RESUMO
Alkylation of 4-methoxy-1 H-pyrazolo[3,4- d]pyrimidine (1b) with iodomethane in THF using NaHMDS as base selectively provided N2-methyl product 4-methoxy-2-methyl-2 H-pyrazolo[3,4- d]pyrimidine (3b) in an 8/1 ratio over N1-methyl product (2b). Interestingly, conducting the reaction in DMSO reversed selectivity to provide a 4/1 ratio of N1/N2 methylated products. Crystal structures of product 3b with N1 and N7 coordinated to sodium indicated a potential role for the latter reinforcing the N2-selectivity. Limits of selectivity were tested with 26 heterocycles which revealed that N7 was a controlling element directing alkylations to favor N2 for pyrazolo- and N3 for imidazo- and triazolo-fused ring heterocycles when conducted in THF. Use of 1H-detected pulsed field gradient-stimulated echo (PFG-STE) NMR defined the molecular weights of ionic reactive complexes. This data and DFT charge distribution calculations suggest close ion pairs (CIPs) or tight ion pairs (TIPs) control alkylation selectivity in THF and solvent-separated ion pairs (SIPs) are the reactive species in DMSO.
RESUMO
Augmentation of cyclic nucleotide signaling through inhibition of phosphodiesterase (PDE) activity has long been understood to enhance memory. Efforts in this domain have focused predominantly on PDE4, a cAMP-specific phosphodiesterase implicated in consolidation. But less is known about the function of other PDEs expressed in neuroanatomical regions critical to memory. The PDE1 isoforms are the only PDEs to regulate neuronal cAMP and cGMP levels in a Ca2+/Calmodulin (CaM) dependent manner. Here, we show that knock-down of PDE1B in hippocampus of adult mice enhances contextual and spatial memory without effect on non-cognitive behaviors. Pharmacological augmentation of memory in rats was observed with a selective inhibitor of PDE1 dosed before and immediately after training, but not with drug dosed either 1 h after training or before recall. Our data clearly demonstrate a role for the PDE1B isoforms as negative regulators of memory, and they implicate PDE1 in an early phase of consolidation, but not retrieval. Inhibition of PDE1B is a promising therapeutic mechanism for treating memory impairment.
RESUMO
A series of milnacipran analogs were synthesized and studied as monoamine transporter inhibitors, and several potent compounds with moderate lipophilicity were identified from the 1S,2R-isomers. Thus, 15l exhibited IC(50) values of 1.7nM at NET and 25nM at SERT, which were, respectively, 20- and 13-fold more potent than 1S,2R-milnacipran 1-II.
Assuntos
Antidepressivos/síntese química , Antidepressivos/farmacologia , Ciclopropanos/síntese química , Ciclopropanos/farmacologia , Norepinefrina/antagonistas & inibidores , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Antidepressivos/química , Técnicas de Química Combinatória , Ciclopropanos/química , Humanos , Concentração Inibidora 50 , Milnaciprano , Estrutura Molecular , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Compounds with various activities and selectivities were discovered through structure-activity relationship studies of bicifadine analogs as monoamine transporter inhibitors. The norepinephrine-selective 2-thienyl compound S-6j was efficacious in a rodent pain model.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Proteínas de Transporte de Neurotransmissores/química , Animais , Células CACO-2 , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Proteínas de Membrana Transportadoras/química , Proteínas de Membrana Transportadoras/farmacologia , Modelos Químicos , Neurotransmissores/metabolismo , Proteínas de Transporte de Neurotransmissores/antagonistas & inibidores , Norepinefrina/química , Dor , Ratos , Relação Estrutura-AtividadeRESUMO
A series of milnacipran analogs containing a heteroaromatic group were synthesized and studied as monoamine transporter inhibitors. Many compounds exhibited higher potency than milnacipran at NET and NET/SERT with no significant change in lipophilicity. For example, compound R-26f was about 10-fold more potent than milnacipran with IC(50) values of 8.7 and 26nM at NET and SERT, respectively.
