ABSTRACT
GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been a target of significant recent therapeutic interest for type II diabetes. Activation of GPR40 by partial agonists elicits insulin secretion only in the presence of elevated blood glucose levels, minimizing the risk of hypoglycemia. GPR40 agoPAMs have shown superior efficacy to partial agonists as assessed in a glucose tolerability test (GTT). Herein, we report the discovery and optimization of a series of potent, selective GPR40 agoPAMs. Compound 24 demonstrated sustained glucose lowering in a chronic study of Goto Kakizaki rats, showing no signs of tachyphylaxis for this mechanism.
ABSTRACT
The design, synthesis, SAR, and biological profile of a substituted 4-morpholine sulfonamide series of γ-secretase inhibitors (GSIs) were described. In several cases, the resulting series of GSIs reduced CYP liabilities and improved γ-secretase inhibition activity compared to our previous research series. Selected compounds demonstrated significant reduction of amyloid-ß (Aß) after acute oral dosing in a transgenic animal model of Alzheimer's disease (AD).
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Morpholines/chemistry , Morpholines/pharmacology , Sulfonamides/chemistry , Alzheimer Disease/drug therapy , Animals , Enzyme Inhibitors/therapeutic use , Female , Male , Mice , Morpholines/therapeutic use , Structure-Activity RelationshipABSTRACT
We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.
ABSTRACT
The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.
Subject(s)
Enzyme Inhibitors/pharmacology , Imines/pharmacology , Pyrimidinones/pharmacology , Renin/antagonists & inhibitors , Administration, Oral , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Imines/chemical synthesis , Imines/chemistry , Models, Molecular , Molecular Structure , Pyrimidinones/chemical synthesis , Pyrimidinones/chemistry , Renin/metabolism , Structure-Activity RelationshipABSTRACT
An investigation is detailed of the structure activity relationships (SAR) of two sulfone side chains of compound (-)-1a (SCH 900229), a potent, PS1-selective γ-secretase inhibitor and clinical candidate for the treatment of Alzheimer's disease. Specifically, 4-CF(3) and 4-Br substituted arylsulfone analogs, (-)-1b and (-)-1c, are equipotent to compound (-)-1a. On the right hand side chain, linker size and terminal substituents of the pendant sulfone group are also investigated.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Benzopyrans/chemical synthesis , Benzopyrans/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Sulfones/chemical synthesis , Sulfones/pharmacology , Benzopyrans/chemistry , Cyclization , Enzyme Activation/drug effects , Humans , Inhibitory Concentration 50 , Molecular Structure , Pyrans/chemical synthesis , Pyrans/chemistry , Pyrans/pharmacology , Structure-Activity Relationship , Sulfones/chemistryABSTRACT
An exploration of the SAR of the side chain of a novel tricyclic series of γ-secretase inhibitors led to the identification of compound (-)-16 (SCH 900229), which is a potent and PS1 selective inhibitor of γ-secretase (Aß40 IC50 = 1.3 nM). Compound (-)-16 demonstrated excellent lowering of Aß after oral administration in preclinical animal models and was advanced to human clinical trials for further development as a therapeutic agent for the treatment of Alzheimer's disease.
ABSTRACT
A novel series of tricyclic gamma-secretase inhibitors was designed and synthesized via a conformational analysis of literature compounds. The preliminary results have shown that compounds in this new series have much improved in vitro potency and in vivo profiles. More importantly, they have greatly reduced Notch related toxicity that was associated with previous gamma-secretase inhibitors.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Receptors, Notch/drug effects , Sulfones/chemistry , Sulfones/pharmacology , Animals , Crystallography, X-Ray , Drug Design , Mice , Models, Molecular , Sulfones/chemical synthesisABSTRACT
A new class of 2,6-disubstituted morpholine N-arylsulfonamide gamma-secretase inhibitors was designed based on the introduction of a morpholine core in lieu or piperidine in our lead series. This resulted in compounds with improved CYP 3A4 profiles. Several analogs that were active at lowering Abeta levels in Tg CRND8 mice upon oral administration were identified.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Cytochrome P-450 CYP3A Inhibitors , Enzyme Inhibitors/chemistry , Morpholines/chemistry , Sulfonamides/chemistry , Administration, Oral , Amyloid Precursor Protein Secretases/metabolism , Animals , Cytochrome P-450 CYP3A/metabolism , Disease Models, Animal , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Humans , Mice , Mice, Transgenic , Morpholines/chemical synthesis , Morpholines/pharmacokinetics , Rats , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokineticsABSTRACT
The design and development of a new class of small 2,6-disubstituted piperidine N-arylsulfonamide gamma-secretase inhibitors is reported. Lowering molecular weight including the use of conformational constraint led to compounds with less CYP 3A4 liability compared to early leads. Compounds active orally in lowering Abeta levels in Tg CRND8 mice were identified as potential treatments for Alzheimer's disease.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Piperidines/chemical synthesis , Piperidines/pharmacology , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Administration, Oral , Amyloid beta-Peptides/biosynthesis , Animals , Area Under Curve , Cytochrome P-450 Enzyme System/metabolism , Drug Design , Magnetic Resonance Spectroscopy , Mice , Molecular Conformation , Molecular Weight , Oxidoreductases/metabolismABSTRACT
Development of cis-2,4,6-trisubstituted piperidine N-arylsulfonamides as gamma-secretase inhibitors for the potential treatment of Alzheimer's disease (AD) is reported.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Cytochrome P-450 CYP3A/drug effects , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Molecular Structure , Piperidines/chemistry , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
Attachment of the cyclopropylcarbamate group to the piperidine core of gamma-secretase inhibitors leads to a dramatic increase of their in vitro potency. Strategies for subsequent improvement of the in vivo pharmacokinetic profile of the series are discussed. Resulting compounds significantly reduce Abeta levels in TgCRND8 mice after a single PO dosing at 30 mpk.
