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1.
J Am Chem Soc ; 140(46): 15916-15923, 2018 11 21.
Article in English | MEDLINE | ID: mdl-30412397

ABSTRACT

Heterocyclic sulfinates are effective reagents in palladium-catalyzed coupling reactions with aryl and heteroaryl halides, often providing high yields of the targeted biaryl. However, the preparation and purification of complex heterocylic sulfinates can be problematic. In addition, sulfinate functionality is not tolerant of the majority of synthetic transformations, making these reagents unsuitable for multistep elaboration. Herein, we show that heterocyclic allylsulfones can function as latent sulfinate reagents and, when treated with a Pd(0) catalyst and an aryl halide, undergo deallylation, followed by efficient desulfinylative cross-coupling. A broad range of allyl heteroarylsulfones are conveniently prepared, using several complementary routes, and are shown to be effective coupling partners with a variety of aryl and heteroaryl halides. We demonstrate that the allylsulfone functional group can tolerate a range of standard synthetic transformations, including orthogonal C- and N-coupling reactions, allowing multistep elaboration. The allylsulfones are successfully coupled with a variety of medicinally relevant substrates, demonstrating their applicability in demanding cross-coupling transformations. In addition, pharmaceutical agents crizotinib and etoricoxib were prepared using allyl heteroaryl sulfone coupling partners, further demonstrating the utility of these new reagents.

3.
Org Lett ; 19(22): 6033-6035, 2017 11 17.
Article in English | MEDLINE | ID: mdl-29043813

ABSTRACT

A range of 5- and 6-membered heterocycle-derived sulfinates are shown to be effective nucleophilic coupling partners with aryl chlorides and bromides using Pd(0) catalysis. The use of optimal reaction conditions, specifically incorporating a P(t-Bu)2Me-derived Pd catalyst, allowed reactions to be performed at moderate temperatures and enabled the inclusion of a variety of sensitive functional groups. Challenging heterocyclic sulfinates, including pyrazine, pyridazine, pyrimidine, pyrazole, and imidazole, were all shown to perform well.

4.
Chem Sci ; 8(6): 4437-4442, 2017 Jun 01.
Article in English | MEDLINE | ID: mdl-28936330

ABSTRACT

Pyridine rings are ubiquitous in drug molecules; however, the pre-eminent reaction used to form carbon-carbon bonds in the pharmaceutical industry, the Suzuki-Miyaura cross-coupling reaction, often fails when applied to these structures. This phenomenon is most pronounced in 2-substituted pyridines, and results from the difficulty in preparing, the poor stability of, and low efficiency in reactions of pyridine-2-boronates. We demonstrate that by replacing these boronates with pyridine-2-sulfinates, a cross-coupling process of unrivalled scope and utility is realized. The corresponding 3- and 4-substituted pyridine variants are also efficient coupling partners. In addition, we apply these sulfinates in a library format to the preparation of medicinally relevant derivatives of the drugs varenicline (Chantix) and mepyramine (Anthisan).

5.
Cell Chem Biol ; 23(11): 1362-1371, 2016 Nov 17.
Article in English | MEDLINE | ID: mdl-27746128

ABSTRACT

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that downregulates low-density lipoprotein (LDL) receptor (LDL-R) levels on the surface of hepatocytes, resulting in decreased clearance of LDL-cholesterol (LDL-C). Phenotypic screening of a small-molecule compound collection was used to identify an inhibitor of PCSK9 secretion, (R)-N-(isoquinolin-1-yl)-3-(4-methoxyphenyl)-N-(piperidin-3-yl)propanamide (R-IMPP), which was shown to stimulate uptake of LDL-C in hepatoma cells by increasing LDL-R levels, without altering levels of secreted transferrin. Systematic investigation of the mode of action revealed that R-IMPP did not decrease PCSK9 transcription or increase PCSK9 degradation, but instead caused transcript-dependent inhibition of PCSK9 translation. In support of this surprising mechanism of action, we found that R-IMPP was able to selectively bind to human, but not E. coli, ribosomes. This study opens a new avenue for the development of drugs that modulate the activity of target proteins by mechanisms involving inhibition of eukaryotic translation.


