RESUMO
A series of novel 1-aminocyclopentyl-3-carboxyamides incorporating substituted tetrahydropyran moieties have been synthesized and subsequently evaluated for their antagonistic activity against the human CCR2 receptor. Among them analog 59 was found to posses potent antagonistic activity.
Assuntos
Química Farmacêutica/métodos , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/química , Administração Oral , Animais , Quimiotaxia , Cães , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Macaca mulatta , Modelos Químicos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A series of low molecular weight antagonists of both the human and murine CC chemokine receptor 2, containing a 1-alkyl-3-(3-methyl-4-spiroindenylpiperidine)-substituted cyclopentanecarboxamide, is described. A SAR study of the C(1) substituent revealed that short, branched alkyl groups such as isopropyl, isobutyl, or cyclopropyl are optimal for both human and murine CCR2 binding activity.
Assuntos
Amidas/química , Amidas/síntese química , Carbono/química , Química Farmacêutica/métodos , Ciclopentanos/química , Ciclopentanos/síntese química , Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Quimiocinas/metabolismo , Animais , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Leucócitos/metabolismo , Masculino , Camundongos , Peso Molecular , Ratos , Ratos Sprague-Dawley , Receptores CCR2 , Relação Estrutura-AtividadeRESUMO
Introduction of ring restrictions to a linear aminobutyramide CC chemokine receptor 2 (CCR2) antagonist lead (2) led to the discovery of a 1,3-disubstituted cyclopentane scaffold with enhanced hCCR2 receptor binding and antagonist activity. (1S,3R)-N-[3,5-Bis(trifluoromethyl)benzyl]-1-methyl-3-[(1R,3'R)-methyl-1'H-spiro[indene-1,4'-piperidin]-1'-yl]cyclopentanecarboxamide (16) had IC50 of 1.3 nM (binding) and 0.45 nM (functional chemotaxis) against hCCR2. It also showed activity against the mouse CCR2 receptor with an IC50 of 130 nM. Compound 16 is selective against other chemokine receptors, including CCR5 ( approximately 500-fold).
Assuntos
Amidas/síntese química , Ciclopentanos/síntese química , Piperidinas/síntese química , Receptores de Quimiocinas/antagonistas & inibidores , Amidas/química , Amidas/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Ciclopentanos/química , Ciclopentanos/farmacologia , Humanos , Técnicas In Vitro , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Piperidinas/química , Piperidinas/farmacologia , Receptores CCR2 , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of racemic and homochiral alpha-aminothiazole-gamma-aminobutyroamides that display high affinities for human and murine CCR2 and functional antagonism by inhibition of monocyte recruitment are described. A representative example is (2S)-2-[2-(acetylamino)-1,3-thiazol-4-yl]-N-[3-methyl-5-(trifluoromethyl)benzyl]-4-(4-phenylpiperidin-1-yl)butanamide, which shows 5 nM affinity for human monocytes and CHO cells expressing the human CCR2b receptor. It also inhibited MCP-1 initiated chemotaxis of human monocytes with an IC50 of 0.69 nM.
Assuntos
Receptores de Quimiocinas/antagonistas & inibidores , Animais , Células CHO , Quimiocina CCL2/antagonistas & inibidores , Quimiocina CCL2/metabolismo , Quimiotaxia/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Cricetinae , Cricetulus , Cães , Desenho de Fármacos , Humanos , Técnicas In Vitro , Indicadores e Reagentes , Membranas/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Antagonistas dos Receptores de Neurocinina-1 , Ratos , Ratos Sprague-Dawley , Receptores CCR2 , Receptores de Quimiocinas/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The synthesis and optimization of a cyclopentane-based hNK1 antagonist scaffold 3, having four chiral centers, will be discussed in the context of its enhanced water solubility properties relative to the marketed anti-emetic hNK1 antagonist EMEND (Aprepitant). Sub-nanomolar hNK1 binding was achieved and oral activity comparable to Aprepitant in two in vivo models will be described.
