A series of novel carboxylic acid-based α-sulfone MMP inhibitors have been synthesized and the in vitro enzyme SAR and in vivo PK evaluation are discussed. These compounds are potent MMP-9 inhibitors ...and are selective over MMP-1.
A series of novel carboxylic acid-based α-sulfone MMP inhibitors have been synthesized and the in vitro enzyme SAR is discussed. A potential binding mode in the active site of the MMP-9 homology model was highlighted. These compounds are potent MMP-9 inhibitors and are selective over MMP-1.
A novel series of arylindenopyrimidines were identified as A sub(2A) and A sub(1) receptor antagonists. The series was optimized for in vitro activity by substituting the 8- and 9-positions with ...methylene amine substituents. The compounds show excellent activity in mouse models of Parkinson's disease when dosed orally.
Two reactive metabolites were identified in vivo for the dual A sub(2A)/A sub(1) receptor antagonist 1. Two strategies were implemented to successfully mitigate the metabolic liabilities associated ...with 1. Optimization of the arylindenopyrimidines led to a number of amide, ether, and amino analogs having comparable in vitro and in vivo activity.
Two reactive metabolites were identified in vivo for the dual A
2A/A
1 receptor antagonist
1. Two strategies were implemented to successfully mitigate the metabolic liabilities associated with
1. ...Optimization of the arylindenopyrimidines led to a number of amide, ether, and amino analogs having comparable in vitro and in vivo activity.
Two reactive metabolites were identified in vivo for the dual A
2A/A
1 receptor antagonist
1. Two strategies were implemented to successfully mitigate the metabolic liabilities associated with
1. Optimization of the arylindenopyrimidines led to a number of amide, ether, and amino analogs having comparable in vitro and in vivo activity.
A novel series of arylindenopyrimidines were identified as A
2A and A
1 receptor antagonists. The series was optimized for in vitro activity by substituting the 8- and 9-positions with methylene ...amine substituents. The compounds show excellent activity in mouse models of Parkinson’s disease when dosed orally.
A novel series of arylindenopyrimidines were identified as A
2A and A
1 receptor antagonists. The series was optimized for in vitro activity by substituting the 8- and 9-positions with methylene amine substituents. The compounds show excellent activity in mouse models of Parkinson’s disease when dosed orally.
A novel series of aminomethyl substituted thieno2,3-dpyrimidines have been identified as adenosine A2A receptor antagonists. Analogues show excellent in vitro activities and have excellent activity ...in vivo in mouse models of Parkinson's disease.
Voltage-sensitive potassium channels are a highly diversified family of ionic channels that fulfill a crucial role in modulating electrical signaling in excitable tissue. The diverse gating ...characteristics exhibited by individual members of this large family allow for precise shaping of excitability by moderating the membrane resting potential, modulating the duration and frequency of action potentials, and by regulating neurotransmitter release. At the single channel level, there appears to be specific mechanisms for differential subcellular distribution of individual K$\sp+$ channels within discrete neurons. Many different individual K$\sp+$ channels may be expressed by the same neuron, and can be found in markedly different membrane regions of the cell. Precise K$\sp+$ channel localization patterns indicate that specific cellular machinery exists for the differential localization of individual or for entire subfamilies of K$\sp+$ channels. The molecular mechanisms responsible for these distributions are, however almost entirely unknown. Kv2.1, a classical delayed-rectifier K$\sp+$ channel, is expressed in the central nervous system exclusively in neurons. Within individual neurons, the channel protein is found localized to the somatodendritic region, where expression is restricted in high density plaques, or clusters. Elucidation of the primary mechanisms that underlie Kv2.1-specific somatodendritic and clustered localization may shed light unto the functional necessity of distinctly localizing this physiologically important K$\sp+$ channel. Expression and mutagenesis studies performed here in two different heterologous cell culture systems define a novel sixteen amino acid domain within the Kv2.1 cytoplasmic carboxy-terminus from residue 590 to 605 that is responsible for restricted localization. Previous correlative localization studies in these cell lines indicate that the basic molecular mechanisms responsible for restricted distribution of membrane proteins may be similar in both these cell lines and in neurons. Biochemical characterization and co-localization studies of Kv2.1 suggests that restricted localization is dependent upon association with one or more aspects of the cellular microfilament cytoskeleton. These findings will enable a more focused study of the mechanisms involved in Kv2.1 localization to continue in actual neuronal systems.
This column focuses on use of learning collaboratives by the Center for Practice Innovations to help programs implement the evidence-based individual placement and support model of supported ...employment in New York State. These learning collaboratives use fidelity and performance indicator data to drive the development of program-specific individualized quality improvement plans. As of 2014, 59 (69%) of 86 eligible programs have joined the initiative. Programs are achieving employment outcomes for consumers on par with national benchmarks, along with improved fidelity.
PDF