ABSTRACT
We recently disclosed a set of heteroaryl-fused piperazine inhibitors of BACE1 that combined nanomolar potency with good intrinsic permeability and low Pgp-mediated efflux. Herein we describe further work on two prototypes of this family of inhibitors aimed at modulating their basicity and reducing binding to the human ether-a-go-go-related gene (hERG) channel. This effort has led to the identification of compound 36, a highly potent (hAß42 cell IC50 = 1.3 nM), cardiovascularly safe, and orally bioavailable compound that elicited sustained Aß42 reduction in mouse and dog animal models.
ABSTRACT
A common challenge for medicinal chemists is to reduce the pKa of strongly basic groups' conjugate acids into a range that preserves the desired effects, usually potency and/or solubility, but avoids undesired effects like high volume of distribution (Vd), limited membrane permeation, and off-target binding to, notably, the hERG channel and monoamine receptors. We faced this challenge with a 3,4,5,6-tetrahydropyridine-2-amine scaffold harboring an amidine, a key structural component of potential inhibitors of BACE1, the rate-limiting enzyme in the production of Aß species that make up amyloid plaques in Alzheimer's disease. In our endeavor to balance potency with desirable properties to achieve brain penetration, we introduced a diverse set of groups in beta position of the amidine that modulate logD, PSA and pKa. Given the synthetic challenge to prepare these highly functionalized warheads, we first developed a design flow including predicted physicochemical parameters which allowed us to select only the most promising candidates for synthesis. For this we evaluated a set of commercial packages to predict physicochemical properties, which can guide medicinal chemists in their endeavors to modulate pKa values of amidine and amine bases.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Electrons , Enzyme Inhibitors/pharmacology , Pyrrolidines/pharmacology , Amidines/chemistry , Amidines/pharmacology , Amyloid Precursor Protein Secretases/metabolism , Animals , Aspartic Acid Endopeptidases/metabolism , Chemistry, Physical , Dogs , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Structure-Activity RelationshipABSTRACT
Despite several years of research, only a handful of ß-secretase (BACE) 1 inhibitors have entered clinical trials as potential therapeutics against Alzheimer's disease. The intrinsic basic nature of low molecular weight, amidine-containing BACE 1 inhibitors makes them far from optimal as central nervous system drugs. Herein we present a set of novel heteroaryl-fused piperazine amidine inhibitors designed to lower the basicity of the key, enzyme binding, amidine functionality. This study resulted in the identification of highly potent (IC50 ≤ 10 nM), permeable lead compounds with a reduced propensity to suffer from P-glycoprotein-mediated efflux.
ABSTRACT
The discovery, design and synthesis of a new series of GSMs is described. The classical imidazole heterocycle has been replaced by a cyano group attached to an indole nucleus. The exploration of this series has led to compound 26-S which combined high in vitro and in vivo potency with an acceptable drug-like profile.
Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Indoles/chemical synthesis , Drug Design , Humans , Structure-Activity RelationshipABSTRACT
In previous studies, the introduction of electron withdrawing groups to 1,4-oxazine BACE1 inhibitors reduced the p Ka of the amidine group, resulting in compound 2 that showed excellent in vivo efficacy, lowering Aß levels in brain and CSF. However, a suboptimal cardiovascular safety margin, based on QTc prolongation, prevented further progression. Further optimization resulted in the replacement of the 2-fluoro substituent by a CF3-group, which reduced hERG inhibition. This has led to compound 3, with an improved cardiovascular safety margin and sufficiently safe in GLP toxicity studies to progress into clinical trials.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Administration, Intravenous , Administration, Oral , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/cerebrospinal fluid , Animals , Aspartic Acid Endopeptidases/metabolism , Biological Availability , Cardiovascular Diseases/chemically induced , Chemical and Drug Induced Liver Injury/etiology , Dogs , Drug Evaluation, Preclinical/methods , Drug Stability , ERG1 Potassium Channel/metabolism , Guinea Pigs , Humans , Male , Mice, Inbred Strains , Oxazines/chemistry , Peptide Fragments/cerebrospinal fluid , Protease Inhibitors/administration & dosage , Protease Inhibitors/adverse effects , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprotein efflux. This led to compounds which were orally bioavailable, centrally active, and which demonstrated robust lowering of brain and CSF Aß levels, respectively, in mouse and dog models. The amyloid lowering potential of these molecules makes them valuable leads in the search for new BACE1 inhibitors for the treatment of Alzheimer's disease.