RESUMO
Novel cyclic peptide derivatives based on ogipeptins A, B, C, and D were synthesized. Starting with a mixture of ogipeptins A-D, a practical four-step synthetic procedure was followed to prepare novel derivatives with various kinds of acyl side chains. Among the 45 new synthetic derivatives identified, the antibacterial activities of compounds 8-3 and 8-38 were comparable with those of ogipeptin A. In in vitro nephrotoxicity screening using LLC-PK1 cells, compounds 8-3 and 8-38 showed significantly lower cytotoxicity (LD20 > 480 µM) than colistin (LD20 = 44.2 µM).
Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Relação Estrutura-Atividade , SuínosRESUMO
We herein report a practical one-step glucuronidation method by biotransformation using Streptomyces sp. SANK 60895. This novel direct method of biotransformation has been shown to be more practical and scalable for glucuronidation than previously reported chemical and enzymatic procedures given its simplicity, high ß-selectivity, cost-effectiveness, and reproducibility. We applied the present method to the synthesis of acyl glucuronide and hydroxy-ß-glucuronide of mycophenolic acid and compound 4, respectively. This method was also shown to be applicable to the N-glucuronidation of various compounds.
Assuntos
Glucuronídeos/metabolismo , Biotransformação , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
FimH is a type I fimbrial lectin located at the tip of type-1 pili of Gram-negative uropathogenic Escherichia coli (UPEC) guiding its ability to adhere and infect urothelial cells. Accordingly, blocking FimH with small molecule inhibitor is considered as a promising new therapeutic alternative to treat urinary tract infections caused by UPEC. Herein, we report that compounds having the S-glycosidic bond (thiomannosides) had improved metabolic stability and plasma exposures when dosed orally. Especially compound 5h showed the potential to inhibit biofilm formation and also to disrupt the preformed biofilm. And compound 5h showed prophylactic effect in UTI model in mice.
Assuntos
Proteínas de Fímbrias/antagonistas & inibidores , Manosídeos/farmacologia , Infecções Urinárias/tratamento farmacológico , Adesinas de Escherichia coli/metabolismo , Administração Oral , Animais , Biofilmes/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Proteínas de Fímbrias/metabolismo , Manosídeos/administração & dosagem , Manosídeos/química , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Infecções Urinárias/urinaRESUMO
We report herein the synthesis and structure-activity relationships (SAR) of a series of benzyl ether compounds as an S1P1 receptor modulator. From our SAR studies, the installation of substituents onto the central benzene ring of 2a was revealed to potently influence the S1P1 and S1P3 agonistic activities, in particular, an ethyl group on the 2-position afforded satisfactory S1P1/S1P3 selectivity. These changes of the S1P1 and S1P3 agonistic activities caused by the alteration of substituents on the 2-position were reasonably explained by a docking study using an S1P1 X-ray crystal structure and S1P3 homology modeling. We found that compounds 2b and 2e had a potent in vivo immunosuppressive efficacy along with acceptable S1P1/S1P3 selectivity, and confirmed that these compounds had less in vivo bradycardia risk through the evaluation of heart rate change after oral administration of the compounds (30 mg/kg, p.o.) in rats.
Assuntos
Éteres/química , Imunossupressores/química , Receptores de Lisoesfingolipídeo/agonistas , Administração Oral , Animais , Sítios de Ligação , Éteres/farmacocinética , Éteres/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Meia-Vida , Frequência Cardíaca/efeitos dos fármacos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Masculino , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Ratos , Ratos Endogâmicos Lew , Receptores de Lisoesfingolipídeo/metabolismo , Relação Estrutura-Atividade , Transplante HomólogoRESUMO
After graduating with a master's degree from Faculty of Pharmaceutical Sciences, Hokkaido University in 1983, I worked in medicinal chemistry for 37 years at a pharmaceutical company and 4 years at a university. On this occasion of my retirement, I would like to summarize the memorable reactions from my life in research over more than 40 years. This includes an overview of my drug discovery research at pharmaceutical companies covering practical and effective synthetic methods of key intermediates for renin inhibitors, 1ß-methylcarbapenem, neurokinin receptor antagonists and sphingosine-1-phosphate receptor agonists. I have also described microbial transformation reactions for phosphorylation and glucuronidation, as well as antibacterial cyclic peptide and ogipeptins. During this time, two years of studying at the Scripps Research Institute and three years of working in India were also very valuable experiences. Finally, I have summarized the results of synthetic research on indole and azaindole derivatives conducted at the Health Sciences University of Hokkaido over a period of four years.
