RESUMEN
As part of a project to generate a library of nucleosides as potential antiviral agents, a small subset of novel acyclic phosphonic acid nucleosides was prepared. Practical synthetic routes are described for three targets, which were then tested against HIV, hepatitis C virus (HCV), and Dengue virus.
Asunto(s)
Ácidos Acíclicos/síntesis química , Antivirales/síntesis química , Nucleósidos/síntesis química , Ácidos Fosforosos/síntesis química , Ácidos Acíclicos/química , Antivirales/química , Dengue/tratamiento farmacológico , Virus del Dengue/efectos de los fármacos , VIH/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Hepacivirus/efectos de los fármacos , Humanos , Estructura Molecular , Nucleósidos/química , Ácidos Fosforosos/química , FosforilaciónRESUMEN
Several non-benzimidazole containing inhibitors of respiratory syncytial virus are described. Core template modification, analysis of antiviral activity, physicochemistry and optimisation of properties led to the thiazole-imidazole 13, that showed a good potency and pharmacokinetic profile in the rat.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Virus Sincitiales Respiratorios/efectos de los fármacos , Animales , Antivirales/química , Bencimidazoles/química , Imidazoles/síntesis química , Imidazoles/farmacocinética , Imidazoles/farmacología , Concentración 50 Inhibidora , Ratas , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacocinética , Tiazoles/farmacologíaRESUMEN
A novel tertiary amine series of potent muscarinic M(3) receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M(3) receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation. Together, these attributes minimize systemic exposure following inhalation, mitigate potential drug-drug interactions, and reduce systemically mediated adverse events. Compound 47 (PF-3635659) is identified as a Phase II clinical candidate from this series with in vivo duration of action studies confirming its potential for once-daily use in humans.
Asunto(s)
Azetidinas/síntesis química , Broncodilatadores/síntesis química , Ácidos Difenilacéticos/síntesis química , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Receptor Muscarínico M3/antagonistas & inhibidores , Administración por Inhalación , Animales , Azetidinas/química , Azetidinas/farmacología , Broncodilatadores/química , Broncodilatadores/farmacología , Células CHO , Línea Celular , Permeabilidad de la Membrana Celular , Cricetinae , Cricetulus , Ácidos Difenilacéticos/química , Ácidos Difenilacéticos/farmacología , Perros , Femenino , Cobayas , Hepatocitos/metabolismo , Humanos , Técnicas In Vitro , Cinética , Masculino , Microsomas Hepáticos/metabolismo , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Ensayo de Unión Radioligante , Ratas , Receptor Muscarínico M3/metabolismo , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Tráquea/efectos de los fármacos , Tráquea/fisiologíaRESUMEN
Lersivirine is a potent non-nucleoside reverse transcriptase inhibitor with exceptional mutant resilience. Here, we compare the pharmacological and pharmacokinetic profile of lersivirine with its pyrazole and imidazole isomers and briefly explore the profile of these series. This work establishes lersivirine as the outstanding molecule in this set.
