RESUMO
The global disruption caused by the 2020 coronavirus pandemic stressed the supply chain of many products, including pharmaceuticals. Multiple drug repurposing studies for COVID-19 are now underway. If a winning therapeutic emerges, it is unlikely that the existing inventory of the medicine, or even the chemical raw materials needed to synthesize it, will be available in the quantities required. Here, we utilize retrosynthetic software to arrive at alternate chemical supply chains for the antiviral drug umifenovir, as well as eleven other antiviral and anti-inflammatory drugs. We have experimentally validated four routes to umifenovir and one route to bromhexine. In one route to umifenovir the software invokes conversion of six C-H bonds into C-C bonds or functional groups. The strategy we apply of excluding known starting materials from search results can be used to identify distinct starting materials, for instance to relieve stress on existing supply chains.
Assuntos
Antivirais/química , Tratamento Farmacológico da COVID-19 , Indóis/química , Software , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Reposicionamento de Medicamentos , Humanos , Indóis/uso terapêutico , SARS-CoV-2/efeitos dos fármacosRESUMO
Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib hold a prominent role in the treatment of B cell malignancies. However, further refinement is needed to this class of agents, particularly in terms of adverse events (potentially driven by kinase promiscuity), which preclude their evaluation in nononcology indications. Here, we report the discovery and preclinical characterization of evobrutinib, a potent, obligate covalent inhibitor with high kinase selectivity. Evobrutinib displayed sufficient preclinical pharmacokinetic and pharmacodynamic characteristics which allowed for in vivo evaluation in efficacy models. Moreover, the high selectivity of evobrutinib for BTK over epidermal growth factor receptor and other Tec family kinases suggested a low potential for off-target related adverse effects. Clinical investigation of evobrutinib is ongoing in several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.
Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Descoberta de Drogas , Doenças do Sistema Imunitário/tratamento farmacológico , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Administração Oral , Tirosina Quinase da Agamaglobulinemia/metabolismo , Relação Dose-Resposta a Droga , Humanos , Doenças do Sistema Imunitário/metabolismo , Estrutura Molecular , Piperidinas/administração & dosagem , Piperidinas/química , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Pirimidinas/administração & dosagem , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
The metabotropic glutamate receptor 4 (mGluR4) is an emerging target for the treatment of Parkinson's disease (PD). However, since the discovery of its therapeutic potential, no ligand has been successfully developed enough to be tested in the clinic. In the present paper, we report for the first time the medicinal chemistry efforts conducted around the pharmacological tool (-)-PHCCC. This work led to the identification of compound 40, a potent and selective mGluR4 positive allosteric modulator (PAM) with good water solubility and demonstrating consistent activity across validated preclinical rodent models of PD motor symptoms after intraperitoneal administration: haloperidol-induced catalepsy in mouse and the rat 6-hydroxydopamine (6-OHDA) lesion model. Moreover, we also describe the identification of compound 60 a close analogue of compound 40 with improved pharmacokinetic profile after oral administration. On the basis of its favorable and unique preclinical profile, compound 60 (PXT002331, now foliglurax) was nominated as a candidate for clinical development.
Assuntos
Antiparkinsonianos/farmacologia , Encéfalo/efeitos dos fármacos , Descoberta de Drogas , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Regulação Alostérica , Animais , Antiparkinsonianos/farmacocinética , Cromatografia Líquida , Células HEK293 , Humanos , Espectrometria de Massas , Camundongos , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Relação Estrutura-AtividadeRESUMO
Gamma-lactam analogs (2) of EP(4) receptor agonists were identified by substitution of the pyrazolidinone ring (1) with a pyrrolidinone ring. Several compounds (such as 2a, 2h) with high potency, selectivity and acceptable PK profiles were discovered. These were assessed in animal models of ovulation induction and bronchoconstriction.