Assuntos
Química Farmacêutica , Medicina , Humanos , Academias e Institutos , Docentes , Preparações FarmacêuticasRESUMO
We report synthesis and optimization of a series of (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as renin inhibitors. Chemical modification of P1', P2' and P3 portions led to a promising 3,5-disubstituted piperidine 32o showing high renin inhibitory activity and favorable oral exposure in both rats and cynomolgus monkeys with acceptable CYP and hERG current inhibition. Compound 32o exhibited a significant blood pressure lowering effect by oral administration in two hypertensive animal models, double transgenic rats and furosemide pretreated cynomolgus monkeys.
Assuntos
Amidas/química , Piperazinas/síntese química , Piperidinas/química , Piperidinas/síntese química , Inibidores de Proteases/síntese química , Renina/antagonistas & inibidores , Administração Oral , Amidas/farmacocinética , Amidas/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Furosemida/farmacologia , Meia-Vida , Hipertensão/tratamento farmacológico , Macaca fascicularis , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/uso terapêutico , Ratos , Ratos Transgênicos , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
With the aim to address an undesired cardiac issue observed with our related compound in the recently disclosed novel series of renin inhibitors, further chemical modifications of this series were performed. Extensive structure-activity relationships studies as well as in vivo cardiac studies using the electrophysiology rat model led to the discovery of clinical candidate trans-adamantan-1-ol analogue 56 (DS-8108b) as a potent renin inhibitor with reduced potential cardiac risk. Oral administration of single doses of 3 and 10 mg/kg of 56 in cynomolgus monkeys pre-treated with furosemide led to significant reduction of mean arterial blood pressure for more than 12 h.
Assuntos
Anti-Hipertensivos/síntese química , Arritmias Cardíacas/prevenção & controle , Coração/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Piperazinas/síntese química , Inibidores de Proteases/síntese química , Renina/antagonistas & inibidores , Administração Oral , Animais , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Pressão Arterial/efeitos dos fármacos , Feminino , Coração/fisiopatologia , Humanos , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Macaca fascicularis , Masculino , Técnicas de Cultura de Órgãos , Piperazinas/farmacocinética , Piperazinas/farmacologia , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/farmacologia , Coelhos , Ratos , Renina/química , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
Introduction of the 2,2-dimethyl-4-phenylpiperazin-5-one scaffold into the P(3)-P(1) portion of the (2S,4S,5S)-5-amino-6-dialkylamino-4-hydroxy-2-isopropylhexanamide backbone dramatically increased the renin inhibitory activity without using the interaction to the S(3)(sp) pocket. Compound 31 exhibited >10,000-fold selectivity over other human proteases, and 18.5% oral bioavailability in monkey.
Assuntos
Amidas/química , Piperazinas/química , Renina/antagonistas & inibidores , Amidas/farmacologia , Aminação , Desenho de Fármacos , Hidroxilação , Metilação , Modelos Moleculares , Piperazina , Relação Estrutura-AtividadeRESUMO
Utilizing X-ray crystal structure analysis, (3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]piperidine-3-carboxamides were designed and identified as renin inhibitors. The most potent compound 15 demonstrated favorable pharmacokinetic and pharmacodynamic profiles in rat.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Descoberta de Drogas , Piperazinas/farmacologia , Piperidinas/farmacologia , Renina/antagonistas & inibidores , Inibidores da Enzima Conversora de Angiotensina/síntese química , Inibidores da Enzima Conversora de Angiotensina/química , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Haplorrinos , Humanos , Modelos Moleculares , Conformação Molecular , Piperazinas/síntese química , Piperazinas/química , Piperidinas/síntese química , Piperidinas/química , Renina/sangue , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
S1P(3)-sparing S1P(1) agonists have attracted attention as a suppressant of autoimmunity with reduced side effects. Our synthetic efforts and extensive SAR studies led to the discovery of 10b named CS-2100 with the EC(50) value of 4.0 nM for human S1P(1) and over 5000-fold selectivity against S1P(3). The in vivo immunosuppressive efficacy was evaluated in rats on host versus graft reaction and the ID(50) value was determined at 0.407mg/kg. The docking studies of CS-2100 with the homology model of S1P(1) and S1P(3) showed that the ethyl group on the thiophene ring of CS-2100 was sterically hindered by Phe263 in S1P(3), not in the case of Leu276 in S1P(1). This observation gives an explanation for the excellent S1P(3)-sparing characteristic of CS-2100.
