RESUMEN
Herein we report the successful incorporation of a lactam as an amide replacement in the design of hepatitis C virus NS5B Site II thiophene carboxylic acid inhibitors. Optimizing potency in a replicon assay and minimizing potential risk for CYP3A4 induction led to the discovery of inhibitor 22a. This lead compound has a favorable pharmacokinetic profile in rats and dogs.
Asunto(s)
Antivirales/farmacología , Ácidos Carboxílicos/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/química , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Perros , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Hepacivirus/efectos de los fármacos , Hepacivirus/enzimología , Lactamas/química , Estructura Molecular , ARN Polimerasa Dependiente del ARN/metabolismo , Ratas , Relación Estructura-Actividad , Tiofenos/química , Proteínas no Estructurales Virales/metabolismoRESUMEN
This paper describes a new FDA's pharmaceutical quality assessment system: Knowledge-aided Assessment & Structured Application (KASA). The KASA system is designed to: 1) capture and manage knowledge during the lifecycle of a drug product; 2) establish rules and algorithms for risk assessment, control, and communication; 3) perform computer-aided analyses of applications to compare regulatory standards and quality risks across applications and facilities; and 4) provide a structured assessment that minimizes text-based narratives and summarization of provided information. When fully developed and implemented, KASA will enrich the effectiveness, efficiency, and consistency of regulatory quality oversight through lifecycle management of products and facilities, and information sharing in a standardized and structured format. Ultimately, KASA will advance FDA's focus on pharmaceutical quality, the foundation for ensuring the safety and efficacy of drugs.
RESUMEN
A co-crystal is defined as a single crystalline structure composed of two or more components with no proton transfer which are solid at room temperature. Our group has come up with the following rationale selection of co-formers for initial co-crystal screening: 1) selection of co-formers with the highest potential for hydrogen bonding with the API and 2) selection of co-formers with diversity of secondary structural characteristics. We demonstrate the feasibility of this technique with a Novartis drug candidate A. In the first tier, 20 co-formers were screened and two hits were identified. By examining the two co-formers, which worked from the first round, a second round of screening was undertaken with more focused chemical matter. Nineteen co-crystal formers closely related to the two hits in the first screen were screened in the second tier. From this screen five hits were identified. All the hits were compared for their physical and chemical stability and dissolution profile. Based on the comparison 4-aminobenzoic co-crystal was chosen for in-vivo comparison with the free form. The co-crystal had 12 times higher exposure than the free form thus overcoming the solubility limited exposure.
Asunto(s)
Ácido 4-Aminobenzoico/química , Ingeniería Química/métodos , Química Farmacéutica/métodos , Oxadiazoles/química , Triazinas/química , Rastreo Diferencial de Calorimetría , Cristalización , Formas de Dosificación , Espectroscopía de Resonancia Magnética , Estructura Molecular , Solubilidad , Difracción de Rayos XRESUMEN
Hydrogen bonding between urea functionalities is a common structural motif employed in crystal-engineering studies. Crystallization of 1,3-bis(3-fluorophenyl)urea, C13H10F2N2O, from many solvents yielded concomitant mixtures of at least two polymorphs. In the monoclinic form, one-dimensional chains of hydrogen-bonded urea molecules align in an antiparallel orientation, as is typical of many diphenylureas. In the orthorhombic form, one-dimensional chains of hydrogen-bonded urea molecules have a parallel orientation rarely observed in symmetrically substituted diphenylureas.