RESUMO
The voltage gated sodium channel NaV1.8 has been postulated to play a key role in the transmission of pain signals. Core hopping from our previously reported phenylimidazole leads has allowed the identification of a novel series of benzimidazole NaV1.8 blockers. Subsequent optimization allowed the identification of compound 9, PF-06305591, as a potent, highly selective blocker with an excellent preclinical in vitro ADME and safety profile.
Assuntos
Benzimidazóis/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/química , Benzimidazóis/farmacocinética , Desenho de Fármacos , Células HEK293 , Humanos , Estrutura Molecular , Solubilidade , Relação Estrutura-Atividade , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinéticaRESUMO
The marine nemertean Cephalothrix simula originates from the Pacific Ocean but in recent years has been discovered in northern Europe. The species has been associated with high levels of the marine neurotoxin Tetrodotoxin, traditionally associated with Pufferfish Poisoning. This study reports the first discovery of two organisms of C. simula in the UK, showing the geographical extent of this species is wider than originally described. Species identification was initially conducted morphologically, with confirmation by Cox 1 DNA sequencing. 16S gene sequencing enabled the taxonomic assignment of the microbiome, showing the prevalence of a large number of bacterial genera previously associated with TTX production including Alteromonas, Vibrio and Pseudomonas. LC-MS/MS analysis of the nemertean tissue revealed the presence of multiple analogues of TTX, dominated by the parent TTX, with a total toxin concentration quantified at 54 µg TTX per g of tissue. Pseudomonas luteola isolated from C. simula, together with Vibrio alginolyticus from the native nemertean Tubulanus annulatus, were cultured at low temperature and both found to contain TTX. Overall, this paper confirms the high toxicity of a newly discovered invasive nemertean species with links to toxin-producing marine bacteria and the potential risk to human safety. Further work is required to assess the geographical extent and toxicity range of C. simula along the UK coast in order to properly gauge the potential impacts on the environment and human safety.
Assuntos
Organismos Aquáticos/microbiologia , Espécies Introduzidas , Invertebrados/microbiologia , Pseudomonas/metabolismo , Tetrodotoxina/metabolismo , Vibrio alginolyticus/metabolismo , Animais , Organismos Aquáticos/metabolismo , Cromatografia Líquida de Alta Pressão , DNA Bacteriano/isolamento & purificação , Inglaterra , Invertebrados/metabolismo , Microbiota , Pseudomonas/genética , Pseudomonas/isolamento & purificação , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Espectrometria de Massas em Tandem , Tetrodotoxina/isolamento & purificação , Vibrio alginolyticus/genética , Vibrio alginolyticus/isolamento & purificaçãoRESUMO
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.
Assuntos
Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Sulfetos/farmacologia , Animais , Área Sob a Curva , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Oxirredução , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Sulfetos/metabolismo , Sulfetos/farmacocinéticaRESUMO
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.
Assuntos
Amidas/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , Piperidinas/síntese química , Piperidinas/farmacologia , Fármacos Anti-HIV/química , Técnicas de Química Combinatória , Desenho de Fármacos , Descoberta de Drogas , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Piperidinas/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antígenos CD4/metabolismo , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Inibidores da Fusão de HIV/química , Isoquinolinas/química , Ácidos Nicotínicos/química , Animais , Células Cultivadas , Desenho de Fármacos , Proteína gp120 do Envelope de HIV/metabolismo , Inibidores da Fusão de HIV/síntese química , Inibidores da Fusão de HIV/farmacocinética , HIV-1/efeitos dos fármacos , Meia-Vida , Humanos , Isoquinolinas/síntese química , Isoquinolinas/farmacocinética , Ácidos Nicotínicos/síntese química , Ácidos Nicotínicos/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antígenos CD4/metabolismo , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Inibidores da Fusão de HIV/química , Piperazinas/química , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Desenho de Fármacos , Proteína gp120 do Envelope de HIV/metabolismo , Inibidores da Fusão de HIV/síntese química , Inibidores da Fusão de HIV/farmacocinética , HIV-1/efeitos dos fármacos , Humanos , Microssomos Hepáticos/metabolismo , Piperazinas/síntese química , Piperazinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
The first asymmetric phase transfer catalyzed alkylation reaction of a range of carbon acids with N-sulfonyl aziridines is reported. When 10 mol % of a cinchona derived quaternary ammonium salt was employed as the catalyst under mildly basic conditions, N-o-(trifluoromethane)benzenesulfonyl aziridine was efficiently ring-opened to afford the amino ethylene products in consistently high yields and high enantioselectivities (up to 97% ee). By employing substituted aziridines in single enantiomeric form, the corresponding enantiopure alkylation products could be obtained with a range of pronucleophiles in high yields and moderate to high diastereoselectivities (up to 30:1 dr).
Assuntos
Aminobutiratos/síntese química , Aziridinas/química , Alquilação , Catálise , Química Farmacêutica , Compostos de Amônio Quaternário , EstereoisomerismoRESUMO
Staurozoan classification is highly subjective, based on phylogeny-free inferences, and suborders, families, and genera are commonly defined by homoplasies. Additionally, many characters used in the taxonomy of the group have ontogenetic and intraspecific variation, and demand new and consistent assessments to establish their correct homologies. Consequently, Staurozoa is in need of a thorough systematic revision. The aim of this study is to propose a comprehensive phylogenetic hypothesis for Staurozoa, providing the first phylogenetic classification for the group. According to our working hypothesis based on a combined set of molecular data (mitochondrial markers COI and 16S, and nuclear markers ITS, 18S, and 28S), the traditional suborders Cleistocarpida (animals with claustrum) and Eleutherocarpida (animals without claustrum) are not monophyletic. Instead, our results show that staurozoans are divided into two groups, herein named Amyostaurida and Myostaurida, which can be distinguished by the absence/presence of interradial longitudinal muscles in the peduncle, respectively. We propose a taxonomic revision at the family and genus levels that preserves the monophyly of taxa. We provide a key for staurozoan genera and discuss the evolution of the main characters used in staurozoan taxonomy.
Assuntos
Sulfonamidas/química , Catálise , Ciclização , Estrutura Molecular , Transição de Fase , EstereoisomerismoRESUMO
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.