Assuntos
Ciclopentanos/química , Ciclopentanos/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Água , Administração Oral , Animais , Células CHO , Cricetinae , Ciclopentanos/efeitos adversos , Ciclopentanos/síntese química , Humanos , Estrutura Molecular , Receptores da Neurocinina-1/genética , Receptores da Neurocinina-1/metabolismo , Solubilidade , Relação Estrutura-AtividadeRESUMO
A systematic examination of the central aromatic portion of the lead (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-(4-fluorophenyl)-4-(1'H-spiro[indene-1,4'-piperidin]-1'-yl)butanamide (9) led to the discovery of a novel class of CCR2 receptor antagonists, which carry small alicyclic groups such as cyclopropyl, cylobutyl, or cyclopropylmethyl attached at C2 of the carbon backbone. The most potent compound discovered, namely (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-cyclopropyl-4-[(1R,3'R)-3'-methyl-1'H-spiro[indene-1,4'-piperidin]-1'-yl]butanamide (29), showed very high binding affinity (IC50 = 4 nM, human monocyte) and excellent selectivity toward other related chemokine receptors. The excellent pharmacokinetic profile of this new lead compound allows for extensive in vivo evaluation.
Assuntos
Amidas/química , Amidas/farmacocinética , Receptores de Quimiocinas/antagonistas & inibidores , Alquilação , Amidas/síntese química , Aminação , Animais , Células Cultivadas , Cricetinae , Humanos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Receptores CCR2 , Receptores de Quimiocinas/metabolismo , Relação Estrutura-AtividadeRESUMO
An initial investigation of the novel cyclopentane scaffold 6 afforded low nanomolar human NK1 antagonists having enhanced water solubility properties compared to morpholine 1. A synthesis of this cyclopentane scaffold, having three contiguous chiral centers, and the unexpected determination that the 1,2-trans-2,3-trans-ring stereochemistry, as opposed to the cis-ether/phenyl configuration of the known structures 1-5, is optimal for this class of antagonist are described.
Assuntos
Ciclopentanos/química , Antagonistas dos Receptores de Neurocinina-1 , Humanos , Estrutura Molecular , Receptores da Neurocinina-1/metabolismo , Solubilidade , Relação Estrutura-AtividadeRESUMO
Systematic modification of a screening lead yielded a class of potent glycinamide based CCR2 antagonists. The best compound (55, (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-{[2-(1-piperidinyl)ethyl]amino}-2-(3-thienyl)acetamide) displayed good binding affinity (IC50=30 and 39 nM) toward human monocytes and CHO cell expressing human CCR2b, respectively. Functionally, it blocked MCP-1 (CCL2)-induced calcium mobilization (IC50=50 nM) and chemotaxis mediated through the CCR2 receptor (9.6 nM). It is selective against other chemokine receptors tested.
Assuntos
Glicina/análogos & derivados , Monócitos/efeitos dos fármacos , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Sítios de Ligação , Células CHO/efeitos dos fármacos , Cálcio/metabolismo , Quimiocina CCL2/antagonistas & inibidores , Quimiocina CCL2/metabolismo , Cricetinae , Glicina/síntese química , Glicina/química , Glicina/farmacologia , Humanos , Concentração Inibidora 50 , Modelos Biológicos , Receptores CCR2 , Receptores de Quimiocinas/metabolismoRESUMO
[reaction: see text] A novel approach to alpha,alpha-disubstituted-beta-amino acids (beta(2,2)-amino acids) was employed in the synthesis of a series of 3-(pyrrolidin-1-yl)propionic acids possessing high affinity for the CCR5 receptor and potent anti-HIV activity. The rat pharmacokinetics for these new analogues featured higher bioavailabilities and lower rates of clearance as compared to cyclopentane 1.
Assuntos
Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , Propionatos/farmacologia , Pirrolidinas/farmacologia , Fármacos Anti-HIV/farmacocinética , Disponibilidade Biológica , Propionatos/farmacocinética , Pirrolidinas/farmacocinéticaRESUMO
Extensive screening of compound libraries was undertaken to identify compounds with high affinity for the rat NK(1) receptor based on inhibition of [(125)I]-substance P binding. RP67580, SR140333, NKP-608 and GR205171 were selected as compounds of interest, with cloned rat NK(1) receptor binding K(i) values of 0.15-1.9 nM. Despite their high binding affinity, NKP-608 and GR205171 exhibited only a moderate functional antagonism of substance P-induced inositol-1-phosphate accumulation and acidification rate at 1 microM using cloned or native rat NK(1) receptors in vitro. The ability of the compounds to penetrate the CNS was determined by inhibition of NK(1) agonist-induced behaviours in gerbils and rats. GR205171 and NKP-608 potently inhibited GR73632-induced foot drumming in gerbils (ID(50) 0.04 and 0.2 mg/kg i.v., respectively). In contrast, RP67580 and SR140333 were poorly brain penetrant in gerbils (no inhibition at 10 mg/kg i.v.) and were not examined further in vivo. In rats, only high doses of GR205171 (10 or 30 mg/kg s.c.) inhibited NK(1) agonist-induced sniffing and hypertension, whilst NKP-608 (1 or 10 mg/kg i.p.) was without effect. GR205171 (3-30 mg/kg s.c.) caused only partial inhibition of separation-induced vocalisations in rat pups, a response that is known to be NK(1) receptor mediated in other species. These observations demonstrate the shortcomings of currently available NK(1) receptor antagonists for rat psychopharmacology assays.
