RESUMO
An efficient regioselective synthesis of substituted 4-alkylamino and 4-arylaminophthalazin-1(1H)-ones 5 is described. This new method features the formation of substituted phthalazin-1(1H)-ones 3 by the reaction of 2-formylbenzoic acids 1 or 3-hydroxyisobenzofuran-1(3H)-ones 2 with hydrazine to generate phthalazin-1(2H)-ones 3. Subsequent regioselective bromination of phthalazin-1(2H)-ones 3 with benzyltrimethylammonium tribromide (BTMA-Br3) followed by mixed copper-copper oxide-catalyzed amination of 4-bromophthalazin-1(2H)-ones 4 with primary amines generates aminophthalazin-1(2H)-ones in good overall yields.
RESUMO
Recent literature reports highlight the importance of the renal outer medullary potassium (ROMK) channel in renal sodium and potassium homeostasis and emphasize the potential impact that ROMK inhibitors could have as a novel mechanism diuretic in heart failure patients. A series of piperazine-based ROMK inhibitors were designed and optimized to achieve excellent ROMK potency, hERG selectivity, and ADME properties, which led to the identification of compound 28 (BMS-986308). BMS-986308 demonstrated efficacy in the volume-loaded rat diuresis model as well as promising in vitro and in vivo profiles and was therefore advanced to clinical development.
Assuntos
Insuficiência Cardíaca , Bloqueadores dos Canais de Potássio , Animais , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Ratos , Bloqueadores dos Canais de Potássio/uso terapêutico , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Potássio/química , Bloqueadores dos Canais de Potássio/farmacocinética , Bloqueadores dos Canais de Potássio/síntese química , Relação Estrutura-Atividade , Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Descoberta de Drogas , Diurese/efeitos dos fármacos , Piperazinas/farmacologia , Piperazinas/química , Piperazinas/uso terapêutico , Piperazinas/síntese química , Piperazinas/farmacocinética , Masculino , Ratos Sprague-DawleyRESUMO
Truncated D-4'-thioadenosine derivatives lacking the 4'-hydroxymethylene moiety were synthesized starting from D-mannose, using cyclization to the 4-thiosugar and one-step conversion of the diol to the acetate as key steps. At the human A3 adenosine receptor (AR), N6-substituted purine analogues bound potently and selectively and acted as antagonists in a cyclic AMP functional assay. An N6-(3-chlorobenzyl)purine analogue 9b displayed a Ki value of 1.66 nM at the human A3 AR. Thus, truncated D-4'-thioadenosine is an excellent template for the design of novel A3 AR antagonists to act at both human and murine species.
Assuntos
Adenosina/análogos & derivados , Receptor A3 de Adenosina/metabolismo , Tionucleosídeos/farmacologia , Adenosina/química , Adenosina/farmacologia , Antagonistas do Receptor A3 de Adenosina , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Ligantes , Tionucleosídeos/químicaRESUMO
Stereoselective functionalization of the 1'-position of 4'-thionucleosides was achieved using a stereoselective S(N)2 reaction controlled by 5-membered ring coordination.
Assuntos
Tionucleosídeos/síntese química , Antagonistas do Receptor A3 de Adenosina , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Estereoisomerismo , Tionucleosídeos/química , Tionucleosídeos/farmacologiaRESUMO
On the basis of potent and selective binding affinity of Cl-IB-MECA to the human A(3) adenosine receptor, its 4'-thioadenosine derivatives were efficiently synthesized starting from D-gulonic gamma-lactone. Among compounds tested, 2-chloro-N(6)-(3-iodobenzyl)- and 2-chloro-N(6)-methyl-4' -thioadenosine-5' -methyluronamides (7a and 7b) exhibited nanomolar range of binding affinity (K(i) = 0.38 nM and 0.28 nM, respectively) at the human A(3)AR. These compounds showed anti-growth effects on HL-60 leukemia cell, which resulted from the inhibition of Wnt signaling pathway.
Assuntos
Agonistas do Receptor A3 de Adenosina , Adenosina/análogos & derivados , Antineoplásicos/química , Antineoplásicos/farmacologia , Tionucleosídeos/química , Tionucleosídeos/farmacologia , Adenosina/síntese química , Adenosina/química , Adenosina/farmacologia , Antineoplásicos/síntese química , Desenho de Fármacos , Células HL-60 , Humanos , Tionucleosídeos/síntese química , Proteínas Wnt/antagonistas & inibidoresRESUMO
We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent IKur current blocker with selectivity versus hERG, Na and Ca channels, and an acceptable preclinical PK profile. Upon further characterization in vivo, compound 1 demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2' position for a series of close analogues by employing hydrogen bond donors. As a result, 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide (25) was identified as the lead compound in this series. Compound 25 showed robust effects in rabbit and canine pharmacodynamic models and an acceptable cross-species pharmacokinetic profile and was advanced as the clinical candidate. Further optimization of 25 to mitigate pH-dependent absorption resulted in identification of the corresponding phosphoramide prodrug (29) with an improved solubility and pharmacokinetic profile.
