RESUMO
The identification of high-quality hits during the early phases of drug discovery is essential if projects are to have a realistic chance of progressing into clinical development and delivering marketed drugs. As the pharmaceutical industry goes through unprecedented change, there are increasing opportunities to collaborate via pre-competitive networks to marshal multifunctional resources and knowledge to drive impactful, innovative science. The 3D Fragment Consortium is developing fragment-screening libraries with enhanced 3D characteristics and evaluating their effect on the quality of fragment-based hit identification (FBHI) projects.
Assuntos
Desenho de Fármacos , Descoberta de Drogas/métodos , Bibliotecas de Moléculas Pequenas/química , Comportamento Cooperativo , Indústria Farmacêutica/organização & administração , Indústria Farmacêutica/tendências , Humanos , Conformação MolecularRESUMO
Rational structure-based design has yielded highly potent inhibitors of cathepsin K (Cat K) with excellent physical properties, selectivity profiles, and pharmacokinetics. Compounds with a 3,4-(CH3O)2Ph motif, such as 31, were found to have excellent metabolic stability and absorption profiles. Through metabolite identification studies, a reactive metabolite risk was identified with this motif. Subsequent structure-based design of isoteres culminated in the discovery of an optimized and balanced inhibitor (indazole, 38).
Assuntos
Catepsina K/antagonistas & inibidores , Cicloexanos/síntese química , Indazóis/síntese química , Animais , Proteínas Sanguíneas/metabolismo , Células Cultivadas , Cicloexanos/farmacocinética , Cicloexanos/farmacologia , Desenho de Fármacos , Hepatócitos/metabolismo , Humanos , Indazóis/farmacocinética , Indazóis/farmacologia , Masculino , Modelos Moleculares , Ligação Proteica , Ratos , Ratos Wistar , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The discovery of nitrile compound 4, a potent inhibitor of Cathepsin K (Cat K) with good bioavailability in dog is described. The compound was used to demonstrate target engagement and inhibition of Cat K in an in vivo dog PD model. The margin to hERG ion channel inhibition was deemed too low for a clinical candidate and an optimisation program to find isosteres or substitutions on benzothiazole group led to the discovery of 20, 24 and 27; all three free from hERG inhibition.
Assuntos
Benzotiazóis/química , Benzotiazóis/farmacologia , Catepsina K/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Nitrilas/química , Nitrilas/farmacologia , Animais , Benzotiazóis/metabolismo , Benzotiazóis/farmacocinética , Catepsina K/metabolismo , Cães , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Nitrilas/metabolismo , Nitrilas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in vitro stability were in fact excellent for this series. The tricycle carboline P3 unit was discovered by hypothesis-based design using existing structural information. Optimization using small substituents, knowledge from matched molecular pairs, and control of lipophilicity yielded compounds very close to the desired profile, of which 34 (AZD4996) was selected on the basis of pharmacokinetic profile.
Assuntos
Carbolinas/farmacologia , Catepsina K/antagonistas & inibidores , Indóis/farmacologia , Osteoartrite/tratamento farmacológico , Inibidores de Proteases/farmacologia , Animais , Carbolinas/metabolismo , Carbolinas/farmacocinética , Carbolinas/uso terapêutico , Catepsina K/química , Cães , Humanos , Indóis/metabolismo , Indóis/farmacocinética , Indóis/uso terapêutico , Concentração Inibidora 50 , Masculino , Modelos Moleculares , Osteoartrite/enzimologia , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/uso terapêutico , Conformação Proteica , Ratos , Especificidade por SubstratoRESUMO
Directed screening has identified a novel series of non-zinc binding MMP13 inhibitors that possess good levels of activity whilst demonstrating excellent selectivity over related MMPs. A lead optimisation campaign has delivered compounds with enhanced MMP13 potency, good selectivity and acceptable bioavailability profiles leading to a predicted twice-a-day dosing regimen in man.
Assuntos
Química Farmacêutica/métodos , Inibidores Enzimáticos/farmacologia , Metaloproteinase 13 da Matriz/química , Inibidores de Metaloproteinases de Matriz , Zinco/química , Animais , Cães , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Osteoartrite/tratamento farmacológico , Ratos , Solubilidade , Relação Estrutura-AtividadeRESUMO
Optimisation of a series of pyrazole inhibitors of the human FPR1 receptor has been achieved. The use of an in vitro media loss assay was utilised to identify sub-series with more robust DMPK profiles. These were subsequently improved to generate analogues with attractive overall profiles.
