RESUMO
We report the discovery of a series of novel zwitterionic hPTHR1 antagonists. Optimization of lead compound 2 led to 4-[[1-[4-(2,9-dichloro-5,5-dimethyl-6-oxo-pyrido[2,3-d][1]benzazepin-7-yl)phenyl]-3-fluoro-azetidin-3-yl]methylamino]cyclohexanecarboxylic acid (19e, DS69910557), a compound with excellent potency and selectivity over activity at the human ether-a-go-go-related-gene (hERG) channel. Compound 19e demonstrated in vivo potency to decrease the plasma calcium concentration in rats upon oral administration. 2022 Elsevier Ltd. All rights reserved.
Assuntos
Benzazepinas/farmacologia , Receptor Tipo 1 de Hormônio Paratireóideo , Administração Oral , Animais , Humanos , Ratos , Relação Estrutura-AtividadeRESUMO
Structural modification of a 1,4-benzodiazepin-2-one-based PTHR1 antagonist 5, a novel type of PTHR1 antagonist previously synthesized in our laboratories, yielded compound 10, which had better chemical stability than compound 5. Successive optimization of the lead 10 improved aqueous solubility, metabolic stability, and animal pharmacokinetics, culminating in the identification of DS37571084 (12). Our study paves the way for the discovery of novel and orally bioavailable PTHR1 antagonists.
Assuntos
Descoberta de Drogas , Receptor Tipo 1 de Hormônio Paratireóideo/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Humanos , Masculino , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of 8-methoxy or 8-methylquinolones bearing novel 3-aminooctahydrocyclopenta[c]pyrrole derivatives at the C-7 position was synthesized, and the pharmacological, physicochemical, and toxicological properties of the individual compounds were evaluated. Novel 8-methylquinolone 7, which includes a 3-amino-7-fluorooctahydrocyclopenta[c]pyrrole moiety at the C-7 position, showed potent antibacterial activity against both Gram-positive and negative pathogens. Compound 7 also demonstrated favorable pharmacokinetic and pharmacodynamic properties and an acceptably safe toxicological profile. Consequently, compound 7 was selected as a clinical candidate.
Assuntos
Antibacterianos/farmacologia , DNA Topoisomerases/metabolismo , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Quinolonas/farmacologia , Convulsões/tratamento farmacológico , Inibidores da Topoisomerase/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Descoberta de Drogas , Canais de Potássio Éter-A-Go-Go/genética , Canais de Potássio Éter-A-Go-Go/metabolismo , Haplorrinos , Humanos , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/química , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição Tecidual , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/químicaRESUMO
In the early 1990's, we reported on the low-molecular selective fXa inhibitor DX-9065a having two amidino groups. However, it had poor oral bioavailability due to its strong basic amidino groups. To obtain fXa inhibitors with improved oral bioavailability, we investigated various non-amidino fXa inhibitors and finally discovered cis-1,2-diaminocyclohexane derivative 4c to have potent fXa inhibition, promising anticoagulant activity, and good oral bioavailability, compared with amidino compound DX-9065a. In addition, we will discuss the influence of the third substituent on the cyclohexane ring on anti-fXa activity, anticoagulant activity, PK profile, and lipophilicity.
Assuntos
Anticoagulantes/química , Anticoagulantes/farmacologia , Inibidores do Fator Xa , Indóis/farmacologia , Propionatos/farmacologia , Tiazóis/farmacologia , Administração Oral , Animais , Anticoagulantes/síntese química , Disponibilidade Biológica , Cristalografia por Raios X , Fator Xa/metabolismo , Haplorrinos , Humanos , Indóis/química , Indóis/farmacocinética , Naftalenos/síntese química , Naftalenos/química , Naftalenos/farmacologia , Propionatos/síntese química , Propionatos/química , Propionatos/farmacocinética , Ligação Proteica , Tiazóis/química , Tiazóis/farmacocinéticaRESUMO
There have been few reports on synthetic methods for cis-1,2-diaminocyclohexane bearing a third ring substituent. Starting from 3-cyclohexenecarboxylic acid, we developed efficient methods for synthesizing the 3,4-diaminocyclohexanecarboxylic acid derivatives 2-5. We also evaluated their anti-Xa and anticoagulant activities. Among the compounds, acid 2a and amide 2b exhibited the most potent in vitro anti-fXa activity, indicating that the position and stereochemistry of a polar functional group on the cyclohexane ring greatly affected the in vitro anti-fXa activity.
