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1.
J Am Chem Soc ; 144(38): 17709-17720, 2022 09 28.
Artículo en Inglés | MEDLINE | ID: mdl-36106767

RESUMEN

A useful protocol for achieving decarboxylative cross-coupling (DCC) of redox-active esters (RAE, isolated or generated in situ) and halo(hetero)arenes is reported. This pragmatically focused study employs a unique Ag-Ni electrocatalytic platform to overcome numerous limitations that have plagued this strategically powerful transformation. In its optimized form, coupling partners can be combined in a surprisingly simple way: open to the air, using technical-grade solvents, an inexpensive ligand and Ni source, and substoichiometric AgNO3, proceeding at room temperature with a simple commercial potentiostat. Most importantly, all of the results are placed into context by benchmarking with state-of-the-art methods. Applications are presented that simplify synthesis and rapidly enable access to challenging chemical space. Finally, adaptation to multiple scale regimes, ranging from parallel milligram-based synthesis to decagram recirculating flow is presented.


Asunto(s)
Ésteres , Catálisis , Ligandos , Oxidación-Reducción , Solventes
2.
Bioorg Med Chem Lett ; 73: 128882, 2022 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-35817293

RESUMEN

Agonism of the apelin receptor (APJ) has demonstrated beneficial effects in models of heart failure. We have previously disclosed compounds such as 4, which showed good APJ agonist activity but were metabolized to the mono-demethylated, non-interconverting atropisomer metabolites. Herein, we detail the design and optimization of a novel series of N-linked APJ agonists with good potency, metabolic stability, and rat pharmacokinetic profile, which are unable to undergo the same metabolic mono-demethylation cleavage.


Asunto(s)
Piridinas , Receptores Acoplados a Proteínas G , Animales , Apelina , Receptores de Apelina/agonistas , Ratas , Receptores Acoplados a Proteínas G/agonistas
3.
J Am Chem Soc ; 142(11): 5117-5125, 2020 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-32098471

RESUMEN

Saturated azacycles are commonly encountered in bioactive compounds and approved therapeutic agents. The development of methods for functionalization of the α-methylene C-H bonds of these highly privileged building blocks is of great importance, especially in drug discovery. While much effort has been dedicated toward this goal by using a directed C-H activation approach, the development of directing groups that are both general as well as practical remains a significant challenge. Herein, the design and development of novel amidoxime directing groups is described for Ir(I)-catalyzed α-C(sp3)-H alkylation of saturated azacycles using readily available olefins as coupling partners. This protocol extends the scope of saturated azacycles to piperidines, azepane, and tetrahydroisoquinoline that are incompatible with our previously reported directing group. A variety of olefin coupling partners, including previously unreactive disubstituted terminal olefins and internal olefins, are compatible with this transformation. The selectivity for a branched α-C(sp3)-alkylation product is also observed for the first time when acrylate is used as the reaction partner. The development of practical, one-step installation and removal protocols further adds to the utility of amidoxime directing groups.


Asunto(s)
Piperidinas/síntesis química , Pirrolidinas/síntesis química , Alquilación , Catálisis , Iridio/química , Modelos Químicos , Estructura Molecular , Oximas/síntesis química
4.
J Med Chem ; 67(5): 3571-3589, 2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38385264

RESUMEN

PAR4 is a promising antithrombotic target with potential for separation of efficacy from bleeding risk relative to current antiplatelet therapies. In an effort to discover a novel PAR4 antagonist chemotype, a quinoxaline-based HTS hit 3 with low µM potency was identified. Optimization of the HTS hit through the use of positional SAR scanning and the design of conformationally constrained cores led to the discovery of a quinoxaline-benzothiazole series as potent and selective PAR4 antagonists. The lead compound 48, possessing a 2 nM IC50 against PAR4 activation by γ-thrombin in platelet-rich plasma (PRP) and greater than 2500-fold selectivity versus PAR1, demonstrated robust antithrombotic efficacy and minimal bleeding in the cynomolgus monkey models.


Asunto(s)
Fibrinolíticos , Trombosis , Animales , Fibrinolíticos/farmacología , Fibrinolíticos/uso terapéutico , Macaca fascicularis , Quinoxalinas/farmacología , Quinoxalinas/uso terapéutico , Receptores de Trombina , Trombina , Hemorragia , Trombosis/tratamiento farmacológico , Trombosis/prevención & control , Receptor PAR-1 , Plaquetas , Agregación Plaquetaria
5.
J Med Chem ; 67(11): 9731-9744, 2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38807539

RESUMEN

Recent literature reports highlight the importance of the renal outer medullary potassium (ROMK) channel in renal sodium and potassium homeostasis and emphasize the potential impact that ROMK inhibitors could have as a novel mechanism diuretic in heart failure patients. A series of piperazine-based ROMK inhibitors were designed and optimized to achieve excellent ROMK potency, hERG selectivity, and ADME properties, which led to the identification of compound 28 (BMS-986308). BMS-986308 demonstrated efficacy in the volume-loaded rat diuresis model as well as promising in vitro and in vivo profiles and was therefore advanced to clinical development.


