ABSTRACT
The amyloid hypothesis asserts that excess production or reduced clearance of the amyloid-ß (Aß) peptides in the brain initiates a sequence of events that ultimately lead to Alzheimer's disease and dementia. The Aß hypothesis has identified BACE1 as a therapeutic target to treat Alzheimer's and led to medicinal chemistry efforts to design its inhibitors both in the pharmaceutical industry and in academia. This review summarizes two distinct categories of inhibitors designed based on conformational states of "closed" and "open" forms of the enzyme. In each category the inhibitors are classified based on the core catalytic interaction group or the aspartyl binding motif (ABM). This review covers the description of inhibitors in each ABM class with X-ray crystal structures of key compounds, their binding modes, related structure-activity data highlighting potency advances, and additional properties such as selectivity profile, P-gp efflux, pharmacokinetic, and pharmacodynamic data.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Alzheimer Disease/enzymology , Amino Acid Sequence , Amyloid Precursor Protein Secretases/chemistry , Animals , Aspartic Acid Endopeptidases/chemistry , Biocatalysis , Blood-Brain Barrier/metabolism , Cell Membrane Permeability , Clinical Trials as Topic , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Models, Molecular , Molecular Sequence Data , Protein Binding , Protein Conformation , Structure-Activity RelationshipABSTRACT
Structure-based design led to the discovery of a novel class of renin inhibitors in which an unprecedented phenyl ring filling the S1 site is attached to the phenyl ring filling the S3 pocket. Optimization for several parameters including potency in the presence of human plasma, selectivity against CYP3A4 inhibition and improved rat oral bioavailability led to the identification of 8d which demonstrated antihypertensive efficacy in a transgenic rat model of human hypertension.
Subject(s)
Antihypertensive Agents/pharmacology , Enzyme Inhibitors/pharmacology , Phenyl Ethers/pharmacology , Renin/antagonists & inhibitors , Animals , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/chemistry , Biological Availability , Crystallography, X-Ray , Cytochrome P-450 CYP3A/blood , Cytochrome P-450 CYP3A Inhibitors , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Discovery , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Hypertension/drug therapy , Models, Molecular , Molecular Conformation , Phenyl Ethers/chemical synthesis , Phenyl Ethers/chemistry , Rats , Rats, Transgenic , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/isolation & purification , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Structure guided optimization of a series of nonpeptidic alkyl amine renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the cyclohexylmethyl group occupying the S1 pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.
ABSTRACT
Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC(50) of 0.83nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10mg/kg resulted in >20h reduction of blood pressure in a double transgenic rat model of hypertension.
Subject(s)
Amines/chemistry , Carbamates/chemistry , Enzyme Inhibitors/chemistry , Piperidines/chemistry , Renin/antagonists & inhibitors , Administration, Oral , Amines/chemical synthesis , Amines/pharmacokinetics , Animals , Binding Sites , Blood Pressure/drug effects , Carbamates/chemical synthesis , Carbamates/pharmacokinetics , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Haplorhini , Humans , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Rats , Rats, Transgenic , Renin/blood , Renin/metabolism , Structure-Activity RelationshipABSTRACT
Structure-based drug design led to the identification of a novel class of potent, low MW alkylamine renin inhibitors. Oral administration of lead compound 21l, with MW of 508 and IC(50) of 0.47nM, caused a sustained reduction in mean arterial blood pressure in a double transgenic rat model of hypertension.
Subject(s)
Antihypertensive Agents/chemistry , Methylamines/chemistry , Renin/antagonists & inhibitors , Administration, Oral , Amino Acid Sequence , Animals , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/pharmacokinetics , Blood Pressure , Computer Simulation , Crystallography, X-Ray , Drug Design , Humans , Methylamines/chemical synthesis , Methylamines/pharmacokinetics , Rats , Rats, Transgenic , Renin/metabolism , Structure-Activity RelationshipABSTRACT
The discovery and synthesis of a series of 2-amino-5-benzoyl-4-(2-furyl)thiazoles as adenosine A(2A) receptor antagonists from a small-molecule combinatorial library using a high-throughput radioligand-binding assay is described. Antagonists were further characterized in the A(2A) binding assay and an A(1) selectivity assay. Selected examples exhibited excellent affinity for A(2A) and good selectivity versus the A(1) receptor.
Subject(s)
Purinergic P1 Receptor Antagonists , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Alkylation , Cell Line , Combinatorial Chemistry Techniques , Drug Discovery , Humans , Radioligand Assay , Receptors, Purinergic P1/metabolism , Thiazoles/metabolismABSTRACT
Inhibition of renin has been shown to be successful in managing hypertension and maintaining cardiac health. Canine models have played a key role in preclinical assessment of renin inhibitors. Here we report the cloning of canine prorenin gene. The amino acid sequence of mature canine renin was approximately 70% identical to that of human renin. The full-length prorenin was expressed in HEK 293 cells, purified and converted to its active form by trypsin-mediated cleavage of the 43 residue propeptide. The mature enzyme was characterized by steady-state kinetics using a peptide corresponding to the canine angiotensinogen sequence, Ac-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser-OH (cleavage between Leu(10)-Leu(11)). The reaction followed Michaelis-Menten kinetics with a K(M) of 120 microM and a second-order rate constant (k(cat)/K(M)) of 1.7 x 10(5) M(-)(1)s(-)(1). The enzyme was inhibited by various human renin inhibitors, but at reduced potency compared to the human renin. The basis of the species specificity was investigated by mutagenesis. Based on primary sequence and structural alignments, three mutants were prepared (G149S-S150T, V286L, G149S-S150T-V286L). Each mutant yielded catalytically active enzymes with lower specific activities than native canine renin. V286L had the greatest effect on substrate specificity, while G149S, S150T mutations produced enzymes with inhibitor profiles similar to human renin.
