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1.
J Am Chem Soc ; 141(37): 14870-14877, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31449745

RESUMO

Controlling site selectivity of C-H activation without using a directing group remains a significant challenge. While Pd(II) catalysts modulated by a mutually repulsive pyridine-type ligand have been shown to favor the relatively electron-rich carbon centers of arenes, reversing the selectivity to favor palladation at the relatively electron-deficient positions has not been possible. Herein we report the first catalytic system that effectively performs meta C-H arylation of a variety of alkoxy aromatics including 2,3-dihydrobenzofuran and chromane with exclusive meta site selectivity, thus reversing the conventional site selectivity governed by native electronic effects. The identification of an effective ligand and modified norbornene (NBE-CO2Me), as well as taking advantage of the statistics, are essential for achieving the exclusive meta selectivity.

3.
Bioorg Med Chem Lett ; 29(15): 1918-1921, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31176700

RESUMO

A low level of high density lipoprotein (HDL) is an independent risk factor for cardiovascular disease. HDL reduces inflammation and plays a central role in reverse cholesterol transport, where cholesterol is removed from peripheral tissues and atherosclerotic plaque. One approach to increase plasma HDL is through inhibition of endothelial lipase (EL). EL hydrolyzes phospholipids in HDL resulting in reduction of plasma HDL. A series of benzothiazole sulfone amides was optimized for EL inhibition potency, lipase selectivity and improved pharmacokinetic profile leading to the identification of Compound 32. Compound 32 was evaluated in a mouse pharmacodynamic model and found to show no effect on HDL cholesterol level despite achieving targeted plasma exposure (Ctrough > 15 fold over mouse plasma EL IC50 over 4 days).

4.
Angew Chem Int Ed Engl ; 58(7): 2134-2138, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30536546

RESUMO

PdII -catalyzed enantioselective C(sp3 )-H cross-coupling of free carboxylic acids with organoborons has been realized using either mono-protected amino acid (MPAA) ligands or mono-protected aminoethyl amine (MPAAM) ligands. A diverse range of aryl- and vinyl-boron reagents can be used as coupling partners to provide chiral carboxylic acids. This reaction provides an alternative approach to the enantioselective synthesis of cyclopropanecarboxylic acids and cyclobutanecarboxylic acids containing α-chiral tertiary and quaternary stereocenters. The utility of this reaction was further demonstrated by converting the carboxylic acid into cyclopropyl amine without loss of optical activity.

5.
J Am Chem Soc ; 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30500192

RESUMO

L,X-type transient directing groups (TDG) based on a reversible imine linkage have emerged as broadly useful tools for C-H activation of ketones and free amines. However, competitive binding interactions among multiple reaction components (TDG itself, substrate, and substrate-TDG adduct) with the palladium catalyst often lead to the formation of multiple unreactive complexes, rendering ligand development extremely challenging. Herein we report the finding of versatile 2-pyridone ligands that addresses these problems and significantly improves the γ-methylene arylation of alkyl amines, extending the coupling partners to a wide range of medicinally important heteroaryl iodides and even previously unreactive heteroaryl bromides. The combination of an appropriate transient directing group and pyridone ligand has also enabled the δ-arylation of alkyl amines. Notably, our transient directing group design reveals the importance of matching the size of the Pd-chelation with different transient directing groups and the size of palladacycles generated from γ- and δ-C-H bonds: TDGs that coordinate with Pd(II) to form a 6-membered chelate are selective toward γ-C-H bonds, whereas TDGs that coordinate with Pd(II) via a 5-membered chelate tend to activate δ-C-H bonds. These findings provide an avenue for developing protecting group free and selective C-H functionalization using the transient directing group strategy.

6.
Bioorg Med Chem Lett ; 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30348490

RESUMO

Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides. Several compounds were advanced to PK evaluation. Among them, compound 4a was one of the most potent with measurable ELHDL hSerum potency and compound 3g demonstrated the best overall pharmacokinetic parameters.