Assuntos
Indóis/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/farmacologia , Quinolinas/farmacologia , Quinuclidinas/farmacologia , Tetrazóis/farmacologia , Animais , Células CHO , Cricetinae , Relação Dose-Resposta a Droga , Feminino , Gerbillinae , Humanos , Indóis/metabolismo , Isoindóis , Masculino , Piperidinas/metabolismo , Quinolinas/metabolismo , Quinuclidinas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores da Neurocinina-1/metabolismo , Tetrazóis/metabolismo , Células Tumorais CultivadasRESUMO
Species selectivity of chemokine receptor antagonists is a potential deterrent to making preclinical assessments in vivo. To determine if rhesus monkey disease models could support these assessments, we pharmacologically and functionally characterized recombinant rhesus CCR2B receptor. For these studies we obtained the CCR2B coding region by PCR from genomic rhesus DNA and expressed the receptor as stable transfectants in Chinese Hamster Ovary cells. The surface expression of recombinant rhesus CCR2B was detected by flow cytometry using a commercially available monoclonal anti-hCCR2B antibody. This antibody was used to detect rhCCR2B on monocytes in peripheral blood mononuclear cell preparations from rhesus whole blood. The recombinantly expressed CCR2B exhibited similar high affinity binding to the CCR2 chemokine ligands from rhesus and human 125I-rhMCP-1 (K(d)=433+/-14 pM) and 125I-hMCP-1 (K(d)=550+/-256 pM). In competition binding, the receptor exhibited selective high affinity binding to the monocyte chemoattractant protein (MCP) family chemokines with little affinity for most other members of the CC family of chemokines. One exception was eotaxin, a high affinity ligand for CCR3, which bound to rhesus CCR2B receptor (K(i)=1467+/-205 pM). Chemokines which exhibited binding affinity for the receptor were tested for their ability to induce intracellular calcium release. In these experiments the relative potencies of the MCP family of chemokines for rhCCR2B were similar to the observed binding affinities. In contrast, eotaxin was functionally inactive as an antagonist or agonist to this receptor. TAK-799 (N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]tetrahydro-2H-pyran-4-aminium chloride), a dual CCR2/CCR5 antagonist, demonstrated high affinity for the rhesus CCR2B in competition with 125I-hMCP-1 binding to the receptor (K(i)=0.5 nM) and also potently blocked the MCP-1 induced calcium mobilization mediated through the receptor.
Assuntos
Quimiocina CCL2/metabolismo , Receptores de Quimiocinas/genética , Sequência de Aminoácidos , Animais , Células CHO , Cálcio/metabolismo , Clonagem Molecular , Cricetinae , Feminino , Citometria de Fluxo , Humanos , Macaca mulatta , Dados de Sequência Molecular , Ensaio Radioligante , Receptores CCR2 , Receptores de Quimiocinas/metabolismo , Homologia de Sequência de Aminoácidos , TransfecçãoRESUMO
A new class of 4-(aminoheterocycle)piperidine derived 1,3,4 trisubstituted pyrrolidine CCR5 antagonists is reported. Compound 4a is shown to have good binding affinity (1.8 nM) and antiviral activity in PBMC's (IC(95)=50 nM). Compound 4a also has improved PK properties relative to 1.
Assuntos
Antagonistas dos Receptores CCR5 , Piperidinas/síntese química , Piperidinas/farmacologia , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Células CHO , Quimiocina CCL4 , Cricetinae , Meia-Vida , Células HeLa , Humanos , Ligação de Hidrogênio , Proteínas Inflamatórias de Macrófagos/metabolismo , Piperidinas/farmacocinética , Pirrolidinas/farmacocinética , RatosRESUMO
The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted pyrrolidine CCR5 antagonist 1 was modified with electron deficient aromatics as well as replacement of the benzylic methylene with sulfones, gem-difluoromethylenes and alcohols in an effort to balance the antiviral potency with reasonable pharmacokinetics.