Asunto(s)
Transcriptasa Inversa del VIH/antagonistas & inhibidores , Imidazoles/farmacocinética , Microsomas Hepáticos/efectos de los fármacos , Nitrilos/farmacocinética , Pirazoles/farmacocinética , Inhibidores de la Transcriptasa Inversa/farmacocinética , Animales , Diseño de Fármacos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Transcriptasa Inversa del VIH/metabolismo , VIH-1/efectos de los fármacos , VIH-1/enzimología , VIH-1/genética , Humanos , Imidazoles/química , Microsomas Hepáticos/enzimología , Modelos Moleculares , Mutación , Nitrilos/química , Pirazoles/química , Ratas , Inhibidores de la Transcriptasa Inversa/química , Relación Estructura-ActividadRESUMEN
Preventing entry of HIV into human host cells has emerged as an attractive approach to controlling viral replication. Maraviroc 1 is an approved antagonist of the human CCR5 receptor which prevents the entry of HIV. Herein, we report the design and discovery of a series of imidazopiperidine CCR5 antagonists which retain the attractive antiviral profile and window over hERG activity of maraviroc 1, combined with improved absorption profiles in rat and dog. Furthermore, this series of compounds has been shown to retain activity against a laboratory generated maraviroc-resistant HIV-1 strain, which indicates an alternative resistance profile to that of maraviroc 1. Compound 41f (PF-232798) was selected as a clinical candidate from the imidazopiperidine series and is currently in phase II clinical trials.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Compuestos de Azabiciclo/síntesis química , Antagonistas de los Receptores CCR5 , VIH-1/efectos de los fármacos , Imidazoles/síntesis química , Animales , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Compuestos de Azabiciclo/química , Compuestos de Azabiciclo/farmacología , Línea Celular , Cricetinae , Ciclohexanos/farmacología , Perros , Farmacorresistencia Viral , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/metabolismo , VIH-1/aislamiento & purificación , Humanos , Imidazoles/química , Imidazoles/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/virología , Maraviroc , Modelos Moleculares , Unión Proteica , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Triazoles/farmacología , TropanosRESUMEN
In an effort to overcome hERG affinity with a lead compound, several S-oxide and N-oxide analogues were synthesised with a much improved hERG profile but low in vivo absorption. This led to the implementation of an in situ oxidation strategy wherein a sulfide was dosed orally and systemic levels of the corresponding sulfoxide and sulfone were monitored. SAR and pharmacokinetic data to support this as a possible strategy are presented, although ultimately the approach was shown not to be suitable due to very low levels of active circulating metabolites.
Asunto(s)
Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Sulfuros/farmacología , Animales , Área Bajo la Curva , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/metabolismo , Oxidación-Reducción , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Sulfuros/metabolismo , Sulfuros/farmacocinéticaRESUMEN
A series of piperazine derivatives were designed and synthesised as gp120-CD4 inhibitors. SAR studies led to the discovery of potent inhibitors in a cell based anti viral assay represented by compounds 9 and 28. The rat pharmacokinetic and antiviral profiles of selected compounds are also presented.
Asunto(s)
Antígenos CD4/metabolismo , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , Inhibidores de Fusión de VIH/química , Piperazinas/química , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Diseño de Fármacos , Proteína gp120 de Envoltorio del VIH/metabolismo , Inhibidores de Fusión de VIH/síntesis química , Inhibidores de Fusión de VIH/farmacocinética , VIH-1/efectos de los fármacos , Humanos , Microsomas Hepáticos/metabolismo , Piperazinas/síntesis química , Piperazinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
The synthesis and structure-activity relationship of a series of novel gp120-CD4 inhibitors are described. Pharmacokinetic studies and antiviral spectrum assessment of lead compounds led to the identification of compound 36, a potent gp120-CD4 inhibitor which exhibited antiviral potency across a spectrum of 25 clade B isolates.
Asunto(s)
Antígenos CD4/metabolismo , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , Inhibidores de Fusión de VIH/química , Isoquinolinas/química , Ácidos Nicotínicos/química , Animales , Células Cultivadas , Diseño de Fármacos , Proteína gp120 de Envoltorio del VIH/metabolismo , Inhibidores de Fusión de VIH/síntesis química , Inhibidores de Fusión de VIH/farmacocinética , VIH-1/efectos de los fármacos , Semivida , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/farmacocinética , Ácidos Nicotínicos/síntesis química , Ácidos Nicotínicos/farmacocinética , Ratas , Relación Estructura-ActividadAsunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Descubrimiento de Drogas/métodos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos del Citocromo P-450 , Humanos , Hígado/enzimología , Preparaciones Farmacéuticas/metabolismo , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
Optimisation of a series of 4-piperidinyltriazoles led to the identification of compound 28a which showed good whole cell antiviral activity, excellent selectivity over the hERG ion channel and complete oral absorption.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Butanos/síntesis química , Antagonistas de los Receptores CCR5 , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/metabolismo , Piperidinas/síntesis química , Animales , Fármacos Anti-VIH/uso terapéutico , Butanos/farmacocinética , Butanos/uso terapéutico , Células CACO-2 , Línea Celular , Perros , Humanos , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Ratas , Receptores CCR5/metabolismo , Estereoisomerismo , Triazoles/síntesis químicaRESUMEN
The development of a new class of CCR5 antagonist replacing the tropane core of maraviroc by piperidine with a branched N-substituent is described. Compound 15h shows good whole cell antiviral activity together with microsomal stability and only weak activity at the hERG ion channel.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Butanos/síntesis química , Butanos/farmacología , Antagonistas de los Receptores CCR5 , Piperidinas/farmacología , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Fármacos Anti-VIH/química , Butanos/química , Técnicas Químicas Combinatorias , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , VIH/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Humanos , Estructura Molecular , Relación Estructura-Actividad , Tropanos/químicaRESUMEN
A major problem associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of HIV is their lack of resilience to mutations in the reverse transcriptase (RT) enzyme. Using structural overlays of the known inhibitors efavirenz and capravirine complexed in RT as a starting point, and structure-based drug design techniques, we have created a novel series of indazole NNRTIs that possess excellent metabolic stability and mutant resilience.
