RESUMEN
N-(5-Bromo-3-methoxypyrazin-2-yl)-5-chlorothiophene-2-sulfonamide 1 was identified as a hit in a CCR4 receptor antagonist high-throughput screen (HTS) of a subset of the AstraZeneca compound bank. As a hit with a lead-like profile, it was an excellent starting point for a CCR4 receptor antagonist program and enabled the rapid progression through the Lead Identification and Lead Optimization phases resulting in the discovery of two bioavailable CCR4 receptor antagonist candidate drugs.
RESUMEN
To an outsider, the exploration of thousands of molecules to find a small number of potential candidate drugs must appear enormously wasteful, but many medicinal chemists would defend this waste as unavoidable. Here, I provide evidence that suggests that modern medicinal chemists are overproductive in that they synthesise many more compounds than are required to achieve the objectives of the project. The difficulties encountered in finding the data for the analysis presented here prompted the design and implementation of a more rigorous approach to capture the essence of a medicinal chemistry program. The result, medicinal chemistry knowledge sharing (MeCKS), was designed to capture and communicate emerging issues and their solutions to the medicinal chemistry community.
Asunto(s)
Química Farmacéutica/métodos , Diseño de Fármacos , Conocimiento , Aprendizaje , Preparaciones Farmacéuticas/química , Química Farmacéutica/educación , Humanos , Preparaciones Farmacéuticas/síntesis químicaRESUMEN
By careful analysis of experimental X-ray ligand crystallographic protein data across several inhibitor series we have discovered a novel, potent and selective series of iNOS inhibitors exemplified by compound 8.
Asunto(s)
Inhibidores Enzimáticos/química , Isoxazoles/química , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Piridinas/química , Animales , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Isoxazoles/síntesis química , Isoxazoles/farmacología , Ratones , Microsomas Hepáticos/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Estructura Terciaria de Proteína , Piridinas/farmacología , RatasRESUMEN
Nitric oxide synthase (NOS) enzymes synthesize nitric oxide, a signal for vasodilatation and neurotransmission at low concentrations and a defensive cytotoxin at higher concentrations. The high active site conservation among all three NOS isozymes hinders the design of selective NOS inhibitors to treat inflammation, arthritis, stroke, septic shock and cancer. Our crystal structures and mutagenesis results identified an isozyme-specific induced-fit binding mode linking a cascade of conformational changes to a new specificity pocket. Plasticity of an isozyme-specific triad of distant second- and third-shell residues modulates conformational changes of invariant first-shell residues to determine inhibitor selectivity. To design potent and selective NOS inhibitors, we developed the anchored plasticity approach: anchor an inhibitor core in a conserved binding pocket, then extend rigid bulky substituents toward remote specificity pockets, which become accessible upon conformational changes of flexible residues. This approach exemplifies general principles for the design of selective enzyme inhibitors that overcome strong active site conservation.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos , Inflamación/tratamiento farmacológico , Inflamación/enzimología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Secuencia de Aminoácidos , Aminopiridinas/química , Aminopiridinas/farmacología , Animales , Bovinos , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Expresión Génica , Humanos , Isoenzimas/antagonistas & inhibidores , Masculino , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Molecular , Mutación , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa/metabolismo , Quinazolinas/química , Quinazolinas/farmacología , RatasRESUMEN
An efficient one-pot, three-component synthesis of substituted 1,2,4-triazoles has been developed, utilizing a wide range of substituted primary amines and acyl hydrazides.
Asunto(s)
Técnicas Químicas Combinatorias , Triazoles/síntesis química , Indicadores y Reactivos , Estructura Molecular , EstereoisomerismoRESUMEN
4-Methylaminopyridine (4-MAP) (5) is a potent but nonselective nitric oxide synthase (NOS) inhibitor. While simple N-methylation in this series results in poor activity, more elaborate N-substitution such as with 4-piperidine carbamate or amide results in potent and selective inducible NOS inhibition. Evidently, a flipping of the pyridine ring between these new inhibitors allows the piperidine to interact with different residues and confer excellent selectivity.
Asunto(s)
Aminopiridinas/síntesis química , Óxido Nítrico Sintasa/antagonistas & inhibidores , Aminopiridinas/química , Animales , Cristalografía por Rayos X , Ratones , Modelos Moleculares , Óxido Nítrico Sintasa/química , Óxido Nítrico Sintasa de Tipo IIRESUMEN
This paper describes the development of a QSAR model for the rational control of functional duration of topical long-acting dual D(2)-receptor/beta(2)-adrenoceptor agonists for the treatment of chronic obstructive pulmonary disease. A QSAR model highlighted the importance of lipophilicity and ionization in controlling beta(2) duration. It was found that design rules logD(7.4) > 2, secondary amine pK(a) > 8.0, yielded ultra-long duration compounds. This model was used successfully to guide the design of long- and ultra-long-acting compounds. The QSAR model is discussed in terms of the exosite model, and the plasmalemma diffusion microkinetic hypothesis, for the control of beta(2) duration. Data presented strongly suggests that beta(2) duration is primarily controlled by the membrane affinity of these compounds.