ABSTRACT
In this Letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing 16 which lowers Αß by 28% and 32% in the cortex and CSF, respectively, in the preclinical wild type Hartley guinea pig animal model when dosed orally at 30mpk BID for 2.5days.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Ethylamines/chemical synthesis , Ethylamines/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Alkylation , Alzheimer Disease , Animals , Brain/metabolism , Cell Line , Dogs , Drug Design , Guinea Pigs , Humans , Indicators and Reagents , Protease Inhibitors/pharmacokinetics , Protein Binding , Structure-Activity RelationshipABSTRACT
Using structure-guided design, hydroxyethylamine BACE-1 inhibitors were optimized to nanomolar Abeta cellular inhibition with selectivity against cathepsin-D. X-ray crystallography illuminated the S1' residues critical to this effort, which culminated in compounds 56 and 57 that exhibited potency and selectivity but poor permeability and high P-gp efflux.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/chemistry , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Drug Design , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Amyloid Precursor Protein Secretases/chemistry , Amyloid Precursor Protein Secretases/genetics , Aspartic Acid Endopeptidases/chemistry , Aspartic Acid Endopeptidases/genetics , Humans , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Substrate SpecificityABSTRACT
The B1 receptor is an attractive target for the treatment of pain and inflammation. A series of 3-carboxamido-5-phenacylamino pyrazole B1 receptor antagonists are described that exhibit good potency against B1 and high selectivity over B2. Initially, N-unsubstituted pyrazoles were studied, but these compounds suffered from extensive glucuronidation in primates. This difficulty could be surmounted by the use of N-substituted pyrazoles. Optimization efforts culminated in compound 41, which has high receptor potency and metabolic stability.
Subject(s)
Benzamides/chemical synthesis , Bradykinin B1 Receptor Antagonists , Pyrazoles/chemical synthesis , Benzamides/chemistry , Benzamides/pharmacology , Crystallography, X-Ray , Fibroblasts/metabolism , Humans , In Vitro Techniques , Lung/cytology , Molecular Structure , Pyrazoles/chemistry , Pyrazoles/pharmacology , Radioligand Assay , Structure-Activity RelationshipABSTRACT
A series of eight N-2-phenylethylphosphonyl derivatives of glutamic acid was prepared to determine if the inhibitory potency of a phenylethylphosphonyl derivative of glutamic acid against prostate-specific membrane antigen (PSMA) could be improved through rational substitutions on the phenyl ring. The design of these eight analogs was based upon the Topliss batchwise approach. Of the inhibitors from the first generation, the 3,4-dichlorophenyl analog exhibited the greatest improvement over the lead compound which was an unsubstituted phenyl derivative, while the 4-methoxyphenyl analog was essentially void of inhibitory potency against PSMA in single-dose studies. From the potency ranking order of the first generation, the parameter most important to the pharmacophore was determined to be pi + sigma. Attempts to optimize further the potency of inhibitors by preparing a second generation of compounds did not result in structures with greater potency than that of the 3,4-dichlorophenyl analog from the first generation. Based upon K(i) values, the 3,4-dichlorophenyl analog represented a potency improvement of nearly one order of magnitude. These results confirm further the usefulness of the Topliss approach to analog development when large library synthesis cannot be achieved readily.
Subject(s)
Organophosphonates/pharmacology , Prostate-Specific Antigen/antagonists & inhibitors , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Fast Atom BombardmentABSTRACT
Potent, small molecule A beta inhibitors have been prepared that incorporate an alanine core bracketed by an N-terminal arylacetyl group and various C-terminal amino alcohols. The compounds exhibit stereospecific inhibition as demonstrated in an in vitro assay.