Asunto(s)
Insuficiencia Cardíaca , Bloqueadores de los Canales de Potasio , Animales , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Ratas , Bloqueadores de los Canales de Potasio/uso terapéutico , Bloqueadores de los Canales de Potasio/farmacología , Bloqueadores de los Canales de Potasio/química , Bloqueadores de los Canales de Potasio/farmacocinética , Bloqueadores de los Canales de Potasio/síntesis química , Relación Estructura-Actividad , Canales de Potasio de Rectificación Interna/antagonistas & inhibidores , Canales de Potasio de Rectificación Interna/metabolismo , Descubrimiento de Drogas , Diuresis/efectos de los fármacos , Piperazinas/farmacología , Piperazinas/química , Piperazinas/uso terapéutico , Piperazinas/síntesis química , Piperazinas/farmacocinética , Masculino , Ratas Sprague-Dawley
6.
Nature ; 446(7134): 404-8, 2007 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-17377577

RESUMEN

The field of organic synthesis has made phenomenal advances in the past fifty years, yet chemists still struggle to design synthetic routes that will enable them to obtain sufficient quantities of complex molecules for biological and medical studies. Total synthesis is therefore increasingly focused on preparing natural products in the most efficient manner possible. Here we describe the preparative-scale, enantioselective, total syntheses of members of the hapalindole, fischerindole, welwitindolinone and ambiguine families, each constructed without the need for protecting groups--the use of such groups adds considerably to the cost and complexity of syntheses. As a consequence, molecules that have previously required twenty or more steps to synthesize racemically in milligram amounts can now be obtained as single enantiomers in significant quantities in ten steps or less. Through the extension of the general principles demonstrated here, it should be possible to access other complex molecular architectures without using protecting groups.


Asunto(s)
Alcaloides/síntesis química , Productos Biológicos/síntesis química , Química Orgánica/métodos , Indoles/síntesis química , Alcaloides/química , Productos Biológicos/química , Cianobacterias/química , Alcaloides Indólicos , Indoles/química , Nitrilos/síntesis química , Nitrilos/química , Agua de Mar/microbiología
7.
J Med Chem ; 65(13): 8843-8854, 2022 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-35729784

RESUMEN

Protease-activated receptor 4 (PAR4) is a G-protein coupled receptor that is expressed on human platelets and activated by the coagulation enzyme thrombin. PAR4 plays a key role in blood coagulation, and its importance in pathological thrombosis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of imidazothiadiazole PAR4 antagonists to a first-in-class clinical candidate, BMS-986120 (43), and a backup clinical candidate, BMS-986141 (49). Both compounds demonstrated excellent antithrombotic efficacy and minimal bleeding time prolongation in monkey models relative to the clinically important antiplatelet agent clopidogrel and provide a potential opportunity to improve the standard of care in the treatment of arterial thrombosis.


Asunto(s)
Agregación Plaquetaria , Trombosis , Benzofuranos , Plaquetas , Humanos , Imidazoles , Morfolinas , Receptor PAR-1 , Receptores de Trombina , Tiazoles , Trombina , Trombosis/tratamiento farmacológico
8.
Org Lett ; 22(10): 3960-3963, 2020 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-32330054

RESUMEN

Pd(II)-catalyzed C-H lactonization of o-methyl benzoic acid substrates has been achieved using molecular oxygen as the oxidant. This finding provides a rare example of C-H oxygenation through Pd(II)/Pd(0) catalysis as well as a method to construct biologically important benzolactone scaffolds. The use of a gas mixture of 5% oxygen in nitrogen demonstrated the possibility for its application in pharmaceutical manufacturing.

9.
J Am Chem Soc ; 130(23): 7247-9, 2008 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-18481847

RESUMEN

The invention of a method for the synthesis of 1,3-diols from the corresponding alcohols is described, via controlled, radical-mediated C-H functionalization. The sequence described herein entails near quantitative conversion to the corresponding trifluoroethyl carbamate, followed by a variant of the Hofmann-Löffler-Freytag reaction, cyclization, and hydrolysis to provide the 1,3-diols. In addition to the 10 examples presented herein, the syntheses of four natural products are facilitated by this directed oxyfunctionalization. This methodology is demonstrated to be orthogonal to other known C-H oxidations. Finally, this sequence is efficient, practical, inexpensive, and scalable.