Assuntos
Ciclopropanos/síntese química , Ciclopropanos/farmacologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Técnicas de Química Combinatória , Ciclopropanos/química , Humanos , Milnaciprano , Estrutura Molecular , Norepinefrina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/química , Relação Estrutura-AtividadeRESUMO
Derivatives of milnacipran were synthesized and studied as monoamine transporter inhibitors. Potent analogs were discovered at NET (9k) and at both NET and SERT (9s and 9u). A pharmacophore model was established based on the conformational analysis of milnacipran in aqueous solution using NMR techniques and was consistent with the SAR results.
Assuntos
Ciclopropanos/química , Ciclopropanos/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Acetamidas/química , Acetamidas/farmacologia , Alquilação , Amidas/química , Amidas/farmacologia , Indóis/química , Indóis/farmacologia , Milnaciprano , Modelos Moleculares , Conformação Molecular , Ressonância Magnética Nuclear Biomolecular , Estereoisomerismo , Relação Estrutura-Atividade , Proteínas Vesiculares de Transporte de Monoamina/químicaRESUMO
A series of potent thienotriazolopyrimidinone-based PDE1 inhibitors was discovered. X-ray crystal structures of example compounds from this series in complex with the catalytic domain of PDE1B and PDE10A were determined, allowing optimization of PDE1B potency and PDE selectivity. Reduction of hERG affinity led to greater than a 3000-fold selectivity for PDE1B over hERG. 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4',3':4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one was identified as an orally bioavailable and brain penetrating PDE1B enzyme inhibitor with potent memory-enhancing effects in a rat model of object recognition memory.
Assuntos
Memória/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Cristalografia por Raios X , Descoberta de Drogas , Inibidores de Fosfodiesterase/químicaRESUMO
Melanin-concentrating hormone receptor antagonists containing thieno- and a benzopyridazinone cores were designed and tested as potential anorectic agents. These ligands showed high affinity for the receptor, potent functional activity in vitro, and good oral bioavailabilty in rats. The thiophene analogue exhibited low iv clearance, long half-life, and high brain penetration. In obese rats, the thienopyridazinone demonstrated a dose-dependent reduction in feeding and body weight with doses between 1 and 10 mg kg-1.
Assuntos
Depressores do Apetite/síntese química , Piridazinas/síntese química , Receptores de Somatostatina/antagonistas & inibidores , Tiofenos/síntese química , Animais , Depressores do Apetite/farmacocinética , Depressores do Apetite/farmacologia , Disponibilidade Biológica , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Meia-Vida , Masculino , Obesidade/tratamento farmacológico , Permeabilidade , Piridazinas/química , Piridazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/farmacocinética , Tiofenos/farmacologiaRESUMO
Two new classes of tricyclic-based corticotropin-releasing factor (CRF(1)) receptor-1 antagonists were designed by constraining known 1H-pyrrolo[2,3-b]pyridine and 1H-pyrazolo[3,4-b]pyridine ligands. Pyrrole- and pyrazole-based molecules 19g and 22a, respectively, were discovered that potently bind the recombinant CRF(1) receptor (K(i) = 3.5, 2.9 nM) and inhibit adrenocorticotropic hormone (ACTH) release from rat pituitary cell culture (IC(50) = 14, 6.8 nM). These compounds show good oral bioavailabity (F = 24%, 7.0%) and serum half-lives in rats (t(1/2) = 6.3, 12 h) and penetrate the rat brain ([brain]/[plasma] = 0.27, 0.52) but tend toward large volumes of distribution (V(D) = 38, 44 L kg(-1)) and rapid clearances (CL = 70, 43 mL min(-1) kg(-1)). When given orally, both the pyrazole and the pyrrole leads dose-dependently inhibit stress-induced ACTH release in vivo. ACTH reductions of 84-86% were observed for 30 mg kg(-1) doses.