Assuntos
Fibrilação Atrial/tratamento farmacológico , Bloqueadores dos Canais de Potássio/uso terapêutico , Quinazolinas/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Cães , Espectrometria de Massas , Bloqueadores dos Canais de Potássio/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Quinazolinas/química , Quinazolinas/farmacologia , Coelhos , Bloqueadores dos Canais de Sódio/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5, and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile. These efforts led to the discovery of BMS-929075 (37), which maintained ligand efficiency relative to early leads, demonstrated efficacy in a triple combination regimen in HCV replicon cells, and exhibited consistently high oral bioavailability and pharmacokinetic parameters across preclinical animal species. The human PK properties from the Phase I clinical studies of 37 were better than anticipated and suggest promising potential for QD administration.
Assuntos
Antivirais/farmacologia , Antivirais/farmacocinética , Benzofuranos/farmacologia , Benzofuranos/farmacocinética , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Sítio Alostérico/efeitos dos fármacos , Animais , Antivirais/química , Benzofuranos/química , Cães , Descoberta de Drogas , Haplorrinos , Hepatite C/virologia , Humanos , Masculino , Simulação de Acoplamento Molecular , Ratos , Ratos Sprague-Dawley , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismoRESUMO
We have established structure-activity relationships of novel 4'-thionucleoside analogues as the A(3) adenosine receptor (AR) agonists. Binding affinity, selectivity toward other AR subtypes, and efficacy in inhibition of adenylate cyclase were studied. From this study, 2-chloro-N(6)-methyl-4'-thioadenosine-5'-methyluronamide (36a) emerged as the most potent and selective agonist at the human A(3) AR. We have also revealed that, similar to 4'-oxoadenosine analogues, at least one hydrogen on the 5'-uronamide moiety was necessary for high-affinity binding at the human A(3) AR, presumably to allow this group to donate a H bond within the binding site. Furthermore, bulky substituents on the 5'-uronamide reduced binding affinity, but in some cases large 5'-uronamide substituents, such as substituted benzyl and 2-phenylethyl groups, maintained moderate affinity with reduced efficacy, leading to A(3) AR partial agonists or antagonists. In several cases for which the corresponding 4'-oxonucleosides have been studied, the 4'-thionucleosides showed higher binding affinity to the A(3) AR.
Assuntos
Agonistas do Receptor A3 de Adenosina , Adenosina/análogos & derivados , Adenosina/farmacologia , Amidas/farmacologia , Ácidos Urônicos/farmacologia , Adenosina/química , Agonistas do Receptor A1 de Adenosina , Agonistas do Receptor A2 de Adenosina , Amidas/síntese química , Amidas/química , Animais , Células CHO , Cricetinae , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Ácidos Urônicos/síntese química , Ácidos Urônicos/químicaRESUMO
Stereoselective synthesis of novel 1'-alpha-substituted-4'-thionucleosides was achieved starting from D-gulonic acid gamma-lactone via stereoselective nucleophilic substitution.
Assuntos
Tionucleosídeos/química , Oxirredução , Estereoisomerismo , Açúcares Ácidos/químicaRESUMO
A new series of phenylquinazoline inhibitors of Kv 1.5 is disclosed. The series was optimized for Kv 1.5 potency, selectivity versus hERG, pharmacokinetic exposure, and pharmacodynamic potency. 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine (13k) was identified as a potent and ion channel selective inhibitor with robust efficacy in the preclinical rat ventricular effective refractory period (VERP) model and the rabbit atrial effective refractory period (AERP) model.
RESUMO
Novel thioiso pyrimidine and purine nucleosides substituted with exocyclic methylene have been synthesized, starting from D-xylose. Cyclization of the dimesylate to the 4-thiosugar 6a proceeded in pure SN2 reaction in the presence of allylic functional group.
Assuntos
Antivirais/síntese química , Metano/análogos & derivados , Nucleosídeos/síntese química , Antivirais/farmacologia , Química Farmacêutica/métodos , Desenho de Fármacos , Hidrocarbonetos/química , Metano/química , Modelos Químicos , Nucleosídeos/química , Estereoisomerismo , Temperatura , Xilose/químicaRESUMO
The classical 4'-oxonucleoside analogs exhibit interesting biological activities such as antibiotic, antiviral and antitumor, which are believed to be the result of inhibition of the viral or cellular DNA or RNA polymerase after being converted to their corresponding 5'-triphosphates. However, the activity of 4'-oxonucleosides were limited by their susceptibility to degradation by nucleoside phosphorylases or acid hydrolysis. This aspect called for the chemical modification of the carbohydrate portion. This compulsion led to two kinds of strategies; (1) replacement of the 4'-oxygen by the methylene group - carbocyclic nucleosides; (2) replacement of the 4' oxygen by sulphur-4'-thionucleosides. This group has also conferred the resistance to the nucleoside cleavage. Although, there were some pioneering work on 4'-thionucleosides in 1960s and 1970s, the interest in this group of compounds was rekindled by the antiviral activities of 2'-deoxy-4'-thionucleosides reported independently by Secrist et al. and Walker et al. Subsequent contributions by the other authors, enhanced its standing as an important class of antiviral agents. Following is a reasonably exhaustive account of this class of compounds reported after 1990.