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Brain/metabolism , Oxazines/chemical synthesis , Oxazines/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/cerebrospinal fluid , Animals , Biological Availability , Blood Proteins/metabolism , Blood-Brain Barrier , Cell Line, Tumor , Cytochrome P-450 Enzyme Inhibitors/chemical synthesis , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Dogs , Drug Design , Female , Humans , Male , Mice , Models, Molecular , Oxazines/pharmacokinetics , Protein BindingABSTRACT
The design and synthesis of a novel series of potent gamma secretase modulators is described. Exploration of various spacer groups between the triazole ring and the aromatic appendix in 2 has led to anilinotriazole 28, which combined high in vitro and in vivo potency with an acceptable drug-like profile.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aniline Compounds/chemistry , Triazoles/chemistry , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/metabolism , Aniline Compounds/chemical synthesis , Aniline Compounds/metabolism , Animals , Brain/metabolism , Drug Design , Humans , Mice , Mice, Transgenic , Protein Binding , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/metabolismABSTRACT
The evolution of amide 3 into conformationally restricted bicyclic triazolo-piperidine 14-S as a γ-secretase modulator is described. This is a potential disease modifying anti-Alzheimer's drug which demonstrated high in vitro and in vivo potency against Aß42 peptide, reduced lipophilicity and enhanced brain free fraction compared to the previous series.
Subject(s)
Alzheimer Disease/enzymology , Amyloid Precursor Protein Secretases/metabolism , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Drug Design , Piperidines/pharmacology , Triazoles/pharmacology , Alzheimer Disease/drug therapy , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/metabolism , Dogs , Humans , Mice , Microsomes, Liver/metabolism , Models, Molecular , Piperidines/chemistry , Piperidines/metabolism , Triazoles/chemistry , Triazoles/metabolismABSTRACT
The design and the synthesis of several chemical subclasses of imidazole containing γ-secretase modulators (GSMs) is described. Conformational restriction of pyridone 4 into bicyclic pyridone isosteres has led to compounds with high in vitro and in vivo potency. This has resulted in the identification of benzimidazole 44a as a GSM with low nanomolar potency in vitro. In mouse, rat, and dog, this compound displayed the typical γ-secretase modulatory profile by lowering Aß42 and Aß40 levels combined with an especially pronounced increase in Aß38 and Aß37 levels while leaving the total levels of amyloid peptides unchanged.
Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Benzimidazoles/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Imidazoles/chemical synthesis , Amyloid beta-Peptides/metabolism , Animals , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Benzoxazoles/chemical synthesis , Benzoxazoles/pharmacokinetics , Benzoxazoles/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Line, Tumor , Dogs , Drug Design , Humans , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Indazoles/chemical synthesis , Indazoles/pharmacokinetics , Indazoles/pharmacology , Male , Mice , Microsomes, Liver/metabolism , Molecular Conformation , Peptide Fragments/metabolism , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Rats, Sprague-DawleyABSTRACT
Pursuing our efforts in designing 5-pyrimidylhydroxamic acid anti-cancer agents, we have identified a new series of potent histone deacetylase (HDAC) inhibitors. These compounds exhibit enzymatic HDAC inhibiting properties with IC(50) values in the nanomolar range and inhibit tumor cell proliferation at similar levels. Good solubility, moderate bioavailability, and promising in vivo activity in xenograft model made this series of compounds interesting starting points to design new potent HDAC inhibitors.
Subject(s)
Antineoplastic Agents/chemistry , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylases/chemistry , Hydroxamic Acids/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation , Drug Design , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacology , Mice , Mice, Nude , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
A series of pyrimidyl-5-hydroxamic acids was prepared for evaluation as inhibitors of histone deacetylase (HDAC). Amino-2-pyrimidinyl can be used as a linker to provide HDAC inhibitors of good enzymatic potency.