Heterocyclic Allylsulfones as Latent Heteroaryl Nucleophiles in Palladium-Catalyzed Cross-Coupling Reactions.

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.

Catalyst Selection Facilitates the Use of Heterocyclic Sulfinates as General Nucleophilic Coupling Partners in Palladium-Catalyzed Coupling Reactions.

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.

Pyridine sulfinates as general nucleophilic coupling partners in palladium-catalyzed cross-coupling reactions with aryl halides.

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).

A Small-Molecule Anti-secretagogue of PCSK9 Targets the 80S Ribosome to Inhibit PCSK9 Protein Translation.

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.

One-Step Synthesis of Sulfonamides from N-Tosylhydrazones.

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.

Discovery of 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999): A Highly Selective Mechanism-Based Myeloperoxidase Inhibitor for the Treatment of Cardiovascular Diseases.

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.

Synthesis of sulfones from organozinc reagents, DABSO, and alkyl halides.

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.

Insights into the novel hydrolytic mechanism of a diethyl 2-phenyl-2-(2-arylacetoxy)methyl malonate ester-based microsomal triglyceride transfer protein (MTP) inhibitor.

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.

Discovery of triazolopyrimidine-based PDE8B inhibitors: exceptionally ligand-efficient and lipophilic ligand-efficient compounds for the treatment of diabetes.

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.

1,5-Substituted nipecotic amides: selective PDE8 inhibitors displaying diastereomer-dependent microsomal stability.

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.

(3R,4S)-4-(2,4,5-Trifluorophenyl)-pyrrolidin-3-ylamine inhibitors of dipeptidyl peptidase IV: synthesis, in vitro, in vivo, and X-ray crystallographic characterization.

A series of pyrrolidine based inhibitors of dipeptidyl peptidase IV were developed from a high throughput screening hit for the treatment of type 2 diabetes. Potency, selectivity, and pharmacokinetic properties were optimized resulting in the identification of a pre-clinical candidate for further profiling.