Assuntos
Compostos Heterocíclicos com 3 Anéis/síntese química , Pirazóis/síntese química , Piridinas/síntese química , Pirróis/síntese química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Acenaftenos , Hormônio Adrenocorticotrópico/antagonistas & inibidores , Animais , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Células Cultivadas , AMP Cíclico/biossíntese , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Técnicas In Vitro , Masculino , Camundongos , Hipófise/citologia , Pirazóis/farmacocinética , Pirazóis/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Pirróis/farmacocinética , Pirróis/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Estresse Psicológico/metabolismo , Relação Estrutura-AtividadeRESUMO
Antagonists of the corticotropin-releasing factor (CRF) neuropeptide should prove to be effective in treating stress and anxiety-related disorders. In an effort to identify antagonists with improved physicochemical properties, new tricyclic CRF(1) antagonists were designed, synthesized, and tested for biological activity. As a result of studies aimed at establishing a relationship between structure and CRF(1) binding affinity, NBI 35965 (12a) was identified as a high-affinity antagonist with a pK(i) value of 8.5. Compound 12a proved to be a functional CRF(1) antagonist with pIC(50) values of 7.1 and 6.9 in the in vitro CRF-stimulated cAMP accumulation and ACTH production assays, respectively, and 12a also reduced CRF or stress induced ACTH production in vivo.
Assuntos
Compostos Heterocíclicos com 3 Anéis/síntese química , Pirazóis/síntese química , Piridinas/síntese química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Acenaftenos , Hormônio Adrenocorticotrópico/biossíntese , Animais , Células Cultivadas , Hormônio Liberador da Corticotropina/metabolismo , AMP Cíclico/biossíntese , Desenho de Fármacos , Feminino , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Conformação Molecular , Adeno-Hipófise/citologia , Pirazóis/química , Pirazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The synthesis and SAR studies of tricyclic imidazo[4,5-b]pyridin-2-ones as human corticotropin-releasing factor receptor (CRF(1)) antagonists are discussed herein. Compound 16g was identified as a functional antagonist that inhibited CRF-stimulated cyclic adenosine monophosphate production and CRF-induced adrenocorticotrophic hormone release. Pharmacokinetics studies in rats showed that 16g was orally bioavailable, had good brain penetration, and had a moderate half-life. In our effort to identify CRF(1) antagonists with improved pharmacokinetics properties, 16g exhibited a favorably lower volume of distribution.
Assuntos
Compostos Heterocíclicos com 3 Anéis/síntese química , Imidazóis/síntese química , Piridinas/síntese química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Administração Oral , Hormônio Adrenocorticotrópico/sangue , Animais , Barreira Hematoencefálica/metabolismo , Células CHO , Hormônio Liberador da Corticotropina/farmacologia , Cricetinae , Cricetulus , AMP Cíclico/antagonistas & inibidores , AMP Cíclico/biossíntese , Desenho de Fármacos , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Imidazóis/farmacocinética , Imidazóis/farmacologia , Injeções Intravenosas , Masculino , Piridinas/farmacocinética , Piridinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Thien-2-yl 1S,2R-milnacipran analogues were synthesized and characterized as norepinephrine/serotonin transporter inhibitors. These compounds possessed higher potencies than 1S,2R-milnacipran (2R-1) while maintaining low molecular weight and moderate lipophilicity, which are the important features for the pharmacological and pharmacokinetic characteristics of milnacipran (1). Thus, compound 5c exhibited IC50 values of 2.3 and 32 nM, respectively, at NET and SERT, which were more than 10-fold better than those of 1 (NET IC50 = 77 nM, SERT IC50 = 420 nM). Moreover, 5c achieved the same efficacy as 1, but with much lower doses, in a rodent spinal nerve ligation pain model. In addition, 5c displayed desirable pharmacokinetic properties in several species, including high oral availability and significant brain penetration.
Assuntos
Ciclopropanos/farmacologia , Neuralgia/tratamento farmacológico , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Medição da Dor/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Estereoisomerismo , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Cristalografia por Raios X , Ciclopropanos/química , Ciclopropanos/metabolismo , Ciclopropanos/farmacocinética , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Masculino , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Milnaciprano , Modelos Moleculares , Estrutura Molecular , Peso Molecular , Neuralgia/patologia , Ratos , Ratos Sprague-Dawley , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Nervos Espinhais/patologia , Nervos Espinhais/cirurgia , Relação Estrutura-AtividadeRESUMO
A series of thienopyrimidinone bis-aminopyrrolidine ureas were designed, synthesized, and evaluated for their ability to bind melanin-concentrating hormone receptor-1. These compounds exhibit potent binding affinity (K(i)=3 nM) and good in vitro metabolic stability.
