RESUMO
Successful early attrition of potential problematic compounds is of great importance in the pharmaceutical industry. The lead compound in a recent project targeting neuropathic pain was susceptible to metabolic bioactivation, which produced reactive metabolites and showed covalent binding to protein. Therefore, as a part of the backup series for this compound several structural modifications were explored to mediate the reactive metabolite and covalent binding risk. A homomorpholine containing series of compounds was identified without compromising potency. However, when these compounds were incubated with human liver microsomes in the presence of GSH, Cys-Gly adducts were identified, instead of intact GSH conjugates. This article examines the formation of the Cys-Gly adduct with AZX ([M+H]+ 486) as a representative compound for this series. The AZX-Cys-Gly-adduct ([M+H]+ 662) showed evidence of ring contraction by formation of a thiazolidine-glycine and was additionally shown to be unstable. During its isolation for structural characterization by 1H NMR spectroscopy, it was found to have decomposed to a product with [M+H]+ 446. The characterization and identification of this labile GSH-derived adduct using LC-MS/MS and 1H NMR are described, along with observations around stability. In addition, various structurally related trapping reagents were employed in an attempt to further investigate the reaction mechanism along with a methoxylamine trapping experiment to confirm the structure of the postulated reactive intermediate.
Assuntos
Morfolinas/metabolismo , Tiazolidinas/química , Tiazolidinas/metabolismo , Bacillus megaterium/enzimologia , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Morfolinas/químicaRESUMO
Purinergic receptor P2X3 has been linked to analgesia in a number of pre-clinical models of pain, and is expressed in the human pain perception pathway. Only few P2X3-selective antagonists have been reported to date. This Letter describes the SAR and in vivo analgesic profile of a novel scaffold of selective P2X3 antagonists.
Assuntos
Analgésicos/síntese química , Dor Crônica/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2/síntese química , Pirimidinonas/síntese química , Pirróis/síntese química , Receptores Purinérgicos P2X3/química , Analgésicos/administração & dosagem , Analgésicos/uso terapêutico , Animais , Dor Crônica/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Triagem em Larga Escala , Humanos , Injeções Espinhais , Injeções Subcutâneas , Antagonistas do Receptor Purinérgico P2/administração & dosagem , Antagonistas do Receptor Purinérgico P2/uso terapêutico , Pirimidinonas/administração & dosagem , Pirimidinonas/uso terapêutico , Pirróis/administração & dosagem , Pirróis/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2X3/metabolismo , Bibliotecas de Moléculas PequenasRESUMO
2,4-Diaminopyrimidines derivatives were developed as a novel class of SNSR4 antagonists. Structure activity relationship of the diamino pyrimidine core was explored and a tool compound suitable for target validation was identified.
Assuntos
Pirimidinas/farmacologia , Receptores de Superfície Celular/antagonistas & inibidores , Células Receptoras Sensoriais/efeitos dos fármacos , Concentração Inibidora 50 , Células Receptoras Sensoriais/metabolismoRESUMO
Neuromedin U (NMU), through its cognate receptor NMUR2 in the central nervous system, regulates several important physiological functions, including energy balance, stress response, and nociception. By random screening of our corporate compound collection with a ligand binding assay, we discovered (R)-5'-(phenylaminocarbonylamino)spiro[1-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine] (R-PSOP), a highly potent and selective NMUR2 antagonist. R-PSOP is a nonpeptidic small-molecule with the chemical composition C(20)N(4)O(2)H(22). In competition binding experiments, this compound was found to bind to NMUR2 with high affinity; the K(i) values were determined to be 52 and 32 nM for the human and rat NMUR2, respectively. Moreover, in functional assays measuring phosphoinositide turnover or intracellular calcium mobilization, R-PSOP strongly inhibited the responses stimulated by peptide agonists NMU-25, NMU-23, and NMU-8 in human embryonic kidney 293 cells expressing NMUR2. From Schild analyses, the functional K(b) values for R-PSOP were determined to be 92 and 155 nM at human and rat NMUR2, respectively. Highly selective for NMUR2, R-PSOP exhibited low affinity to the other subtype of NMU receptor, NMUR1, with a K(i) value >10 microM. R-PSOP in vivo attenuated NMU-23-evoked nociceptive responses in a rat spinal reflex preparation. To our knowledge, this is the first antagonist ever reported for NMU receptors. This compound could serve as a valuable tool for further understanding the physiological and pathophysiological roles of NMU system, while providing a chemical starting point that may lead to development of new therapeutics for treatment of eating disorders, obesity, pain, and stress-related disorders.
Assuntos
Neuropeptídeos/metabolismo , Neuropeptídeos/farmacologia , Receptores de Neurotransmissores/antagonistas & inibidores , Receptores de Neurotransmissores/metabolismo , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Masculino , Neuropeptídeos/química , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de Neurotransmissores/agonistasRESUMO
Guided by available X-ray crystal structure data on the serine protease thrombin, a series of pyridin-2-one derivatives were designed and synthesized having diverse functionality at the P(1) and P(3) sites. Potent in vitro activity against thrombin, with excellent selectivity over trypsin was found for selected analogues.