7.
Angew Chem Int Ed Engl ; 57(44): 14560-14565, 2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-30212610

RESUMO

The direct union of primary, secondary, and tertiary carboxylic acids with a chiral glyoxylate-derived sulfinimine provides rapid access into a variety of enantiomerically pure α-amino acids (>85 examples). Characterized by operational simplicity, this radical-based reaction enables the modular assembly of exotic α-amino acids, including both unprecedented structures and those of established industrial value. The described method performs well in high-throughput library synthesis, and has already been implemented in three distinct medicinal chemistry campaigns.

8.
J Am Chem Soc ; 140(32): 10363-10367, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30029574

RESUMO

An acetyl-protected aminoethyl phenyl thioether has been developed to promote C(sp3)-H activation. Significant ligand enhancement is demonstrated by the realization of the first Pd(II)-catalyzed olefination of C(sp3)-H bonds of free carboxylic acids without using an auxiliary. Subsequent lactonization of the olefinated product via 1,4 addition provided exclusively monoselectivity in the presence of multiple ß-C-H bonds. The product γ-lactone can be readily opened to give either the highly valuable ß-olefinated or γ-hydroxylated aliphatic acids. Considering the challenges in developing Heck couplings using alkyl halides, this reaction offers a useful alternative.

9.
J Org Chem ; 83(8): 4323-4335, 2018 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-29537839

RESUMO

Macrocyclic peptides containing N-alkylated amino acids have emerged as a promising therapeutic modality, capable of modulating protein-protein interactions and an intracellular delivery of hydrophilic payloads. While multichannel automated solid-phase peptide synthesis (SPPS) is a practical approach for peptide synthesis, the requirement for slow and inefficient chromatographic purification of the product peptides is a significant limitation to exploring these novel compounds. Herein, we invent a "catch-release" strategy for the nonchromatographic purification of macrocyclic peptides. A traceless catch process is enabled by the invention of a dual-functionalized N-terminal acetate analogue, which serves as a handle for capture onto a purification resin and as a leaving group for macrocyclization. Displacement by a C-terminal nucleophilic side chain thus releases the desired macrocycle from the purification resin. By design, this catch/release process is a logic test for the presence of the key components required for cyclization, thus removing impurities which lack the required functionality, such as common classes of peptide impurities, including hydrolysis fragments and truncated sequences. The method was shown to be highly effective with three libraries of macrocyclic peptides, containing macrocycles of 5-20 amino acids, with either thioether- or amine-based macrocyclic linkages; in this latter class, the reported method represents an enabling technology. In all cases, the catch-release protocol afforded significant enrichment of the target peptides purity, in many cases completely obviating the need for chromatography. Importantly, we have adapted this process for automation on a standard multichannel peptide synthesizer, achieving an efficient and completely integrated synthesis and purification platform for the preparation of these important molecules.

10.
Nat Chem ; 10(2): 205-211, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29359756

RESUMO

The advent of antibody-drug conjugates as pharmaceuticals has fuelled a need for reliable methods of site-selective protein modification that furnish homogeneous adducts. Although bioorthogonal methods that use engineered amino acids often provide an elegant solution to the question of selective functionalization, achieving homogeneity using native amino acids remains a challenge. Here, we explore visible-light-mediated single-electron transfer as a mechanism towards enabling site- and chemoselective bioconjugation. Specifically, we demonstrate the use of photoredox catalysis as a platform to selectivity wherein the discrepancy in oxidation potentials between internal versus C-terminal carboxylates can be exploited towards obtaining C-terminal functionalization exclusively. This oxidation potential-gated technology is amenable to endogenous peptides and has been successfully demonstrated on the protein insulin. As a fundamentally new approach to bioconjugation this methodology provides a blueprint toward the development of photoredox catalysis as a generic platform to target other redox-active side chains for native conjugation.