Subject(s)
Isoquinolines/pharmacology , PCSK9 Inhibitors , Proprotein Convertase 9/metabolism , Protein Biosynthesis/drug effects , Ribosomes/drug effects , Small Molecule Libraries/pharmacology , Cell Line, Tumor , Humans , Isoquinolines/chemistry , Ribosomes/metabolism , Small Molecule Libraries/chemistry
6.
Org Lett ; 18(3): 508-11, 2016 Feb 05.
Article in English | MEDLINE | ID: mdl-26771228

ABSTRACT

The first described reaction between N-tosylhydrazone and SO2 is reported to provide alkyl sulfonamides in the presence of various amines. In this procedurally simple method, hydrazones of both unsaturated aldehydes and ketones proceed in moderate to excellent yields. Primary and secondary aliphatic amines are accommodated in this reaction, which provides a novel route to sulfonamides.


Subject(s)
Hydrazones/chemistry , Sulfonamides/chemical synthesis , Aldehydes/chemistry , Amines/chemistry , Catalysis , Ketones/chemistry , Molecular Structure , Sulfonamides/chemistry , Sulfur Dioxide/chemistry
7.
J Med Chem ; 58(21): 8513-28, 2015 Nov 12.
Article in English | MEDLINE | ID: mdl-26509551

ABSTRACT

Myeloperoxidase (MPO) is a heme peroxidase that catalyzes the production of hypochlorous acid. Clinical evidence suggests a causal role for MPO in various autoimmune and inflammatory disorders including vasculitis and cardiovascular and Parkinson's diseases, implying that MPO inhibitors may represent a therapeutic treatment option. Herein, we present the design, synthesis, and preclinical evaluation of N1-substituted-6-arylthiouracils as potent and selective inhibitors of MPO. Inhibition proceeded in a time-dependent manner by a covalent, irreversible mechanism, which was dependent upon MPO catalysis, consistent with mechanism-based inactivation. N1-Substituted-6-arylthiouracils exhibited low partition ratios and high selectivity for MPO over thyroid peroxidase and cytochrome P450 isoforms. N1-Substituted-6-arylthiouracils also demonstrated inhibition of MPO activity in lipopolysaccharide-stimulated human whole blood. Robust inhibition of plasma MPO activity was demonstrated with the lead compound 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999, 8) upon oral administration to lipopolysaccharide-treated cynomolgus monkeys. On the basis of its pharmacological and pharmacokinetic profile, PF-06282999 has been advanced to first-in-human pharmacokinetic and safety studies.


Subject(s)
Acetamides/pharmacology , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/enzymology , Enzyme Inhibitors/pharmacology , Peroxidase/antagonists & inhibitors , Pyrimidinones/pharmacology , Acetamides/chemistry , Acetamides/pharmacokinetics , Animals , Drug Discovery , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Humans , Peroxidase/metabolism , Pyrimidinones/chemistry , Pyrimidinones/pharmacokinetics , Rats, Wistar
8.
Org Lett ; 16(1): 154-7, 2014 Jan 03.
Article in English | MEDLINE | ID: mdl-24308287

ABSTRACT

Organozinc reagents react with the SO2 surrogate DABSO, and the resulting zinc sulfinate salts are alkylated in situ to afford sulfones. This transformation has a broad scope and is compatible with a wide range of structural motifs of medicinal chemistry relevance including nitrile, secondary carbamates, and nitrogen-containing heterocycles.


Subject(s)
Dapsone/chemistry , Hydrocarbons, Halogenated/chemistry , Organometallic Compounds/chemistry , Sulfones/chemical synthesis , Zinc/chemistry , Molecular Structure , Sulfones/chemistry
9.
Chem Res Toxicol ; 25(10): 2138-52, 2012 Oct 15.
Article in English | MEDLINE | ID: mdl-22989032