Asunto(s)
Alcoholes/síntesis química , Carbamatos/química , Ciclización , Hidrólisis , Oxidación-Reducción , Propanoles/química
10.
J Am Chem Soc ; 130(52): 17938-54, 2008 Dec 31.
Artículo en Inglés | MEDLINE | ID: mdl-19035635

RESUMEN

Full details are provided for the total synthesis of several members of the hapalindole family of natural products, including hapalindole Q, 12-epi-hapalindole D, 12-epi-fischerindole U, 12-epi-fischerindole G, 12-epi-fischerindole I, and welwitindolinone A. Use of the recently developed direct indole coupling enabled an efficient, practical, scalable, and protecting-group-free synthesis of each of these natural products. The original biosynthetic proposal is reviewed, and a revised biosynthetic hypothesis is suggested, validated by the above syntheses. The syntheses are also characterized by an adherence to the concept of "redox economy". Analogous to "atom economy" or "step economy", "redox economy" minimizes the superfluous redox manipulations within a synthesis; rather, the oxidation state of intermediates linearly and steadily increases throughout the course of the synthesis.


Asunto(s)
Alcaloides/síntesis química , Indoles/síntesis química , Alcaloides/biosíntesis , Materiales Biomiméticos/química , Alcaloides Indólicos , Nitrilos/síntesis química , Oxidación-Reducción , Estereoisomerismo
11.
ACS Med Chem Lett ; 8(1): 67-72, 2017 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-28105277

RESUMEN

Two novel series of meta-linked phenylglycine-based macrocyclic FVIIa inhibitors have been designed to improve the rodent metabolic stability and PK observed with the precursor para-linked phenylglycine macrocycles. Through iterative structure-based design and optimization, the TF/FVIIa Ki was improved to subnanomolar levels with good clotting activity, metabolic stability, and permeability.

13.
J Am Chem Soc ; 129(42): 12857-69, 2007 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-17900115

RESUMEN

Full details are provided for a recently invented method to couple indoles and pyrroles to carbonyl compounds. The reaction is ideally suited for structurally complex substrates and exhibits high levels of chemoselectivity (functional group tolerability), regioselectivity (coupling occurs exclusively at C-3 of indole or C-2 of pyrrole), stereoselectivity (substrate control), and practicality (amenable to scaleup). In addition, quaternary stereocenters are easily and predictably generated. The reaction has been applied to a number of synthetic problems including total syntheses of members of the hapalindole family of natural products, ketorolac, acremoauxin A, and oxazinin 3. Mechanistically, this coupling protocol appears to operate by a single electron-transfer process requiring generation of an electron-deficient radical adjacent to a carbonyl which is then intercepted by an indole or pyrrole anion.


Asunto(s)
Carbono/química , Indoles/química , Morfolinas/síntesis química , Oxazinas/química , Pirroles/química , Química Orgánica/métodos , Dimerización , Electrones , Indoles/síntesis química , Ketorolaco/química , Modelos Químicos , Conformación Molecular , Oxígeno/química , Fosfinas/química , Estereoisomerismo
14.
J Am Chem Soc ; 127(44): 15394-6, 2005 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-16262402

RESUMEN

The first total syntheses of welwitindolinone A and the most complex members of the fischerindole family, fischerindoles I and G, are reported. Highlights of these short, protecting-group-free syntheses include the application of the recently developed direct indole-carbonyl coupling, a simple approach for installing the quaternary center with neighboring chlorine atom, a regioselective dehydrogenation/dehydration cascade to access fischerindole I, and a remarkably facile oxidative ring contraction to construct welwitindolinone A. An alternative biogenetic hypothesis, whose accuracy is suggested by the success of the current syntheses, is also put forth for this alkaloid family.


Asunto(s)
Alcaloides/síntesis química , Indoles/síntesis química , Nitrilos/síntesis química , Alcaloides/química , Cianobacterias/química , Alcaloides Indólicos , Indoles/química , Estructura Molecular , Nitrilos/química , Estereoisomerismo
15.
J Am Chem Soc ; 126(24): 7450-1, 2004 Jun 23.
Artículo en Inglés | MEDLINE | ID: mdl-15198586

RESUMEN

The invention of a method for the direct union of indoles and carbonyl compounds (ketones, amides, esters) is described. Using this new method, a short, enantioselective, gram-scale and protecting group-free synthetic entry to the fischerindole and hapalindole indole alkaloid family has been achieved from carvone and indole. Total syntheses of (+)-hapalindole Q and (-)-12-epi-fischerindole U isothiocyanate are reported. The absolute stereochemistry of the latter natural product has also been determined.


Asunto(s)
Aldehídos/química , Alcaloides/síntesis química , Indoles/síntesis química , Monoterpenos Ciclohexánicos , Indoles/química , Estructura Molecular , Monoterpenos , Estereoisomerismo , Terpenos/química
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