ABSTRACT
Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles, including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction. This relationship is consistent with a clinical outcomes trial of a CETP inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction compared to standard of care alone. We discuss here the discovery of MK-8262, a CETP inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk.
Subject(s)
Anticholesteremic Agents/therapeutic use , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Coronary Disease/drug therapy , Oxazolidinones/therapeutic use , Animals , Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/pharmacokinetics , Anticholesteremic Agents/toxicity , Dogs , Humans , Macaca mulatta , Mice, Inbred C57BL , Molecular Structure , Oxazolidinones/chemical synthesis , Oxazolidinones/pharmacokinetics , Oxazolidinones/toxicity , Rats, Wistar , Structure-Activity RelationshipABSTRACT
Proprotein convertase substilisin-like/kexin type 9 (PCSK9) is a serine protease involved in a protein-protein interaction with the low-density lipoprotein (LDL) receptor that has both human genetic and clinical validation. Blocking this protein-protein interaction prevents LDL receptor degradation and thereby decreases LDL cholesterol levels. Our pursuit of small-molecule direct binders for this difficult to drug PPI target utilized affinity selection/mass spectrometry, which identified one confirmed hit compound. An X-ray crystal structure revealed that this compound was binding in an unprecedented allosteric pocket located between the catalytic and C-terminal domain. Optimization of this initial hit, using two distinct strategies, led to compounds with high binding affinity to PCSK9. Direct target engagement was demonstrated in the cell lysate with a cellular thermal shift assay. Finally, ligand-induced protein degradation was shown with a proteasome recruiting tag attached to the high-affinity allosteric ligand for PCSK9.
Subject(s)
Drug Discovery , Drug Evaluation, Preclinical , Proprotein Convertase 9/metabolism , Proteolysis/drug effects , Serine Proteinase Inhibitors/pharmacology , Small Molecule Libraries/pharmacology , Humans , Ligands , Models, Molecular , Molecular Structure , Serine Proteinase Inhibitors/chemistry , Small Molecule Libraries/chemistryABSTRACT
Using the collective body of known (CETP) inhibitors as inspiration for design, a structurally novel series of tetrahydroquinoxaline CETP inhibitors were discovered. An exemplar from this series, compound 5, displayed potent in vitro CETP inhibition and was efficacious in a transgenic cynomologus-CETP mouse HDL PD (pharmacodynamic) assay. However, an undesirable metabolic profile and chemical instability hampered further development of the series. A three-dimensional structure of tetrahydroquinoxaline inhibitor 6 was proposed from (1)H NMR structural studies, and this model was then used in silico for the design of a new class of compounds based upon an indoline scaffold. This work resulted in the discovery of compound 7, which displayed potent in vitro CETP inhibition, a favorable PK-PD profile relative to tetrahydroquinoxaline 5, and dose-dependent efficacy in the transgenic cynomologus-CETP mouse HDL PD assay.
ABSTRACT
Screening of the Merck sample collection identified compound 1 as a weakly potent GPR119 agonist (hEC(50)=3600 nM). Dual termini optimization of 1 led to compound 36 having improved potency, selectivity, and formulation profile, however, modest physical properties (PP) hindered its utility. Design of a new core containing a cyclopropyl restriction yielded further PP improvements and when combined with the termini SAR optimizations yielded a potent and highly selective agonist suitable for further preclinical development (58).
Subject(s)
Diabetes Mellitus, Type 2 , Drug Design , Receptors, G-Protein-Coupled/agonists , Animals , Diabetes Mellitus, Type 2/drug therapy , Ethers, Cyclic/chemical synthesis , Ethers, Cyclic/chemistry , Humans , Mice , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of oxazole-substituted indanylacetic acids were prepared which show a spectrum of activity as ligands for PPAR nuclear receptor subtypes.
Subject(s)
Acetates/pharmacology , Oxazoles/chemistry , PPAR alpha/agonists , PPAR gamma/agonists , Acetates/administration & dosage , Acetates/chemical synthesis , Administration, Oral , Animals , Blood Glucose/drug effects , Cholesterol, HDL/blood , Cholesterol, HDL/drug effects , Drug Evaluation, Preclinical , Ligands , Mice , Mice, Mutant Strains , Mice, Obese , Molecular Structure , PPAR alpha/metabolism , PPAR gamma/metabolism , Structure-Activity Relationship , Triglycerides/blood , Triglycerides/metabolismABSTRACT
Novel, potent inhibitors of dipeptidyl peptidase IV (DPP IV, EC 3.4.14.5, CD26), containing the fluoroolefin peptide isostere psi [CFz.dbnd6;C], have been prepared via the intermediacy of the Peterson fluoroolefination reaction. The nitrile containing inhibitors were found to inhibit dipeptidyl peptidase IV competitively with K(i) values for the l-3 and u-3 inhibitors of 7.69 and 6.03 microM, respectively. In contrast to earlier reported fluoroolefin containing inhibitors, the nitriles underwent no detectable degradation at pH 7.6 under buffered conditions.
