RESUMEN
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.
Asunto(s)
Bencimidazoles/farmacología , Canal de Sodio Activado por Voltaje NAV1.8/metabolismo , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/química , Bencimidazoles/farmacocinética , Diseño de Fármacos , Células HEK293 , Humanos , Estructura Molecular , Solubilidad , Relación Estructura-Actividad , Bloqueadores del Canal de Sodio Activado por Voltaje/síntesis química , Bloqueadores del Canal de Sodio Activado por Voltaje/química , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacocinéticaRESUMEN
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
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-ActividadRESUMEN
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 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 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).
Asunto(s)
Aminobutiratos/síntesis química , Aziridinas/química , Alquilación , Catálisis , Química Farmacéutica , Compuestos de Amonio Cuaternario , EstereoisomerismoAsunto(s)
Sulfonamidas/química , Catálisis , Ciclización , Estructura Molecular , Transición de Fase , EstereoisomerismoRESUMEN
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.