Assuntos
Lactamas/síntese química , Lactamas/farmacologia , Receptores de Prostaglandina E/agonistas , Animais , Feminino , Cobaias , Humanos , Lactamas/farmacocinética , Masculino , Camundongos , Indução da Ovulação , Receptores de Prostaglandina E Subtipo EP2 , Receptores de Prostaglandina E Subtipo EP4 , Relação Estrutura-AtividadeRESUMO
INTRODUCTION: Despite the widespread use of prostaglandin E(1) as an efficacious treatment for male erectile dysfunction for more than two decades, research on prostanoid function in penile physiology has been limited. AIM: To characterize the pharmacological and physiological activity of novel subtype-selective EP and DP receptor agonists. METHODS: Radioligand binding and second messenger assays were used to define receptor subtype specificity of the EP and DP agonists. Functional activity was further characterized using isolated human and rabbit penile cavernosal tissue in organ baths. In vivo activity was assessed in rabbits and rats by measuring changes in cavernous pressure after intracavernosal injection of receptor agonists. MAIN OUTCOME MEASURES: Receptor binding and signal transduction, smooth muscle contractile activity, erectile function. RESULTS: In organ bath preparations of human cavernosal tissue contracted with phenylephrine, EP2- and EP4-selective agonists exhibited variable potency in causing relaxation. One of the compounds caused mild contraction, and none of the compounds was as effective as PGE(1) (EC(50) = 0.23 microM). There was no consistent correlation between the pharmacological profile (receptor binding and second messenger assays) of the EP agonists and their effect on cavernosal tissue tone. In contrast, the DP1-selective agonist AS702224 (EC(50) =29 nM) was more effective in relaxing human cavernosal tissue than either PGE(1), PGD(2) (EC(50) = 58 nM), or the DP agonist BW245C (EC(50) =59 nM). In rabbit cavernosal tissue, PGE(1) and PGD(2) caused only contraction, while AS702224 and BW245C caused relaxation. Intracavernosal administration of AS702224 and BW245C also caused penile tumescence in rabbits and rats. For each compound, the erectile response improved with increasing dose and was significantly higher than vehicle alone. CONCLUSIONS: These data suggest that AS702224 is a potent DP1-selective agonist that causes penile erection. The DP1 receptor mediates relaxation in human cavernosal tissue, and stimulates pro-erectile responses in rat and rabbit. Thus, rabbits and rats can be useful models for investigating the physiological function of DP1 receptors.
Assuntos
Músculo Liso/efeitos dos fármacos , Ereção Peniana/efeitos dos fármacos , Prostaglandina D2/farmacologia , Receptores de Prostaglandina E/agonistas , Receptores de Prostaglandina/agonistas , Idoso , Alprostadil/farmacologia , Animais , Sítios de Ligação , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Hidantoínas/farmacologia , Técnicas In Vitro , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Fenilefrina/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Coelhos , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E/fisiologia , Receptores de Prostaglandina E Subtipo EP2 , Especificidade da Espécie , Vasodilatadores/farmacologiaRESUMO
Replacement of the hydroxy cyclopentanone ring in PGE(2) with chemically more stable heterocyclic rings and substitution of the unsaturated alpha-alkenyl chain with a metabolically more stable phenethyl chain led to the development of potent and selective analogs of PGE(2). Compound 10f showed the highest potency and selectivity for EP(4) the receptor.
Assuntos
Dinoprostona/síntese química , Pirazóis/síntese química , Receptores de Prostaglandina E/agonistas , Animais , Dinoprostona/farmacologia , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Camundongos , Pirazóis/farmacologia , Ratos , Receptores de Prostaglandina E/fisiologia , Receptores de Prostaglandina E Subtipo EP2 , Receptores de Prostaglandina E Subtipo EP4RESUMO
Analogs of PGE(2) with introduction of diene groups at the omega-side chain have been synthesized and evaluated for their binding affinity for EP(2) and EP(4) receptors. An optimized analog (compound 9b) showed high potency and selectivity for the EP(4) receptor over other known receptors.
Assuntos
Dinoprostona/análogos & derivados , Receptores de Prostaglandina E/agonistas , Animais , Linhagem Celular , Dinoprostona/farmacocinética , Dinoprostona/farmacologia , Meia-Vida , Humanos , Ratos , Receptores de Prostaglandina E Subtipo EP2 , Receptores de Prostaglandina E Subtipo EP4RESUMO
In the course of a high throughput screening, a series of pyrazole compounds were identified with luteinizing hormone receptor (LH-R) agonist activity. A focused pyrazole library was produced by solid-phase synthesis and key pyrazole regioisomers were obtained selectively in solution. Evaluation of those compounds in a cAMP assay in CHO cells transfected with h-LH receptor allowed us to propose a structure-activity relationship model for this series and led to the identification of the first low molecular weight molecule with in vitro activity in a Leydig cells assay (ED(50)=1.31 microM) and in vivo in a model of testosterone induction in rats (significant effect at 32 mpk ip).