ABSTRACT
The discovery of a pan-genotypic hepatitis C virus (HCV) NS3/4A protease inhibitor based on a P1-P3 macrocyclic tripeptide motif is described. The all-carbon tether linking the P1-P3 subsites of 21 is functionalized with alkyl substituents, which are shown to effectively modulate both potency and absorption, distribution, metabolism, and excretion (ADME) properties. The CF3Boc-group that caps the P3 amino moiety was discovered to be an essential contributor to metabolic stability, while positioning a methyl group at the C1 position of the P1' cyclopropyl ring enhanced plasma trough values following oral administration to rats. The C7-fluoro, C6-CD3O substitution pattern of the P2* isoquinoline heterocycle of 21 was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CD3O redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CH3O prototype.
Subject(s)
Antiviral Agents/pharmacology , Peptides, Cyclic/pharmacology , Serine Proteinase Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Antiviral Agents/pharmacokinetics , CHO Cells , Cricetulus , Drug Discovery , Drug Stability , Hepacivirus/drug effects , Hepacivirus/enzymology , Microbial Sensitivity Tests , Microsomes, Liver/metabolism , Molecular Structure , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/metabolism , Peptides, Cyclic/pharmacokinetics , Rats , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/metabolism , Serine Proteinase Inhibitors/pharmacokinetics , Structure-Activity RelationshipABSTRACT
Naphthalene-linked P2-P4 macrocycles within a tri-peptide-based acyl sulfonamide chemotype have been synthesized and found to inhibit HCV NS3 proteases representing genotypes 1a and 1b with single digit nanomolar potency. The pharmacokinetic profile of compounds in this series was optimized through structural modifications along the macrocycle tether as well as the P1 subsite. Ultimately a compound with oral bioavailability of 100% in rat, and a long half-life in plasma was obtained. However, compounds in this macrocyclic series exhibited cardiac effects in an isolated rabbit heart model and for this reason further optimization efforts were discontinued.
Subject(s)
Antiviral Agents/chemistry , Macrocyclic Compounds/chemistry , Naphthalenes/chemistry , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Animals , Antiviral Agents/pharmacology , Drug Evaluation, Preclinical , Half-Life , Heart/drug effects , Heart/physiology , Hepacivirus/drug effects , Hepacivirus/enzymology , Macrocyclic Compounds/pharmacokinetics , Macrocyclic Compounds/pharmacology , Microsomes, Liver/metabolism , Molecular Conformation , Protease Inhibitors/pharmacokinetics , Protease Inhibitors/pharmacology , Rabbits , Rats , Viral Nonstructural Proteins/metabolismABSTRACT
Current antithrombotic discovery efforts target compounds that are highly efficacious in thrombus reduction with less bleeding liability than the standard of care. Preclinical data suggest that P2Y1 antagonists may have lower bleeding liabilities than P2Y12 antagonists while providing similar antithrombotic efficacy. This article describes our continuous SAR efforts in a series of 7-hydroxyindolinyl diaryl ureas. When dosed orally, 4-trifluoromethyl-7-hydroxy-3,3-dimethylindolinyl analogue 4 was highly efficacious in a model of arterial thrombosis in rats with limited bleeding. The chemically labile CF3 group in 4 was then transformed to various groups via a novel one-step synthesis, yielding a series of potent P2Y1 antagonists. Among them, the 4-benzothiazole-substituted indolines had desirable PK properties in rats, specifically, low clearance and small volume of distribution. In addition, compound 40 had high i.v. exposure and modest bioavailability, giving it the best overall profile.
Subject(s)
Purinergic P2Y Receptor Antagonists/pharmacology , Urea/analogs & derivatives , Animals , Humans , Magnetic Resonance Spectroscopy , Purinergic P2Y Receptor Antagonists/pharmacokinetics , Spectrometry, Mass, Electrospray Ionization , Urea/pharmacokinetics , Urea/pharmacologyABSTRACT
Spiropiperidine indoline-substituted diaryl ureas had been identified as antagonists of the P2Y1 receptor. Enhancements in potency were realized through the introduction of a 7-hydroxyl substitution on the spiropiperidinylindoline chemotype. SAR studies were conducted to improve PK and potency, resulting in the identification of compound 3e, a potent, orally bioavailable P2Y1 antagonist with a suitable PK profile in preclinical species. Compound 3e demonstrated a robust antithrombotic effect in vivo and improved bleeding risk profile compared to the P2Y12 antagonist clopidogrel in rat efficacy/bleeding models.
Subject(s)
Phenylurea Compounds/chemistry , Platelet Aggregation Inhibitors/chemistry , Purinergic P2Y Receptor Antagonists/chemistry , Receptors, Purinergic P2Y1/chemistry , Thiazoles/chemistry , Urea/analogs & derivatives , Administration, Oral , Animals , Dogs , Half-Life , Macaca fascicularis , Phenylurea Compounds/pharmacokinetics , Phenylurea Compounds/pharmacology , Phenylurea Compounds/therapeutic use , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation Inhibitors/therapeutic use , Purinergic P2Y Receptor Antagonists/pharmacokinetics , Purinergic P2Y Receptor Antagonists/pharmacology , Purinergic P2Y Receptor Antagonists/therapeutic use , Rats , Receptors, Purinergic P2Y1/metabolism , Structure-Activity Relationship , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Thiazoles/therapeutic use , Thrombosis/drug therapy , Urea/pharmacokinetics , Urea/pharmacology , Urea/therapeutic useABSTRACT
Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y1 antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y12 antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound 1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y1 antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound 3l will also be presented. Compound 3l was our first P2Y1 antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models.