ABSTRACT

Inhibition of intestinal and hepatic microsomal triglyceride transfer protein (MTP) is a potential strategy for the treatment of dyslipidemia and related metabolic disorders. Inhibition of hepatic MTP, however, results in elevated liver transaminases and increased hepatic fat deposition consistent with hepatic steatosis. Diethyl 2-((2-(3-(dimethylcarbamoyl)-4-(4'-(trifluoromethyl)-[1,1'-biphenyl]-2-ylcarboxamido)phenyl)acetoxy)methyl)-2-phenylmalonate (JTT-130) is an intestine-specific inhibitor of MTP and does not cause increases in transaminases in short-term clinical trials in patients with dyslipidemia. Selective inhibition of intestinal MTP is achieved via rapid hydrolysis of its ester linkage by liver-specific carboxylesterase(s), resulting in the formation of an inactive carboxylic acid metabolite 1. In the course of discovery efforts around tissue-specific inhibitors of MTP, the mechanism of JTT-130 hydrolysis was examined in detail. Lack of ¹8O incorporation in 1 following the incubation of JTT-130 in human liver microsomes in the presence of H2¹8O suggested that hydrolysis did not occur via a simple cleavage of the ester linkage. The characterization of atropic acid (2-phenylacrylic acid) as a metabolite was consistent with a hydrolytic pathway involving initial hydrolysis of one of the pendant malonate ethyl ester groups followed by decarboxylative fragmentation to 1 and the concomitant liberation of the potentially electrophilic acrylate species. Glutathione conjugates of atropic acid and its ethyl ester were also observed in microsomal incubations of JTT-130 that were supplemented with the thiol nucleophile. Additional support for the hydrolysis mechanism was obtained from analogous studies on diethyl 2-(2-(2-(3-(dimethylcarbamoyl)-4-(4'-trifluoromethyl)-[1,1'-biphenyl]-2-ylcarboxamido)phenyl)acetoxy)ethyl)-2-phenylmalonate (3), which cannot participate in hydrolysis via the fragmentation pathway because of the additional methylene group. Unlike the case with JTT-130, ¹8O was readily incorporated into 1 during the enzymatic hydrolysis of 3, suggestive of a mechanism involving direct hydrolytic cleavage of the ester group in 3. Finally, 3-(ethylamino)-2-(ethylcarbamoyl)-3-oxo-2-phenylpropyl 2-(3-(dimethylcarbamoyl)-4-(4'-(trifluoromethyl)-[1,1'-biphenyl]-2-ylcarboxamido)phenyl)acetate (4), which possessed an N,N-diethyl-2-phenylmalonamide substituent (in lieu of the diethyl-2-phenylmalonate motif in JTT-130) proved to be resistant to the hydrolytic cleavage/decarboxylative fragmentation pathway that yielded 1, a phenomenon that further confirmed our hypothesis. From a toxicological standpoint, it is noteworthy to point out that the liberation of the electrophilic acrylic acid species as a byproduct of JTT-130 hydrolysis is similar to the bioactivation mechanism established for felbamate, an anticonvulsant agent associated with idiosyncratic aplastic anemia and hepatotoxicity.


Subject(s)
Benzamides/metabolism , Carrier Proteins/antagonists & inhibitors , Malonates/metabolism , Microsomes, Liver/metabolism , Benzamides/pharmacology , Glutathione/metabolism , Humans , Hydrolysis , Malonates/pharmacology , Phenylpropionates/metabolism , Tandem Mass Spectrometry
10.
Bioorg Med Chem Lett ; 22(17): 5721-6, 2012 Sep 01.
Article in English | MEDLINE | ID: mdl-22858141

ABSTRACT

PDE8B is a cAMP-specific isoform of the broader class of phosphodiesterases (PDEs). As no selective PDE8B inhibitors had been reported, a high throughput screen was run with the goal of identifying selective tools for exploring the potential therapeutic utility of PDE8B inhibition. Of the numerous hits, one was particularly attractive since it was amenable to rapid deconstruction leading to inhibitors with very high ligand efficiency (LE) and lipophilic ligand efficiency (LLE). These triazolopyrimidines were optimized for potency, selectivity and ADME properties ultimately leading to compound 42. This compound was highly potent and selective with good bioavailability and advanced into pre-clinical development.


Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Diabetes Mellitus/enzymology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Animals , Cells, Cultured , Diabetes Mellitus/drug therapy , Drug Discovery , Enzyme Inhibitors/metabolism , High-Throughput Screening Assays , Humans , Insulin/metabolism , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Ligands , Microsomes, Liver/metabolism , Protein Binding , Pyrimidines/metabolism , Rats , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/metabolism , Triazoles/pharmacology
11.
Bioorg Med Chem Lett ; 21(10): 3095-8, 2011 May 15.
Article in English | MEDLINE | ID: mdl-21459572

ABSTRACT

The first highly potent and selective PDE8 inhibitors are disclosed. The initial tetrahydroisoquinoline hit was transformed into a nipecotic amide series in order to address a reactive metabolite issue. Reduction of lipophilicity to address metabolic liabilities uncovered an interesting diastereomer-dependent trend in turnover by human microsomes.


Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacology , Enzyme Inhibitors/pharmacology , Microsomes/drug effects , Nipecotic Acids/chemistry , Amides/chemistry , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Ligands , Models, Molecular , Molecular Structure
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