Assuntos
Antineoplásicos/química , Antivirais/química , Tionucleosídeos/química , Animais , Antineoplásicos/uso terapêutico , Antivirais/uso terapêutico , Humanos , Tionucleosídeos/uso terapêuticoRESUMO
4'-Thio analogues 3-5 of Cl-IB-MECA (2) (K(i) = 1.0 +/- 0.2 nM at the human A(3) adenosine receptor) were synthesized from d-gulono-gamma-lactone via 4-thioribosyl acetate 14 as the key intermediate. All synthesized 4'-thionucleosides exhibited higher binding affinity to the human A(3) adenosine receptor than Cl-IB-MECA, among which 4 showed the most potent binding affinity (K(i) = 0.28 +/- 0.09 nM). 4 was also selective for A(3) vs human A(1) and human A(2A) receptors by 4800- and 36000-fold, respectively.
Assuntos
Adenosina/análogos & derivados , Adenosina/química , Agonistas do Receptor Purinérgico P1 , Tionucleosídeos/síntese química , Animais , Células CHO , Córtex Cerebral/metabolismo , Corpo Estriado/metabolismo , Cricetinae , Humanos , Ligantes , Ensaio Radioligante , Ratos , Receptor A3 de Adenosina , Relação Estrutura-Atividade , Tionucleosídeos/química , Tionucleosídeos/farmacologiaRESUMO
Synthesis of 2'-deoxy-2'-fluoro-N6-substituted adenosines as bioisosteres of Cl-IB-MECA and their binding affinities to A3 adenosine receptor are described.
Assuntos
Adenosina/análogos & derivados , Adenosina/farmacocinética , Receptor A3 de Adenosina/metabolismo , Adenosina/síntese química , Adenosina/química , Animais , Encéfalo/metabolismo , Desenho de Fármacos , Fluoretos , Humanos , Ligantes , RatosRESUMO
A large series of N6-substituted-4'-thioadenosines were synthesized starting from D-gulonic-gamma-lactone, and structure-activity relationships were studied at the human A3 and other subtypes of adenosine receptors (ARs). 2-Chloro-substituted and 2-H analogues were compared. 2-Chloro-N6-methyl-4'-thioadenosine 19b was a highly potent and selective agonist (Ki=0.8+/-0.1 nM in binding) at the A3AR, and displayed the same relative efficacy in receptor activation as a known full agonist, Cl-IB-MECA. Most of N6-substituted-4'-thioadenosines were less potent in binding than the corresponding N6-substituted-adenosines or N6-substituted-4'-thioadenosine-5'-uronamides. N6-(3-Iodobenzyl) derivative 19g was demonstrated to be an A3AR-selective partial agonist displaying a Ki value of 3.2 nM.
Assuntos
Agonistas do Receptor A3 de Adenosina , Adenosina/análogos & derivados , Tionucleosídeos/síntese química , Tionucleosídeos/farmacologia , Adenosina/síntese química , Adenosina/química , Adenosina/metabolismo , Adenosina/farmacologia , Animais , Células CHO , Cricetinae , AMP Cíclico/metabolismo , Desenho de Fármacos , Humanos , Técnicas In Vitro , Cinética , Ligantes , Espectroscopia de Ressonância Magnética , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/metabolismo , Proteínas Recombinantes/agonistas , Relação Estrutura-Atividade , Tionucleosídeos/química , Tionucleosídeos/metabolismoRESUMO
Novel thioiso pyrimidine and purine nucleosides substituted with exocyclic methylene have been synthesized, starting from D-xylose. The glycosyl donor 14 was synthesized from D-xylose, using cyclization of dimesylate 10 with sodium sulfide as a key step. Cyclization proceeded in pure S(N)2 reaction without going through S(N)1 reaction in the presence of an allylic functional group at low reaction temperature (0 degrees C) in polar solvent (DMF), affording compound 12 as a major product. At higher temperatures, S(N)2' product 11 was almost exclusively obtained as a major product. On the other hand, glycosylation of 14 with 6-chloropurine under Mitsunobu conditions afforded the desired S(N)2 product 26, while palladium-catalyzed glycosylation resulted in the sole formation of S(N)2' product 34.
Assuntos
Antivirais/síntese química , Didesoxinucleosídeos/síntese química , Metano/análogos & derivados , Metano/química , Tionucleotídeos/síntese química , Catálise , Ciclização , Glicosilação , Hidrocarbonetos , Paládio/química , Purinas/química , Pirimidinas/química , Solventes , Temperatura , Xilose/químicaRESUMO
The present work describes the asymmetric synthesis of D- and L-apio-2',3'-dideoxynucleoside analogues, 4 and 5 with 2'-hydroxyl group via a common intermediate 9, starting from D-galactose. Stereoselective dihydroxylation and deoxygenation through radical inversion were successfully employed to synthesize the key intermediate 12 with D-apio structure, while stereoselecetive hydroboration-oxidation was used for the synthesis of another key intermediate 18 with L-apio structure.