Assuntos
Fármacos Anti-HIV/síntese química , Antagonistas dos Receptores CCR5 , Pirrolidinas/farmacocinética , Animais , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Cães , Meia-Vida , Humanos , Leucócitos Mononucleares , Macaca mulatta , Taxa de Depuração Metabólica , Piperidinas/química , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Ensaio Radioligante , Ratos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Hemokinin-1 (HK-1) is a novel substance P (SP)-like peptide that is encoded by the preprotachykinin C (PPT-C) gene recently identified in mouse B cells and shown to be a potentially important regulator of B cell development (Nat. Immunol. 1 (2000) 392). We have now isolated and characterized the human and rat orthologs of PPT-C and examined activities of human and mouse HK-1 on the three tachykinin receptors, neurokinin-1-3 (NK1-3). The rat PPT-C polypeptide is highly homologous to mouse PPT-C and contains the same processing sites to generate predicted HK-1. The human PPT-C polypeptide is also homologous to mouse PPT-C, however, it contains two potential monobasic cleavage sites rather than a single dibasic cleavage site at the amino-terminal end of the predicted HK-1 peptide. Thus, human PPT-C has the potential to generate full length predicted HK-1 as well as a truncated version (HK-1(4-11)). Polymerase chain reaction analysis revealed that both human and mouse PPT-C were expressed in a variety of tissues with strong signals detected in the skin of both species and in the mouse brain. Binding and functional analysis indicated that human and mouse HK-1 peptides were nearly identical to SP in their overall activity profile on the three NK receptors with the most potent affinity for the NK1 receptor. The results indicate that PPT-C encodes another high affinity ligand of the NK1 receptor which may play an important role in mediating some of the physiological roles previously assigned to the NK1 receptor.
Assuntos
Precursores de Proteínas/genética , Receptores de Taquicininas/metabolismo , Taquicininas/genética , Sequência de Aminoácidos , Animais , Ligação Competitiva/efeitos dos fármacos , Células CHO , Cricetinae , Bases de Dados Genéticas , Relação Dose-Resposta a Droga , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Precursores de Proteínas/química , Precursores de Proteínas/metabolismo , Ensaio Radioligante , Ratos , Receptores da Neurocinina-1/metabolismo , Receptores da Neurocinina-2/metabolismo , Receptores da Neurocinina-3/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Taquicininas/química , Taquicininas/metabolismo , Taquicininas/farmacologiaRESUMO
A series of novel spiroether-based neurokinin-1 (NK(1)) antagonists is described. The effect of modifications to the spiroether ring and aromatic substituents are discussed, leading to the identification of compounds with high affinity and excellent CNS penetration.
Assuntos
Éteres/síntese química , Éteres/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Animais , Antieméticos/síntese química , Antieméticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Ligação Competitiva/efeitos dos fármacos , Células CHO , Cricetinae , Cães , Furões , Gerbillinae , Humanos , RatosRESUMO
A series of alpha-(pyrrolidin-1-yl)acetic acids is presented as selective and potent antivirals against HIV. Several of the pyrrolidine zwitterions demonstrated reasonable in vitro properties, enhanced antiviral activities and improved pharmacokinetic profiles over pyrrolidine 1.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , HIV-1/efeitos dos fármacos , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Animais , Fármacos Anti-HIV/farmacocinética , Células CHO , Permeabilidade da Membrana Celular , Fenômenos Químicos , Físico-Química , Quimiocina CCL4 , Cricetinae , Células HeLa , Humanos , Indicadores e Reagentes , Proteínas Inflamatórias de Macrófagos/antagonistas & inibidores , Pirrolidinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Although drugs that lead to cholesterol and lipid lowering have proved to have significant effects in lowering cardiovascular morbidity and mortality, coronary artery disease remains a principal cause of death worldwide. There is a clear need to discover further therapeutic approaches to control this disease adequately. This review focuses on the mechanisms that have been implicated in the recruitment, activation and differentiation of inflammatory monocytes/macrophages in nascent vascular lesions into lipid-laden foam cells. These mechanisms might provide attractive targets for novel therapies for coronary artery disease.
Assuntos
Anti-Inflamatórios/uso terapêutico , Arteriosclerose/patologia , Doença das Coronárias/tratamento farmacológico , Movimento Celular , Doença das Coronárias/etiologia , Modelos Animais de Doenças , Células Espumosas/fisiologia , Humanos , Mediadores da Inflamação/fisiologia , Leucócitos/fisiologia , Macrófagos/fisiologiaRESUMO
A series of CCR5 antagonists containing bicyclic isoxazolidines was generated through a nitrone mediated cycloaddition with olefins bearing the preferred pharmacophores previously described. Potent antagonists (3 and 16) were generated with enhanced affinity for the CCR5 receptor while maintaining antiviral activity against HIV.