Assuntos
Descoberta de Drogas , Oxidiazóis/síntese química , Receptores de Lisoesfingolipídeo/agonistas , Tiofenos/síntese química , Administração Oral , Animais , Ligação Competitiva , Humanos , Sistema Imunitário/efeitos dos fármacos , Imunossupressores/química , Imunossupressores/farmacologia , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Oxidiazóis/administração & dosagem , Oxidiazóis/farmacologia , Ratos , Relação Estrutura-Atividade , Tiofenos/administração & dosagem , Tiofenos/farmacologiaRESUMO
We have previously disclosed 1,2,4-oxadiazole derivative 3 as a potent S1P(3)-sparing S1P(1) agonist. Although compound 3 exhibits potent and manageable immunosuppressive efficacy in various in vivo models, recent studies have revealed that its 1,2,4-oxadiazole ring is subjected to enterobacterial decomposition. As provisions for unpredictable issues, a series of alternative compounds were synthesized on the basis of compound 3. Extensive SAR studies led to the finding of 1,3-thiazole 24c with the EC(50) value of 3.4 nM for human S1P(1), and over 5800-fold selectivity against S1P(3). In rat on host versus graft reaction (HvGR), the ID(50) value of 24c was determined at 0.07 mg/kg. The pharmacokinetics in rat and monkey is also reported. Compared to compound 3, 24c showed excellent stability against enterobacteria.
Assuntos
Piridinas/síntese química , Receptores de Lisoesfingolipídeo/agonistas , Tiazóis/química , Tiofenos/síntese química , Animais , Haplorrinos , Humanos , Piridinas/farmacologia , Ratos , Relação Estrutura-Atividade , Tiazóis/farmacologia , Tiofenos/farmacologiaRESUMO
The first total synthesis of ogipeptin A was achieved. Recently, using the advanced Marfey's method, we determined the absolute configuration patterns of three ß-hydroxy-α,γ-diaminobutyric acids (ß-OH Dabs) composing ogipeptins. On the basis of this result, we conducted solid-phase total synthesis of three diastereomers of ogipeptin A. The analytical data of one diastereomer exactly corresponded with those of natural ogipeptin A. Therefore, the absolute configurations of ogipeptins have been elucidated.
RESUMO
With the goal of improving metabolic stability and further enhancing FBPase inhibitory activity, a series of tricyclic 8H-indeno[1,2-d][1,3]thiazoles was designed and synthesized with the aid of structure-based drug design. Extensive SAR studies led to the discovery of 19a with an IC(50) value of 1nM against human FBPase. X-ray crystallographic studies revealed that high affinity of 19a was due to the hydrophobic interaction arising from better shape complementarity and to the hydrogen bonding network involving the side chain on the tricyclic scaffold.
Assuntos
Desenho de Fármacos , Frutose-Bifosfatase/antagonistas & inibidores , Tiazóis/síntese química , Tiazóis/farmacologia , Cristalografia por Raios X , Frutose-Bifosfatase/química , Frutose-Bifosfatase/metabolismo , Humanos , Relação Estrutura-AtividadeRESUMO
For the purpose of reducing the strong CYP3A4 inhibitory potency of diamide prodrug 4, cyclic prodrugs of tricyclic-based FBPase inhibitors were synthesized. Extensive SAR studies led to the discovery of pyridine-containing cyclic prodrug 20, which strongly inhibited glucose production in monkey hepatocytes and also showed weak CYP3A4 inhibitory potency.
Assuntos
Alanina/análogos & derivados , Inibidores do Citocromo P-450 CYP3A , Inibidores Enzimáticos/química , Organofosfonatos/química , Pró-Fármacos/química , Piridinas/química , Tiazóis/química , Alanina/síntese química , Alanina/química , Alanina/farmacologia , Animais , Células Cultivadas , Cristalografia por Raios X , Citocromo P-450 CYP3A/metabolismo , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Haplorrinos , Conformação Molecular , Organofosfonatos/síntese química , Organofosfonatos/farmacologia , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologiaRESUMO
With the aim of exploring the effect of tricyclic-based FBPase inhibitors in cells and in vivo, a series of prodrugs of tricyclic phosphonates was designed and synthesized. Introducing prodrug moieties into tricyclic-based phosphonates led to the discovery of prodrug 15c, which strongly inhibited glucose production in monkey hepatocytes. Furthermore, prodrug 15c lowered blood glucose levels in fasted cynomolgus monkeys.
Assuntos
Frutose-Bifosfatase/antagonistas & inibidores , Frutose-Bifosfatase/metabolismo , Glucose/antagonistas & inibidores , Organofosfonatos/farmacologia , Pró-Fármacos/farmacologia , Administração Oral , Animais , Glicemia/metabolismo , Células Cultivadas , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Frutose-Bifosfatase/química , Hepatócitos/metabolismo , Humanos , Macaca fascicularis , Modelos Moleculares , Organofosfonatos/síntese química , Organofosfonatos/química , Pró-Fármacos/síntese química , Pró-Fármacos/químicaRESUMO
With the aim of discovering a novel class of fructose-1,6-bisphosphatase (FBPase) inhibitors, a series of compounds based on tricyclic scaffolds was synthesized. Extensive SAR studies led to the finding of 8l with an IC50 value of 0.013 microM against human FBPase. An X-ray crystallographic study revealed that 8l bound at AMP binding sites of human liver FBPase with hydrogen bonding interactions similar to AMP.
