ABSTRACT
4-(1,3-Benzothiazol-2-yl)thiophene-2-sulfonamide (4a) was found to be a moderately potent inhibitor of cyclin-dependent kinase 5 (cdk5) from a HTS screen. The synthesis and SAR around this hit is described. The X-ray coordinates of ligand 4a with cdk5 are also reported, showing an unusual binding mode to the hinge region via a water molecule.
Subject(s)
Cyclin-Dependent Kinase 5/antagonists & inhibitors , Nerve Tissue Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Thiophenes/chemistry , Thiophenes/pharmacology , Crystallography, X-Ray , Cyclin-Dependent Kinase 5/metabolism , Dose-Response Relationship, Drug , Models, Molecular , Molecular Structure , Nerve Tissue Proteins/metabolism , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Thiophenes/chemical synthesisABSTRACT
The syntheses and SAR of new series of beta-amyloid binding agents are reported. The effort to optimize signal-to-background ratios for these ligands are described. Compounds 8, 21 and 30 displayed desirable lipophilicity and pharmacokinetic properties. Compounds 8 and 21 were evaluated with in vitro autoradiographic studies and in vivo in APP/PS1 transgenic mice. It is shown that it was possible to increase the signal-to-background ratios compared to PIB 1, as demonstrated by compounds 8 and 21.
Subject(s)
Amyloid beta-Peptides/metabolism , Benzofurans/chemical synthesis , Benzofurans/pharmacokinetics , Benzothiazoles/chemical synthesis , Benzothiazoles/pharmacokinetics , Benzoxazoles/chemical synthesis , Benzoxazoles/pharmacokinetics , Positron-Emission Tomography , Animals , Carbon Radioisotopes , Half-Life , Mice , Mice, Transgenic , Radioligand Assay , Structure-Activity RelationshipABSTRACT
We have developed two parallel series, A and B, of CX3CR1 antagonists for the treatment of multiple sclerosis. By modifying the substituents on the 7-amino-5-thio-thiazolo[4,5-d]pyrimidine core structure, we were able to achieve compounds with high selectivity for CX3CR1 over the closely related CXCR2 receptor. The structure-activity relationships showed that a leucinol moiety attached to the core-structure in the 7-position together with α-methyl branched benzyl derivatives in the 5-position displayed promising affinity, and selectivity as well as physicochemical properties, as exemplified by compounds 18a and 24h. We show the preparation of the first potent and selective orally available CX3CR1 antagonists.
Subject(s)
Multiple Sclerosis/drug therapy , Pyrimidines/pharmacology , Receptors, Chemokine/antagonists & inhibitors , Thiazoles/pharmacology , Amino Alcohols/chemical synthesis , Amino Alcohols/pharmacokinetics , Amino Alcohols/pharmacology , Animals , CX3C Chemokine Receptor 1 , Caco-2 Cells , Humans , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/pharmacokinetics , Rats , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistry , Thiazoles/pharmacokineticsABSTRACT
The evaluation of a series of aminoisoindoles as ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors and the discovery of a clinical candidate drug for Alzheimer's disease, (S)-32 (AZD3839), are described. The improvement in permeability properties by the introduction of fluorine adjacent to the amidine moiety, resulting in in vivo brain reduction of Aß40, is discussed. Due to the basic nature of these compounds, they displayed affinity for the human ether-a-go-go related gene (hERG) ion channel. Different ways to reduce hERG inhibition and increase hERG margins for this series are described, culminating in (S)-16 and (R)-41 showing large in vitro margins with BACE1 cell IC(50) values of 8.6 and 0.16 nM, respectively, and hERG IC(50) values of 16 and 2.8 µM, respectively. Several compounds were advanced into pharmacodynamic studies and demonstrated significant reduction of ß-amyloid peptides in mouse brain following oral dosing.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Indoles/chemical synthesis , Pyrimidines/chemical synthesis , Administration, Oral , Alkynes/chemical synthesis , Alkynes/pharmacokinetics , Alkynes/pharmacology , Amides/chemical synthesis , Amides/pharmacokinetics , Amides/pharmacology , Amyloid Precursor Protein Secretases/chemistry , Amyloid beta-Peptides/metabolism , Animals , Aspartic Acid Endopeptidases/chemistry , Biological Availability , Brain/drug effects , Brain/metabolism , Cell Line , Crystallography, X-Ray , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Female , Fluorescence Resonance Energy Transfer , Humans , Hydrogen Bonding , Indoles/pharmacokinetics , Indoles/pharmacology , Mice , Mice, Inbred C57BL , Models, Molecular , Molecular Structure , Peptide Fragments/metabolism , Permeability , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Amino-2H-imidazoles are described as a new class of BACE-1 inhibitors for the treatment of Alzheimer's disease. Synthetic methods, crystal structures, and structure-activity relationships for target activity, permeability, and hERG activity are reported and discussed. Compound (S)-1m was one of the most promising compounds in this report, with high potency in the cellular assay and a good overall profile. When guinea pigs were treated with compound (S)-1m, a concentration and time dependent decrease in Aß40 and Aß42 levels in plasma, brain, and CSF was observed. The maximum reduction of brain Aß was 40-50%, 1.5 h after oral dosing (100 µmol/kg). The results presented highlight the potential of this new class of BACE-1 inhibitors with good target potency and with low effect on hERG, in combination with a fair CNS exposure in vivo.