11.
J Pharm Sci ; 107(5): 1352-1360, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29317226

RESUMO

BMS-A is an inhibitor of cholesteryl ester transfer protein and is a highly lipophilic compound (clogP 10.5) with poor aqueous solubility (<0.0001 mg/mL at pH 6.5). The compound exhibits low oral exposure when dosed as cosolvent solution formulations. The purpose of this study was to evaluate lipid-based formulations for enabling high-dose toxicology studies and enhancing toxicology margins of BMS-A in preclinical studies in nonrodent species. The solubility of BMS-A was screened in lipid and cosolvent/surfactant excipients, and prototype formulations were developed. In vitro tests showed that fine/microemulsions were formed after aqueous dilution of lipid formulations, and BMS-A was transferred from oil phase to aqueous phase with enhanced solubility following lipid digestion. When dosed in dogs at 200 mg/kg, a Gelucire-based formulation exhibited more than 10-fold higher exposure compared to the solution formulation and was thus selected for toxicology studies in dogs. For monkeys, an olive oil formulation was developed, and the exposure was about 7-fold higher than that from the solution. In summary, lipid-based drug delivery could be applied in early stages of drug discovery to enhance oral exposure and enable preclinical toxicology studies of highly lipophilic compounds, while facilitating the candidate selection of a molecule which is more specifically designed for bioperformance in a lipid-based drug delivery strategy.

12.
Nature ; 551(7681): 489-493, 2017 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-29168802

RESUMO

The directed activation of carbon-hydrogen bonds (C-H) is important in the development of synthetically useful reactions, owing to the proximity-induced reactivity and selectivity that is enabled by coordinating functional groups. Palladium-catalysed non-directed C-H activation could potentially enable further useful reactions, because it can reach more distant sites and be applied to substrates that do not contain appropriate directing groups; however, its development has faced substantial challenges associated with the lack of sufficiently active palladium catalysts. Currently used palladium catalysts are reactive only with electron-rich arenes, unless an excess of arene is used, which limits synthetic applications. Here we report a 2-pyridone ligand that binds to palladium and accelerates non-directed C-H functionalization with arene as the limiting reagent. This protocol is compatible with a broad range of aromatic substrates and we demonstrate direct functionalization of advanced synthetic intermediates, drug molecules and natural products that cannot be used in excessive quantities. We also developed C-H olefination and carboxylation protocols, demonstrating the applicability of our methodology to other transformations. The site selectivity in these transformations is governed by a combination of steric and electronic effects, with the pyridone ligand enhancing the influence of sterics on the selectivity, thus providing complementary selectivity to directed C-H functionalization.


Assuntos
Carbono/química , Hidrocarbonetos Aromáticos/química , Hidrogênio/química , Piridonas/química , Alcenos/química , Produtos Biológicos/química , Catálise , Ligantes , Paládio/química , Preparações Farmacêuticas/química
13.
Org Lett ; 19(22): 6196-6199, 2017 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-29115835

RESUMO

Tetrachloro-N-hydroxyphthalimide tetramethyluronium hexafluorophosphate (CITU) is disclosed as a convenient and economical reagent for both acylation and decarboxylative cross-coupling chemistries. Within the former set of reactions, CITU displays reactivity similar to that of common coupling reagents, but with increased safety and reduced cost. Within the latter, increased yields, more rapid conversion, and a simplified procedure are possible across a range of reported decarboxylative transformations.


Assuntos
Peptídeos/química , Acilação , Indicadores e Reagentes , Estrutura Molecular
14.
Angew Chem Int Ed Engl ; 56(36): 10924-10927, 2017 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-28714148

RESUMO

The palladium(II)-catalyzed C(sp3 )-H alkynylation of oligopeptides was developed with tetrabutylammonium acetate as a key additive. Through molecular design, the acetylene motif served as a linchpin to introduce a broad range of carbonyl-containing pharmacophores onto oligopeptides, thus providing a chemical tool for the synthesis and modification of novel oligopeptide-pharmacophore conjugates by C-H functionalization. Dipeptide conjugates with coprostanol and estradiol were synthesized by this method for potential application in targeted drug delivery to tumor cells with overexpressed nuclear hormone receptors.