Assuntos
Benzotiazóis/síntese química , Ácidos Carboxílicos/farmacologia , Cicloexilaminas/síntese química , Inibidores do Fator Xa , Animais , Anticoagulantes/farmacologia , Antitrombina III/química , Antitrombina III/farmacologia , Benzotiazóis/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Ácidos Carboxílicos/química , Química Farmacêutica/métodos , Cicloexanos/química , Cicloexilaminas/farmacologia , Desenho de Fármacos , Fator Xa/química , Concentração Inibidora 50 , Modelos Químicos , Inibidores de Serina Proteinase/síntese química , Estereoisomerismo , Fatores de TempoRESUMO
Novel 7-[(3 aS,7 aS)-3 a-aminohexahydropyrano[3,4- c]pyrrol-2(3 H)-yl]-6-fluoro-1-[(1 R,2 S)-2- fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 5 (DS21412020) was designed and synthesized to obtain potent antibacterial drugs for the treatment of respiratory tract infections. Compound 5 possessing a trans-fused pyranose ring on the pyrrolidine moiety at the C-7 position of the quinolone scaffold exhibited potent in vitro antibacterial activity against respiratory pathogens, including quinolone-resistant and methicillin-resistant Staphylococcus aureus (QR- MRSA) and quinolone-resistant Escherichia coli (QR- E. coli). Furthermore, compound 5 showed in vivo activity against the experimental murine pneumonia model due to penicillin-resistant Streptococcus pneumoniae ( PRSP) and favorable profiles in preliminary toxicological and nonclinical pharmacokinetic studies. In particular, the reduced lipophilicity and basicity of compound 5 as compared to those of the previously synthesized carba-type compound 4 resulted in a significant reduction in the human ether-a-go-go (hERG) related gene channel inhibition, which have the potential to prolong the QT interval.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Infecções Respiratórias/microbiologia , Animais , Antibacterianos/síntese química , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Farmacorresistência Bacteriana/efeitos dos fármacos , Canal de Potássio ERG1/antagonistas & inibidores , Escherichia coli/efeitos dos fármacos , Feminino , Humanos , Macaca fascicularis , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos Endogâmicos CBA , Testes de Sensibilidade Microbiana , Infecções Pneumocócicas/tratamento farmacológico , Infecções Pneumocócicas/microbiologia , Quinolinas/química , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/patogenicidadeRESUMO
A new tandem coupling approach to synthesize 2-alkynyl indoles and benzofurans is described. This reaction utilizes easily accessible gem-dibromovinyl substrates and terminal alkynes and proceeds via Pd/C- and CuI-catalyzed tandem Ullman/Sonogashira couplings.
Assuntos
Benzofuranos/síntese química , Cobre/química , Indóis/síntese química , Paládio/química , CatáliseRESUMO
Novel 7-[7-amino-7-methyl-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]- 8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 2a and 2b were designed and synthesized to obtain potent antibacterial drugs for the treatment of respiratory tract infections. Among these, compound 2a possessing (S)-configuration for the asymmetrical carbon on the pyrolidine moiety at the C-7 position of the quinolone scaffold exhibited potent in vitro antibacterial activity against respiratory pathogens including gram-positive (Streptococcus pneumoniae and Staphylococcus aureus), gram-negative (Haemophilus influenzae and Moraxcella catarrhalis), and atypical strains (Chalmydia pneumoniae and Mycoplasma pneumoniae), as well as multidrug-resistant Streptococcus pneumoniae and quinolone-resistant and methicillin-resistant Staphylococcus aureus). Furthermore, compound 2a showed excellent in vivo activity against the experimental murine pneumonia model due to multidrug resistant Streptococcus pneumoniae (MDRSP) and favorable profiles in preliminary toxicological and nonclinical pharmacokinetic studies.