Subject(s)
Drug Design , Molecular Conformation , Phenylurea Compounds/pharmacology , Phenylurea Compounds/pharmacokinetics , Purinergic P2Y Receptor Antagonists/pharmacology , Purinergic P2Y Receptor Antagonists/pharmacokinetics , Receptors, Purinergic P2Y1/metabolism , Spiro Compounds/pharmacology , Spiro Compounds/pharmacokinetics , Urea/pharmacology , Urea/pharmacokinetics , Animals , Biological Availability , Humans , Indoles/chemistry , Models, Molecular , Phenylurea Compounds/chemistry , Phenylurea Compounds/metabolism , Purinergic P2Y Receptor Antagonists/chemistry , Purinergic P2Y Receptor Antagonists/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Purinergic P2Y1/chemistry , Sequence Homology, Amino Acid , Spiro Compounds/chemistry , Spiro Compounds/metabolism , Urea/chemistry , Urea/metabolismABSTRACT
This article describes the details of our synthetic studies toward the complex marine alkaloid sarain A. Various strategies were conceived, setbacks encountered, and solutions developed, ultimately leading to a successful enantioselective total synthesis. Our route to (+)-sarain A features a number of key steps, including an asymmetric Michael addition to install the C4'-C3'-C7' stereotriad, an enoxysilane-N-sulfonyliminium ion cyclization to set the C3 quaternary carbon stereocenter, and assemble the diazatricycloundecane core, a ring-closing metathesis to construct the 13-membered ring, an intramolecular Stille coupling to fashion the unsaturated 14-membered macrocycle, and a late-stage installation of the tertiary amine-aldehyde proximity interaction.
Subject(s)
Bridged-Ring Compounds/chemical synthesis , Alkaloids/chemical synthesis , Alkaloids/chemistry , Alkanes/chemical synthesis , Animals , Bridged-Ring Compounds/chemistry , Cyclization , Models, Molecular , Porifera , StereoisomerismABSTRACT
The previously unknown stereoisomers 3, 4, ent-1, and ent-4 of the tris(pyrrolidinoindoline) alkaloids hodgkinsine (1) and hodgkinsine B (2) were prepared by stereocontrolled total synthesis. In each synthesis, a catalyst-controlled intramolecular Heck reaction was the key step in appending a third cis-pyrrolidinoindoline ring to a hexacyclic chimonanthine precursor. Results of the preliminary evaluation of these hodgkinsine stereoisomers in the tail flick and capsaicin pain models are reported.
Subject(s)
Alkaloids/chemical synthesis , Analgesics, Non-Narcotic/chemical synthesis , Indoles/chemical synthesis , Alkaloids/chemistry , Alkaloids/pharmacology , Alkaloids/therapeutic use , Analgesics, Non-Narcotic/chemistry , Analgesics, Non-Narcotic/pharmacology , Analgesics, Non-Narcotic/therapeutic use , Animals , Disease Models, Animal , Indoles/chemistry , Indoles/pharmacology , Indoles/therapeutic use , Mice , Molecular Structure , Pain/drug therapy , Stereoisomerism , ThermodynamicsABSTRACT
A high-yielding N-sulfonyliminium ion-enoxysilane cyclization and a ring-closing metathesis are key steps in the enantioselective synthesis of late-stage intermediates en route to sarain A. Also revealed is an unprecedented rearrangement of the tetracyclic sarain A core under mildly acidic conditions. [structure: see text]
Subject(s)
Bridged-Ring Compounds/chemistry , Bridged-Ring Compounds/chemical synthesis , Catalysis , Cyclization , Indicators and Reagents , Molecular Structure , StereoisomerismABSTRACT
We have explored the scope of the palladium-catalyzed nucleophilic ring opening methodology. New highly selective and highly active catalysts have been found for the ring opening of oxabenzonorbornadienes. Employing these catalysts, the addition of various alkyl nucleophiles to oxabenzonorbornadiene has been achieved. In addition, reaction of diethylzinc with [3.2.1] oxabicyclic alkenes has been accomplished to yield ring-opened products as well as functionalized alkene addition products.
ABSTRACT
Over the past five years, several metal-catalyzed asymmetric ring-cleaving reactions have been developed that generate ring-opened products in high yield and enantiomeric excess. These reactions can be carried out with a range of nucleophiles including hydride, stabilized and nonstabilized carbanions, alcohols, amines, and carboxylates. To achieve these results, three different transition metals have been employed, namely nickel, palladium, and rhodium, leading not only to synthetically useful transformations but also to a greater understanding of the reaction manifolds possible with these metals. This Account covers the work by our group and by others toward the development of new metal-catalyzed asymmetric ring-opening reactions of oxabicyclic alkenes.
ABSTRACT
[structure: see text] The total synthesis of the polyether antibiotic ionomycin, a calcium ionophore, is described. The synthesis demonstrates the utility of ring-opening methodologies as applied to the synthesis of polypropionate and deoxypolypropionate subunits, which are found in two of the four fragments in the synthesis.