Assuntos
Benzotiazóis/síntese química , Inibidores Enzimáticos/síntese química , Frutose-Bifosfatase/antagonistas & inibidores , Compostos Heterocíclicos com 3 Anéis/síntese química , Organofosfatos/síntese química , Organofosfonatos/síntese química , Benzotiazóis/química , Benzotiazóis/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Frutose-Bifosfatase/metabolismo , Gluconeogênese , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Ligação de Hidrogênio , Organofosfatos/química , Organofosfatos/farmacologia , Organofosfonatos/química , Organofosfonatos/farmacologia , Relação Estrutura-AtividadeRESUMO
A novel orally bioavailable renin inhibitor, DS-8108b (5), showing potent renin inhibitory activity and excellent in vivo efficacy is described. We report herein the synthesis and pharmacological effects of 5 including renin inhibitory activity in vitro, suppressive effects of ex vivo plasma renin activity (PRA) in cynomolgus monkey, pharmacokinetic data, and blood pressure-lowering effects in an animal model. Compound 5 demonstrated inhibitory activities toward human renin (IC50 = 0.9 nM) and human and monkey PRA (IC50 = 1.9 and 6.3 nM, respectively). Oral administration of single doses of 3 and 10 mg/kg of 5 in cynomolgus monkey on pretreatment with furosemide led to dose-dependent significant reductions in ex vivo PRA and sustained lowering of mean arterial blood pressure for more than 12 h.
RESUMO
Modulators of sphingosine phosphate receptor-1 (S1P(1)) have recently been focused as a suppressant of autoimmunity. We have discovered a 4-ethylthiophene-based S1P(1) agonist 1-({4-Ethyl-5-[5-(4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methyl)azetidine-3-carboxylic acid (CS-2100, 8) showing potent S1P(1) agonist activity against S1P(3) and an excellent in vivo potency. We report herein the synthesis of CS-2100 (8) and pharmacological effects such as S1P(1) and S1P(3) agonist activity in vitro, peripheral blood lymphocyte lowering effects and the suppressive effects on adjuvant-induced arthritis and experimental autoimmune encephalomyelitis (EAE) in animal models. The pharmacokinetic data were also reported. CS-2100 (8) had >5000-fold greater agonist activity for human S1P(1) (EC(50); 4.0 nM) relative to S1P(3) (EC(50); >20,000 nM). Following administration of single oral doses of 0.1 and 1 mg/kg of CS-2100 (8) in rats, lymphocyte counts decreased significantly, with a nadir at 8 and/or 12 h post-dose and recovery to vehicle control levels by 24-48 h post-dose. CS-2100 (8) is efficacious in the adjuvant-induced arthritis model in rats (ID(50); 0.44 mg/kg). In the EAE model compared to the vehicle-treated group, significant decreases in the cumulative EAE scores were observed for 0.3 and 1 mg/kg CS-2100 (8) groups in mice. While CS-2100 (8) showed potent efficacy in various animal disease models, it was also revealed that the central 1,2,4-oxadiazole ring of CS-2100 (8) was decomposed by enterobacteria in intestine of rats and monkeys, implicating the latent concern about an external susceptibility in its metabolic process in the upcoming clinical studies.
Assuntos
Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Tiofenos/síntese química , Tiofenos/farmacologia , Administração Oral , Animais , Técnicas de Química Sintética , Desenho de Fármacos , Feminino , Meia-Vida , Humanos , Masculino , Camundongos , Oxidiazóis/administração & dosagem , Oxidiazóis/farmacocinética , Ratos , Tiofenos/administração & dosagem , Tiofenos/química , Tiofenos/farmacocinéticaRESUMO
CS-0777 (3) is phosphorylated in vivo, and the phosphate of CS-0777 (CS-0777-P) (4) acts as a selective S1P receptor-1 (S1P1) modulator. We report herein the synthesis of CS-0777 and CS-0777-P, pharmacological effects such as S1P1 and S1P3 agonist activity in vitro, peripheral blood lymphocyte lowering effects and the suppressive effect on experimental autoimmune encephalomyelitis (EAE), and also the pharmacokinetics in rats. CS-0777-P had â¼320-fold greater agonist activity for human S1P1 (EC50; 1.1 nM) relative to S1P3 (EC50; 350 nM). Following administration of single oral doses of 0.1 and 1 mg/kg of CS-0777 in rats, lymphocyte counts decreased significantly, with a nadir at 12 h postdose and recovery to vehicle control levels by 5 days postdose. In the EAE model compared to the vehicle-treated group, significant decreases in the cumulative EAE scores were observed for the 0.1 and 1 mg/kg CS-0777 groups in rats. CS-0777 is currently in clinical trials for the treatment of multiple sclerosis (MS).