Asunto(s)
Fármacos Anti-VIH/química , Indazoles/química , Inhibidores de la Transcriptasa Inversa/química , Alquinos , Fármacos Anti-VIH/farmacología , Benzoxazinas/farmacología , Cristalografía por Rayos X , Ciclopropanos , Diseño de Fármacos , Farmacorresistencia Viral/efectos de los fármacos , Farmacorresistencia Viral/genética , Estabilidad de Medicamentos , VIH/efectos de los fármacos , VIH/enzimología , VIH/genética , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/genética , Humanos , Imidazoles/farmacología , Indazoles/farmacología , Estructura Molecular , Mutación , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-Actividad , Compuestos de Azufre/farmacologíaRESUMEN
The synthesis of a range of novel amine-containing structures and their primary potency as inhibitors of HIV-1 fusion via blocking of the CCR5 receptor is described. The development of the medicinal chemistry strategy and SAR's which led to the identification of the piperidine amide compounds 33 and 36 as excellent leads for further evaluation is described, along with key physicochemical data which highlighted their lead potential.
Asunto(s)
Amidas/farmacología , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Antagonistas de los Receptores CCR5 , Piperidinas/síntesis química , Piperidinas/farmacología , Fármacos Anti-VIH/química , Técnicas Químicas Combinatorias , Diseño de Fármacos , Descubrimiento de Drogas , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , VIH-1/efectos de los fármacos , Humanos , Microsomas Hepáticos/efectos de los fármacos , Estructura Molecular , Piperidinas/química , Relación Estructura-ActividadRESUMEN
A major problem associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of HIV is their vulnerability to mutations in the allosteric binding site of reverse transcriptase that can result in the development of a resistant virus. Herein we present the optimization of a series of 5-aryloxy imidazoles, which possess a balanced pharmacological profile against both wild-type enzyme and the clinically relevant mutations K103N and Y181C. Subtle structural changes were used to probe structure-activity relationships relating to both potency and metabolic stability, which led to an imidazole derivative with an impressive overall profile.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Antivirales/farmacología , Imidazoles/química , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Sitio Alostérico , Línea Celular , Química Farmacéutica/métodos , Diseño de Fármacos , Farmacorresistencia Viral/efectos de los fármacos , Transcriptasa Inversa del VIH/química , Humanos , Imidazoles/farmacología , Concentración 50 Inhibidora , Modelos Químicos , Mutación , Compuestos de Azufre/química , Compuestos de Azufre/farmacologíaRESUMEN
A series of thio-alkyl containing diphenylethers were designed and evaluated, as a strategy to competitively direct metabolism away from unwanted amine N-demethylation and deliver a pharmacologically inactive S-oxide metabolite. Overall, sulfonamide 20 was found to possess the best balance of target pharmacology, pharmacokinetics and metabolism profile.
