RESUMO
Development of SAR in a 3-cyano-5-fluoro-N-arylbenzamide series of non-competitive antagonists of mGlu(5) using a functional cell-based assay is described in this Letter. Further characterization of selected potent compounds in in vitro assays designed to measure their metabolic stability and protein binding is also presented. Subsequent evaluation of two new compounds in pharmacokinetic studies using intraperitoneal dosing in rats demonstrated good exposure in both plasma and brain samples.
Assuntos
Benzamidas/química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Regulação Alostérica , Animais , Benzamidas/síntese química , Benzamidas/farmacocinética , Proteínas Sanguíneas/metabolismo , Encéfalo/metabolismo , Microssomos Hepáticos/metabolismo , Ligação Proteica , Ratos , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/química , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-AtividadeRESUMO
The optimization of tertiary carbinamine derived inhibitors of BACE1 from its discovery as an unstable lead to low nanomolar cell active compounds is described. Five-membered heterocycles are reported as stable and potency enhancing linkers. In the course of this work, we have discovered a clear trend where the activity of inhibitors at a given assay pH is dependent on pK(a) of the amino group that interacts directly with the catalytic aspartates. The potency of compounds as inhibitors of Alphabeta production in a cell culture assay correlated much better with BACE1 enzyme potency measured at pH 7.5 than at pH 4.5.
Assuntos
Aminas/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico/metabolismo , Inibidores Enzimáticos/farmacologia , Catálise , Humanos , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
This Letter describes the discovery and SAR of three novel series of mGluR5 non-competitive antagonists/negative allosteric modulators (NAMs) not based on manipulation of an MPEP/MTEP chemotype. This work demonstrates fundamentally new mGluR5 NAM chemotypes with submicromolar potencies, and the first example of a mode of pharmacology 'switch' to provide PAMs with a non-MPEP scaffold.
Assuntos
Compostos Heterocíclicos com 3 Anéis/química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Regulação Alostérica , Descoberta de Drogas , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Concentração Inibidora 50 , Receptor de Glutamato Metabotrópico 5 , Relação Estrutura-AtividadeRESUMO
We describe the discovery and optimization of tertiary carbinamine derived inhibitors of the enzyme beta-secretase (BACE-1). These novel non-transition-state-derived ligands incorporate a single primary amine to interact with the catalytic aspartates of the target enzyme. Optimization of this series provided inhibitors with intrinsic and functional potency comparable to evolved transition state isostere derived inhibitors of BACE-1.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/química , Compostos de Anilina/síntese química , Oxidiazóis/síntese química , Compostos de Anilina/química , Cristalografia por Raios X , Modelos Moleculares , Oxidiazóis/químicaRESUMO
There is an increasing amount of literature data showing the positive effects on preclinical antiparkinsonian rodent models with selective positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu(4)). However, most of the data generated utilize compounds that have not been optimized for druglike properties, and as a consequence, they exhibit poor pharmacokinetic properties and thus do not cross the blood-brain barrier. Herein, we report on a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides with improved PK properties with excellent potency and selectivity as well as improved brain exposure in rodents. Finally, ML182 was shown to be orally active in the haloperidol induced catalepsy model, a well-established antiparkinsonian model.
Assuntos
Antiparkinsonianos/síntese química , Isoindóis/síntese química , Ácidos Picolínicos/síntese química , Receptores de Glutamato Metabotrópico/fisiologia , Administração Oral , Regulação Alostérica , Animais , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacologia , Disponibilidade Biológica , Células CHO , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Cricetinae , Cricetulus , Haloperidol , Humanos , Técnicas In Vitro , Isoindóis/farmacocinética , Isoindóis/farmacologia , Microssomos Hepáticos/metabolismo , Ácidos Picolínicos/farmacocinética , Ácidos Picolínicos/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
This Letter describes the design and synthesis of tertiary carbinamine macrocyclic inhibitors of the beta-secretase (BACE-1) enzyme. These macrocyclic inhibitors, some of which incorporate novel P2 substituents, display a 2- to 100-fold increase in potency relative to the previously described acyclic analogs while affording greater stability.
Assuntos
Aminas/química , Aminas/farmacologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Aminas/síntese química , Ciclização , Desenho de Fármacos , Modelos Moleculares , Inibidores de Proteases/síntese química , Relação Estrutura-AtividadeRESUMO
Structural modifications of the aminopyridine P(1)(') group of imidazole acetic acid based TAFIa inhibitors led to the discovery of the aminocyclopentyl analog 28, a 1 nM TAFIa inhibitor with CLT(50) functional activity of 14 nM but without selectivity against CPB. While not as active, aminobutyl derivative 27 provided an improved 6.7-fold selectivity for TAFIa versus CPB.