Assuntos
Desenho de Fármacos , Piridonas/síntese química , Piridonas/farmacologia , Trombina/antagonistas & inibidores , Aminas/química , Cristalografia por Raios X , Humanos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Piridonas/química , Relação Estrutura-Atividade , Sulfonamidas/química , Trombina/metabolismo , Tripsina/química , Tripsina/metabolismoRESUMO
A practical and asymmetric synthesis of a small-molecule CXCR7 modulator featuring a highly functionalized and hindered tertiary ß-amino amide framework is reported. The cornerstone of this strategy relied on the intermediacy of a reactive aziridinium species, which, following regioselective ring opening with cyanide, furnished the desired chiral ß-tertiary amino nitrile for further elaboration. As a means of further highlighting this synthetic strategy, an expanded scope of hindered ß-amino amide synthesis is also presented.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Receptores CXCR/metabolismo , Amidas/química , Técnicas de Química Sintética , Compostos de Epóxi/química , EstereoisomerismoRESUMO
Molecular modeling based on the X-ray crystal structure of the Tang-Ghosh heptapeptide inhibitor 1 (OM99-2) of BACE led to the design and synthesis of a series of constrained P(1)' analogues. A cyclopentane ring was incorporated in 1 spanning the P(1)' Ala methyl group and the adjacent methylene carbon atom of the chain. Progressive truncation at the P(2)'-P(4)' sites led to a potent truncated analogue 5 with good selectivity over Cathepsin D. Using the same backbone replacement concept, a series of cyclopentane, cyclopentanone, tetrahydrofuran, pyrrolidine, and pyrrolidinone analogues were synthesized with considerable variation at the P and P' sites. The cyclopentanone and 2-pyrrolidinone analogues 45 and 57 showed low nM BACE inhibition. X-ray cocrystal structures of two analogues 5 and 45 revealed excellent convergence with the original inhibitor 1 structure while providing new insights into other interactions which could be exploited for future modifications.
Assuntos
Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ciclopentanos/síntese química , Furanos/síntese química , Peptídeos/química , Pirrolidinas/síntese química , Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases/química , Sítios de Ligação , Catepsina D/antagonistas & inibidores , Cristalografia por Raios X , Ciclopentanos/química , Endopeptidases , Furanos/química , Humanos , Modelos Moleculares , Mimetismo Molecular , Pirrolidinas/química , Pirrolidinonas/síntese química , Pirrolidinonas/química , Relação Estrutura-AtividadeRESUMO
Prototypical thrombin inhibitors were synthesized based on a trisubstituted phenol as a core motif. A naphthylsulfonamide analogue showed excellent antithrombin activity. An X-ray co-crystal structure showed the expected interactions.
Assuntos
Anticoagulantes , Antitrombinas , Fenóis , Trombina/antagonistas & inibidores , Anticoagulantes/síntese química , Anticoagulantes/química , Anticoagulantes/farmacologia , Antitrombinas/síntese química , Antitrombinas/química , Antitrombinas/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Modelos Moleculares , Estrutura Molecular , Fenóis/síntese química , Fenóis/química , Fenóis/farmacologia , Relação Estrutura-AtividadeRESUMO
The synthesis of diastereomeric 3-substituted-tetrahydrofuran 2-carboxylic acids in enantiopure form was achieved relying on aldol condensations of N-substituted alpha-amino aldehydes with enolates and enol silyl ethers of gamma-butyrolactone. Catalytic YbFOD leads to a high yield of a syn/syn-alpha-amino alcohol isomer. This was used as a constrained THF subunit in the synthesis of a peptidomimetic intended as an inhibitor of the enzyme BACE1, which is implicated in the cascade of events leading to plaque formation in Alzheimer's disease.
Assuntos
Aldeídos/química , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácidos Carboxílicos/síntese química , Etilenos/síntese química , Furanos/síntese química , Inibidores de Proteases/síntese química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Espectrofotometria InfravermelhoRESUMO
A series of tricyclic pyrrolizidinone carboxylic acids harboring an angular methano group were synthesized as mimics of carbapenems and carbapenams. A key reaction involved a novel intramolecular cyclopropanation mediated by a trimethylstannylmethyl group and an adjacent iminium ion. Enolate chemistry on a tricyclic lactam ring unit allowed the introduction of various substituents. Further elaboration afforded tricyclic pyrrolidinone carboxylic acids, which were found to be inactive as inhibitors against a panel of bacterial strains. However, the antibacterial activity of ceftazidine was enhanced in the presence of the tricyclic analogues.
Assuntos
Carbapenêmicos/química , Carbapenêmicos/síntese química , Hidrocarbonetos Policíclicos Aromáticos/química , Hidrocarbonetos Policíclicos Aromáticos/síntese química , Pirróis/química , Catálise , Ceftazidima/farmacologia , Ciclização , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Mimetismo Molecular , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A concise, stereocontrolled, and practical synthesis of a neuraminidase inhibitor consisting of a highly functionalized D-proline scaffold is described. Key features involve a stereocontrolled addition of a propiolate ester to a chiral nonracemic nitrone derived originally from D-serine and the manipulation of acyclic and cyclic motifs en route to the target in 12.8% overall yield over 22 steps. Several crystalline intermediates were suitable for single-crystal X-ray analysis.