Assuntos
Pirazóis/síntese química , Pirazóis/farmacologia , Receptores de Formil Peptídeo/antagonistas & inibidores , Animais , Química Farmacêutica/métodos , Físico-Química/métodos , Desenho de Fármacos , Hepatócitos/citologia , Humanos , Concentração Inibidora 50 , Masculino , Microssomos Hepáticos/metabolismo , Modelos Químicos , Ratos , Ratos Sprague-Dawley , Receptores de Formil Peptídeo/químicaRESUMO
A series of pyrazole inhibitors of the human FPR1 receptor have been identified from high throughput screening. The compounds demonstrate potent inhibition in human neutrophils and attractive physicochemical and in vitro DMPK profiles to be of further interest.
Assuntos
Pirazóis/farmacologia , Receptores de Formil Peptídeo/antagonistas & inibidores , Descoberta de Drogas , Humanos , Neutrófilos/efeitos dos fármacos , Pirazóis/química , Relação Estrutura-AtividadeRESUMO
Directed screening has identified a novel series of MMP13 inhibitors that possess good levels of activity whilst possessing excellent selectivity over related MMPs. The binding mode of the series has been solved by co-crystallisation and demonstrates an interesting mode of inhibition without interaction with the catalytic zinc atom.
Assuntos
Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/química , Zinco/química , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Metaloproteinase 13 da Matriz/metabolismo , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A number of molecular recognition features have been exploited in structure-based design of selective Cathepsin inhibitors.
Assuntos
Catepsinas/antagonistas & inibidores , Inibidores de Proteases/química , Catepsinas/metabolismo , Simulação por Computador , Cristalografia por Raios X , Desenho de Fármacos , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Relação Estrutura-AtividadeRESUMO
A novel approach to inhibition of the alphavbeta3 integrin is described, which uses compounds designed to generate nM potency without using the arginine binding site.
Assuntos
Integrina alfaVbeta3/antagonistas & inibidores , Animais , Sítios de Ligação , Simulação por Computador , Desenho de Fármacos , Humanos , Integrina alfaVbeta3/metabolismo , Oligopeptídeos/química , Ratos , Bibliotecas de Moléculas Pequenas , Relação Estrutura-AtividadeRESUMO
A series of potent Cathepsin L inhibitors with good selectivity with respect to other cysteine Cathepsins is described and SAR is discussed with reference to the crystal structure of a protein-ligand complex.
Assuntos
Catepsina L/antagonistas & inibidores , Catepsina L/química , Nitrilas/síntese química , Animais , Cartilagem Articular/patologia , Catálise , Química Farmacêutica/métodos , Cristalografia por Raios X/métodos , Desenho de Fármacos , Humanos , Ligantes , Camundongos , Camundongos Transgênicos , Nitrilas/química , Nitrilas/farmacologia , Peptídeos/síntese química , Peptídeos/farmacologia , Proteínas/química , Relação Estrutura-AtividadeRESUMO
A series of pyrimidine nitrile inhibitors of Cathepsin K with reduced glutathione reactivity has been identified and Molecular Core Matching (MoCoM) has been used to quantify the effect of an amino substituent at C5.
Assuntos
Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/síntese química , Nitrilas/síntese química , Catepsina K , Catepsinas/química , Química Farmacêutica/métodos , Inibidores de Cisteína Proteinase/farmacologia , Desenho de Fármacos , Humanos , Lisossomos/enzimologia , Modelos Químicos , Estrutura Molecular , Osteoartrite/tratamento farmacológico , Osteoclastos , Osteoporose/tratamento farmacológico , Pirimidinas/química , Relação Estrutura-Atividade , Tecnologia Farmacêutica/métodosRESUMO
A quantitative assay involving the reaction of nitriles with glutathione and cysteine has been used as a simple in vitro screen to assess potential toxicity risk of candidate compounds in drug discovery. Studies have indicated that, when benchmarked with selected compounds, the reaction of the nitriles with glutathione can provide a useful tool for deciding whether or not to progress compounds in the absence of radiolabelling studies.
Assuntos
Descoberta de Drogas , Nitrilas/toxicidade , Cisteína/análise , Cisteína/toxicidade , Glutationa/análise , Glutationa/toxicidade , Estrutura Molecular , Nifedipino/análogos & derivados , Nifedipino/farmacologia , Nitrilas/análiseRESUMO
Two series of novel thienopyrrole inhibitors of recombinant human liver glycogen phosphorylase a (GPa) which are effective in reducing glucose output from rat hepatocytes are described. Representative compounds have been shown to bind at the dimer interface site of the rabbit muscle enzyme by X-ray crystallography.
Assuntos
Glicogênio Fosforilase/antagonistas & inibidores , Pirróis/farmacologia , Animais , Cristalografia por Raios X , Humanos , Pirróis/síntese química , Pirróis/química , Coelhos , Ratos , Relação Estrutura-AtividadeRESUMO
Using structure-based design, a new class of inhibitors of protein tyrosine phosphatase-1B (PTP1B) has been identified, which incorporate the 1,2,5-thiadiazolidin-3-one-1,1-dioxide template.