Asunto(s)
Bencilaminas/síntesis química , Bencilaminas/farmacología , Éteres Fenílicos/síntesis química , Éteres Fenílicos/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Bencilaminas/química , Técnicas Químicas Combinatorias , Humanos , Estructura Molecular , Éteres Fenílicos/química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
A series of substituted benzylamines 2-48 were prepared as part of a strategy to identify structurally differentiated and synthetically more accessible selective serotonin reuptake inhibitors, relative to clinical candidate 1. In particular, 44 and 48; demonstrated low nanomolar potency and good selectivity, in a structurally simplified template and, in vivo, very low Vdu, significantly lower than l, and a more rapid T(max), consistent with our clinical objectives.
Asunto(s)
Bencilaminas/química , Química Farmacéutica/métodos , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Cinética , Modelos Químicos , Conformación Molecular , Receptores de Serotonina/metabolismo , Serotonina/química , Serotonina/metabolismo , Relación Estructura-ActividadRESUMEN
A series of substituted glutaramides were synthesised using Candoxatrilat 1 as a lead and evaluated for potency against neutral endopeptidase (NEP) as a potential treatment for female sexual arousal disorder (FSAD). In this paper, we describe studies in which we were able to increase NEP activity substantially over the levels reported for previous compounds from this programme by appropriate substitution in both the P(1)(') and P(2)(') regions. Optimisation led to the 4-chlorophenpropylamide S-30 which was selected as a candidate for further study.
Asunto(s)
Ácidos Ciclohexanocarboxílicos/química , Ácidos Ciclohexanocarboxílicos/síntesis química , Neprilisina/antagonistas & inhibidores , Inhibidores de Proteasas/química , Inhibidores de Proteasas/síntesis química , Disfunciones Sexuales Psicológicas/tratamiento farmacológico , Animales , Ácidos Ciclohexanocarboxílicos/farmacocinética , Perros , Femenino , Humanos , Concentración de Iones de Hidrógeno , Masculino , Estructura Molecular , Inhibidores de Proteasas/farmacocinética , Conejos , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Especificidad por Sustrato , PorcinosRESUMEN
A series of zwitterionic delta-opioid agonists, with targeted physicochemistry, as a strategy to limit potential for CNS exposure, were prepared. These agents were found to possess exquisite potency and selectivity over mu and kappa-opiate activity. Furthermore, analogue 3a was found to display restricted CNS exposure, as evidenced by its inactivity in a rodent hyperlocomotion assay of central opiate activity. Dog pharmacokinetic studies on 3a indicated encouraging oral bioavailability.
Asunto(s)
Indoles/farmacología , Isoquinolinas/farmacología , Receptores Opioides delta/agonistas , Animales , Perros , Diseño de Fármacos , Indoles/administración & dosificación , Indoles/síntesis química , Isoquinolinas/administración & dosificación , Isoquinolinas/síntesis química , Ratones , Conformación Molecular , Peso Molecular , Relación Estructura-ActividadRESUMEN
A series of sertraline analogues 4-39 which possess polar groups on the fused tetrahydronaphthalene ring, targeting reduced V(d) as a strategy to reduce T(max) and increase rate of elevation of central 5-HT levels, were prepared. These studies led to the successful identification of 22a, which demonstrated equivalent pharmacology and metabolic stability to 1, but which possessed greatly reduced V(d) leading to significantly shorter T(max), in rat pharmacokinetic studies.
Asunto(s)
Diseño de Fármacos , Naftalenos/química , Naftalenos/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Serotonina/metabolismo , Animales , Encéfalo/irrigación sanguínea , Encéfalo/efectos de los fármacos , Células CACO-2 , Humanos , Estructura Molecular , Naftalenos/síntesis química , Ratas , Flujo Sanguíneo Regional , Sensibilidad y Especificidad , Relación Estructura-Actividad , Especificidad por Sustrato , Factores de TiempoRESUMEN
A series of piperidone analogues of 1b-q, seeking replacements for the polar sulfamide moiety in clinical candidate UK-224,671 1a, possessing reduced H-bonding potential as a strategy to improve oral absorption, were prepared. These studies led to the successful identification of 1n, which demonstrated equivalent pharmacology and metabolic stability to 1a, and greatly improved oral absorption as assessed in rat PK studies.