In an attempt to increase selectivity vs Cathepsin D (CatD) in our BACE1 program, a series of 1,3,4,4a,10,10a-hexahydropyrano[4,3-b]chromene analogues was developed. Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Using structure-based design, substitutions to improve binding to both the S3 and S2' sites of BACE1 were explored. An acyl guanidine moiety provided the most potent analogues. These compounds demonstrated 10-420 fold selectivity for BACE1 vs CatD, and were highly potent in a cell assay measuring Aß1-40 production (5-99 nM). They also suffered from high efflux. Despite this undesirable property, two of the acyl guanidines achieved free brain concentrations (Cfree,brain) in a guinea pig PD model sufficient to cover their cell IC50s. Moreover, a significant reduction of Aß1-40 in guinea pig, rat, and cyno CSF (58%, 53%, and 63%, respectively) was observed for compound 62.
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Aspartic Acid Endopeptidases/antagonists & inhibitors , Brain/metabolism , Chromans/chemical synthesis , Pyrans/chemical synthesis , Spiro Compounds/chemical synthesis , Animals , CHO Cells , Cell Line, Tumor , Chromans/pharmacokinetics , Chromans/pharmacology , Cricetinae , Cricetulus , Crystallography, X-Ray , Guinea Pigs , HEK293 Cells , Humans , Macaca fascicularis , Male , Mice , Models, Molecular , Pyrans/pharmacokinetics , Pyrans/pharmacology , Rats , Rats, Sprague-Dawley , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Stereoisomerism , Structure-Activity Relationship
A hallmark of Alzheimer's disease is the brain deposition of amyloid beta (Aß), a peptide of 36-43 amino acids that is likely a primary driver of neurodegeneration. Aß is produced by the sequential cleavage of APP by BACE1 and γ-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer's disease. Herein we describe BACE1 inhibitors with limited molecular flexibility and molecular weight that decrease CSF Aß in vivo, despite efflux. Starting with spirocycle 1a, we explore structure-activity relationships of core changes, P3 moieties, and Asp binding functional groups in order to optimize BACE1 affinity, cathepsin D selectivity, and blood-brain barrier (BBB) penetration. Using wild type guinea pig and rat, we demonstrate a PK/PD relationship between free drug concentrations in the brain and CSF Aß lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF Aß in rodents and in monkey.
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/cerebrospinal fluid , Aspartic Acid Endopeptidases/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Spiro Compounds/chemical synthesis , Animals , Blood-Brain Barrier/metabolism , Chromans/chemical synthesis , Chromans/pharmacokinetics , Chromans/pharmacology , Guinea Pigs , HEK293 Cells , Humans , Hydantoins/chemical synthesis , Hydantoins/pharmacokinetics , Hydantoins/pharmacology , Male , Protease Inhibitors/pharmacokinetics , Protease Inhibitors/pharmacology , Rats , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Structure-Activity Relationship
Aniline 'headgroups' were synthesized and incorporated into an alkynyl thienopyrimidine series of EGFR and ErbB-2 inhibitors. Potent inhibition of enzyme activity and cellular proliferation was observed. In certain instances, protein binding was reduced and oral exposure was found to be somewhat improved relative to compounds containing the reference aniline.
Aniline Compounds/chemical synthesis , ErbB Receptors/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Receptor, ErbB-2/antagonists & inhibitors , Administration, Oral , Aniline Compounds/administration & dosage , Aniline Compounds/pharmacology , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Evaluation, Preclinical/methods , ErbB Receptors/metabolism , Growth Inhibitors/administration & dosage , Growth Inhibitors/chemical synthesis , Growth Inhibitors/pharmacology , Humans , Mice , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacology , Pyrimidines/administration & dosage , Pyrimidines/pharmacology , Receptor, ErbB-2/metabolism
A novel class of pyrrolidinyl-acetyleneic thieno[3,2-d]pyrimidines has been identified which potently inhibit the EGFR and ErbB-2 receptor tyrosine kinases. Synthetic modifications of the pyrrolidine carbamate moiety result in a range of effects on enzyme and cellular potency. In addition, the impact of the absolute stereochemical configuration on cellular potency and oral mouse pharmacokinetics is described.
Antineoplastic Agents/chemistry , ErbB Receptors/antagonists & inhibitors , Pyrimidines/pharmacology , Pyrrolidines/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Administration, Oral , Animals , Mice , Pharmacokinetics , Pyrimidines/chemical synthesis , Pyrrolidines/chemical synthesis , Structure-Activity Relationship
A novel series of P1 modified HIV protease inhibitors was synthesized and evaluated for in vitro antiviral activity against wild-type virus and protease inhibitor-resistant viruses. Optimization of the P1 moiety resulted in compounds with femtomolar enzyme activities and cellular antiviral activities in the low nanomolar range culminating in the identification of clinical candidate GW0385.
HIV Protease Inhibitors/pharmacology , Sulfonamides/pharmacology , HIV Protease Inhibitors/chemistry , Molecular Structure , Sulfonamides/chemistry
A series of dianilinopyrimidineureas demonstrate potency as VEGFR2 kinase inhibitors.
Enzyme Inhibitors/chemical synthesis , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/chemical synthesis , Urea/analogs & derivatives , Urea/chemical synthesis , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Aniline Compounds/chemistry , Enzyme Inhibitors/pharmacology , HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/pharmacology , Protein-Tyrosine Kinases/metabolism , Pyrimidines/pharmacology , Stereoisomerism , Structure-Activity Relationship , Urea/pharmacology , Vascular Endothelial Growth Factor Receptor-2/metabolism
A series of novel N-alkoxy-arylsulfonamide HIV protease inhibitors with low picomolar enzyme activity and single digit nanomolar antiviral activity is disclosed.
HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/pharmacology , HIV Protease/metabolism , Sulfonamides/chemical synthesis , Benzene Derivatives/chemistry , Drug Design , Drug Resistance, Multiple, Viral , HIV Protease/drug effects , Humans , Structure-Activity Relationship , Sulfonamides/pharmacology , Virus Replication/drug effects