15.
Science ; 355(6324): 499-503, 2017 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-28154075

RESUMO

The enzymatic ß-C-H hydroxylation of the feedstock chemical isobutyric acid has enabled the asymmetric synthesis of a wide variety of polyketides. The analogous transition metal-catalyzed enantioselective ß-C-H functionalization of isobutyric acid-derived substrates should provide a versatile method for constructing useful building blocks with enantioenriched α-chiral centers from this abundant C-4 skeleton. However, the desymmetrization of ubiquitous isopropyl moieties by organometallic catalysts has remained an unanswered challenge. Herein, we report the design of chiral mono-protected aminomethyl oxazoline ligands that enable desymmetrization of isopropyl groups via palladium insertion into the C(sp3)-H bonds of one of the prochiral methyl groups. We detail the enantioselective ß-arylation, -alkenylation, and -alkynylation of isobutyric acid/2-aminoisobutyric acid derivatives, which may serve as a platform for the construction of α-chiral centers.

16.
Angew Chem Int Ed Engl ; 56(3): 728-732, 2017 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-27860140

RESUMO

A method for the decarboxylative macrocyclization of peptides bearing N-terminal Michael acceptors has been developed. This synthetic method enables the efficient synthesis of cyclic peptides containing γ-amino acids and is tolerant of functionalities present in both natural and non-proteinogenic amino acids. Linear precursors ranging from 3 to 15 amino acids cyclize effectively under this photoredox method. To demonstrate the preparative utility of this method in the context of bioactive molecules, we synthesized COR-005, a somatostatin analogue that is currently in clinical trials.


Assuntos
Peptídeos/síntese química , Catálise , Ciclização , Descarboxilação , Substâncias Macromoleculares/síntese química , Substâncias Macromoleculares/química , Estrutura Molecular , Oxirredução , Peptídeos/química , Processos Fotoquímicos
17.
J Org Chem ; 81(19): 9499-9506, 2016 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-27615449

RESUMO

A one-step synthesis of Fmoc-protected aryl/heteroaryl-substituted phenylalanines (Bip derivatives) using the nonaqueous palladium-catalyzed Suzuki-Miyaura cross-coupling (SMC) reaction of Fmoc-protected bromo- or iodophenylalanines is reported. This protocol allows for the direct formation of a variety of unnatural biaryl-containing amino acids in good to excellent yield, which can be readily used in subsequent Fmoc solid-phase peptide synthesis. The synthetic utility of this method is also demonstrated by the SMC reaction of bromophenylalanine-containing tripeptides.

18.
J Med Chem ; 58(22): 9010-26, 2015 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-26524347

RESUMO

Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies.


Assuntos
Anticolesterolemiantes/síntese química , Anticolesterolemiantes/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Benzilaminas/síntese química , Benzilaminas/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Animais , Anticolesterolemiantes/farmacocinética , Aterosclerose/tratamento farmacológico , Benzamidas/farmacocinética , Benzilaminas/farmacocinética , Pressão Sanguínea/efeitos dos fármacos , Linhagem Celular , Colesterol/metabolismo , HDL-Colesterol/sangue , Cricetinae , Citocromo P-450 CYP11B2/antagonistas & inibidores , Cães , Descoberta de Drogas , Humanos , Macaca fascicularis , Masculino , Mesocricetus , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Quinolinas/farmacologia , Ratos , Ratos Sprague-Dawley
19.
ChemMedChem ; 9(10): 2327-43, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24989964

RESUMO

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.


Assuntos
Antagonistas do Receptor Purinérgico P2Y/farmacologia , Ureia/análogos & derivados , Animais , Humanos , Espectroscopia de Ressonância Magnética , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Espectrometria de Massas por Ionização por Electrospray , Ureia/farmacocinética , Ureia/farmacologia
20.
Bioorg Med Chem Lett ; 24(15): 3341-5, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24951330

RESUMO

In an effort to identify a potential back-up to apixaban (Eliquis®), we explored a series of diversified P4 moieties. Several analogs with substituted gem-dimethyl moieties replacing the terminal lactam of apixaban were identified which demonstrated potent FXa binding affinity (FXa Ki), good human plasma anticoagulant activity (PT EC2x), cell permeability, and oral bioavailability.


Assuntos
Inibidores do Fator Xa/farmacologia , Fator Xa/metabolismo , Pirazóis/farmacologia , Piridonas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Permeabilidade da Membrana Celular/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/química , Humanos , Estrutura Molecular , Pirazóis/administração & dosagem , Pirazóis/química , Piridonas/administração & dosagem , Piridonas/química , Relação Estrutura-Atividade
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