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacology , Sulfones/chemistry , Cell Line , Humans , Indoles/chemical synthesis , Serotonin Antagonists/chemical synthesis , Sulfonamides/chemistry
8.
Arch Pharm (Weinheim) ; 342(12): 740-7, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19921682

ABSTRACT

Synthesis, biological evaluation, and structure-activity relationships (SAR) for a series of novel gamma-carboline analogues of Dimebon are described. Among the studied compounds, tetrahydro-gamma-carboline 5b (2,8-dimethyl-5-[cis-2-pyridin-3-ylvinyl]-2,3,4,5-tetrahydro-carboline) has been identified as the most potent small molecule antagonist, in particular against histamine H(1) and serotonin 5-HT(6) receptors (IC(50) < 0.45 microM and IC(50) = 0.73 microM, respectively). A thorough comparative SAR study performed for the tested compounds has revealed significant correlations between the nature of side substituents and the related antagonistic activity.


Subject(s)
Carbolines/chemical synthesis , Carbolines/pharmacology , Histamine H1 Antagonists/pharmacology , Receptors, Serotonin/drug effects , Cell Line , Drug Evaluation, Preclinical , Humans , Indoles/pharmacology , Radioligand Assay , Structure-Activity Relationship
9.
Bioorg Med Chem Lett ; 19(12): 3183-7, 2009 Jun 15.
Article in English | MEDLINE | ID: mdl-19443217

ABSTRACT

Synthesis, biological evaluation and structure-activity relationships for a series of novel gamma-carboline analogues of Dimebon are described. Among the studied compounds, gamma-carbolines 3{8} and 3{14} have been identified as potent small molecule antagonists of histamine H(1) (IC(50)=0.1 microM) and serotonin 5-HT(6) (IC(50)=0.37 microM) receptors, respectively.


Subject(s)
Carbolines/chemistry , Receptors, Serotonin/drug effects , Serotonin Antagonists/chemistry , Carbolines/chemical synthesis , Carbolines/pharmacology , Cell Line , Histamine H1 Antagonists/chemical synthesis , Histamine H1 Antagonists/chemistry , Histamine H1 Antagonists/pharmacology , Humans , Indoles/chemistry , Inhibitory Concentration 50 , Receptors, Histamine H1/drug effects , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacology , Structure-Activity Relationship
10.
Farmaco ; 60(10): 804-9, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16182295

ABSTRACT

A convenient synthesis of novel 8-sulfonyl-1,3-dioxo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines is described. As key steps to assemble the target molecular scaffold, our method features (a) Pfitzinger reaction of isatin-5-sulfonate 1 with methyl 3-oxo-3-phenylpropanoate, (b) formation of 1-(1H-pyrazol-4-yl)-1H-pyrrole-2,5-dione intermediate 5, and (c) reaction of sulfinic acid 9 with acrylate or methylacrylate leading to the corresponding sulfonyl propionates. Two compounds, ester 11 and morpholide 13, have been identified as potent inhibitors of caspase-3 with IC50 = 6 nM. Our primary data suggest noncompetitive and reversible character of caspase-3 inhibition.


Subject(s)
Caspase Inhibitors , Enzyme Inhibitors , Quinolines , Caspase 3 , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Molecular Structure , Quinolines/chemical synthesis , Quinolines/chemistry , Quinolines/pharmacology , Structure-Activity Relationship
11.
Eur J Med Chem ; 40(12): 1377-83, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16169127

ABSTRACT

Synthesis, biological evaluation and structure-activity relationships for a series of 2-substituted 4-methyl-8-(morpholine-4-sulfonyl)-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines are described. These compounds represent a new chemotype of nonpeptide small molecule inhibitors of caspase-3. Among the studied compounds, several potent inhibitors with IC50 in the range of 3-10 nM have been identified. The most active compound within this series, 7{49} and 7{58}, inhibited caspase-3 with IC50=3 nM.


Subject(s)
Caspase Inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Quinolones/chemical synthesis , Quinolones/pharmacology , Caspase 3 , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Molecular Structure , Quinolones/chemistry , Stereoisomerism , Structure-Activity Relationship
12.
J Med Chem ; 48(11): 3680-3, 2005 Jun 02.
Article in English | MEDLINE | ID: mdl-15916416

ABSTRACT

Synthesis, biological evaluation, and SAR dependencies for a series of novel 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinoline inhibitors of caspase-3 are described. The inhibitory activity of the synthesized compounds is highly dependent on the nature of 4-substituents on the core scaffold. 4-methyl-and 4-phenyl-substituted derivatives, which were the most active compounds within this series, inhibited caspase-3 with IC50 of 23 and 27 nM, respectively.


Subject(s)
Caspase Inhibitors , Enzyme Inhibitors/chemical synthesis , Morpholines/chemical synthesis , Pyrroles/chemical synthesis , Quinolines/chemical synthesis , Apoptosis/drug effects , Caspase 3 , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Jurkat Cells , Morpholines/chemistry , Morpholines/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Structure-Activity Relationship
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