Assuntos
Química Farmacêutica/métodos , Pirrolidinas/química , Receptores de Somatostatina/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/química , Animais , Inibidores do Citocromo P-450 CYP2D6 , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Cinética , Camundongos , Modelos Químicos , Conformação Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
The design, synthesis, and SAR of a series of substituted spirohydantoins are described. Optimization of an in-house screening hit gave compounds that exhibited potent binding affinity and functional activity at MCH-R1.
Assuntos
Fármacos Antiobesidade/síntese química , Hidantoínas/síntese química , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Compostos de Espiro/síntese química , Fármacos Antiobesidade/farmacologia , Desenho de Fármacos , Humanos , Hidantoínas/farmacologia , Cinética , Ligação Proteica , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of substituted chromones were designed, synthesized, and evaluated for their ability to bind melanin-concentrating hormone receptor 1. Compounds with subnanomolar binding affinity and 66% oral bioavailability in rats were discovered.
Assuntos
Química Farmacêutica/métodos , Cromonas/síntese química , Melaninas/química , Quinolonas/síntese química , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Receptores do Hormônio Hipofisário/química , Administração Oral , Animais , Cromonas/química , Desenho de Fármacos , Humanos , Microssomos Hepáticos/metabolismo , Modelos Químicos , Quinolonas/química , Ratos , Fatores de TempoRESUMO
The design, synthesis, and SAR of a series of retro bis-aminopyrrolidine ureas are described. Compounds from this series exhibited potent binding affinity and functional activity at MCH-R1, and good oral bioavailability in rat.
Assuntos
Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Ureia/análogos & derivados , Animais , Estrutura Molecular , Pirrolidinas/química , Ratos , Receptores do Hormônio Hipofisário/metabolismo , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/química , Ureia/farmacologiaRESUMO
Ureas derived from two substituted 3-aminopyrrolidine subunits were prepared as constrained analogs of a linear lead compound and tested as antagonists of the MCH(1) receptor. The series was optimized for substitution and stereochemistry to generate a functional antagonist with a K(i) of 3.3 nM and IC(50) of 12 nM (GTPgammaS).
Assuntos
Receptores do Hormônio Hipofisário/antagonistas & inibidores , Ureia/química , Ureia/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Pirrolidinas/química , Pirrolidinas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel series of bis-aminopyrrolidine ureas containing either a 4-biphenylcarboxmide or 5-phenyl-2-thiophenecarboxamide group have been identified as potent and functional antagonists of the melanin-concentrating hormone receptor-1. Syntheses and SAR are described, which led to the discovery of compounds with high binding affinity (Ki = 1 nM) for the receptor. Preliminary in vitro metabolic stability data are also reported for key compounds.
Assuntos
Amidas , Pirrolidinas , Receptores de Somatostatina/antagonistas & inibidores , Ureia , Amidas/síntese química , Amidas/farmacologia , Animais , Desenho de Fármacos , Conformação Molecular , Peso Molecular , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacologiaRESUMO
The melanocortin-4 receptor (MC4R) plays an important role in the regulation of energy homeostasis. Recent studies have shown that blockade of the MC4R reverses tumor-induced weight loss in mice. Herein, we describe the synthesis and identification of potent and selective non-peptide antagonists of the human MC4R from a series of 2-ethoxycarbonylcyclohexyl-piperazines. Compound 12i was found to possess low nanomolar affinity for the MC4R, and exhibit oral bioavailability in rats. More importantly, when administered orally to mice (10 mg/kg), it led to statistically significant increases in food intake over a 24-h period.
Assuntos
Piperazinas/síntese química , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Caquexia/tratamento farmacológico , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ligação Proteica , Ratos , Relação Estrutura-AtividadeRESUMO
Incorporation of substituted phenyl piperazine privileged structures into a known MC4 specific dipeptoid consensus sequence resulted in a series of potent (EC(50)=24 nM) and selective MC4-R agonists. We report the SAR of this series of compounds using in vitro cAMP functional assays in cells transfected with the MC4 or other melancortin receptors.