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1.
Med Chem Res ; 32(6): 1039-1062, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37305209

RESUMEN

Small molecule drugs that covalently bind irreversibly to their target proteins have several advantages over conventional reversible inhibitors. They include increased duration of action, less-frequent drug dosing, reduced pharmacokinetic sensitivity, and the potential to target intractable shallow binding sites. Despite these advantages, the key challenges of irreversible covalent drugs are their potential for off-target toxicities and immunogenicity risks. Incorporating reversibility into covalent drugs would lead to less off-target toxicity by forming reversible adducts with off-target proteins and thus reducing the risk of idiosyncratic toxicities caused by the permanent modification of proteins, which leads to higher levels of potential haptens. Herein, we systematically review electrophilic warheads employed during the development of reversible covalent drugs. We hope the structural insights of electrophilic warheads would provide helpful information to medicinal chemists and aid in designing covalent drugs with better on-target selectivity and improved safety.

2.
J Org Chem ; 83(4): 2382-2388, 2018 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-29333860

RESUMEN

2-Aminophenyl-1H-pyrazole has been identified as a viable directing group to promote copper(II)-mediated ortho-selective sp2 C-H bond tandem alkynylation/annulation of anilides with terminal alkynes to offer arylmethylene isoindolinones. Meanwhile, copper(II)-mediated ortho-selective sp2 C-H hydroxylation of anilides has also been optimized as the major reaction pathway by using Cu(OAc)2 as the promoter and 1,1,3,3-tetramethylguanidine as an organic base. Recovery of the directing group was achieved by hydrazinolysis for arylmethylene isoindolinones and basic hydrolysis for the hydroxylation products.

3.
J Org Chem ; 82(21): 11620-11625, 2017 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-29016134

RESUMEN

Palladium-catalyzed ortho-arylation of anilides was achieved using 2-aminophenyl-1H-pyrazole (2-APP) as a new directing group. Using Pd(OAc)2 as the catalyst and AgO as the promoter, mono- and diarylation of anilides were realized in up to 89% isolated yield. Further manipulation of the arylation product may be accomplished by a 2-step sequence involving an acidic hydrolysis of the methylated amide. More interestingly, in the presence of K2CO3, tandem C-C/C-N cyclization products were obtained for a couple of substrates.

4.
Org Biomol Chem ; 16(1): 43-47, 2017 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-29214248

RESUMEN

A Rh(iii)-catalyzed C-H alkynylation of substituted N-phenoxyacetamides has been developed with the aid of hypervalent iodine-alkyne reagents. Complementary to the Sonogashira coupling reaction, this protocol provides an efficient and straightforward method to access aryl alkynes at room temperature. The multifunctional directing group is preserved which can be further employed for ortho-directed functionalizations to obtain additional new complex products.

5.
J Med Chem ; 67(11): 9431-9446, 2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38818879

RESUMEN

Synthetic lethality has recently emerged as a new approach for the treatment of mutated genes that were previously considered undruggable. Targeting methionine adenosyltransferase 2A (MAT2A) in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene leads to synthetic lethality and thus has attracted significant interest in the field of precise anticancer drug development. Herein, we report the discovery of a series of novel MAT2A inhibitors featuring a pyrazolo[3,4-c]quinolin-4-one skeleton based on structure-based drug design. Further optimization led to compound 39, which has a high potency for inhibiting MAT2A and a remarkable selectivity for MTAP-deleted cancer cell lines. Compound 39 has a favorable pharmacokinetic profile with high plasma exposure and oral bioavailability, and it exhibits significant efficacy in xenograft MTAP-depleted models. Moreover, 39 demonstrates excellent brain exposure with a Kpuu of 0.64 in rats.


Asunto(s)
Encéfalo , Diseño de Fármacos , Inhibidores Enzimáticos , Metionina Adenosiltransferasa , Metionina Adenosiltransferasa/antagonistas & inhibidores , Metionina Adenosiltransferasa/metabolismo , Humanos , Animales , Relación Estructura-Actividad , Ratas , Encéfalo/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/síntesis química , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Antineoplásicos/química , Antineoplásicos/síntesis química , Ratones , Masculino , Ratas Sprague-Dawley , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Bioorg Med Chem Lett ; 20(1): 306-8, 2010 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-19900809

RESUMEN

A thyroid hormone receptor beta subtype-selective thyromimetic 5 was found to be efficacious in both mouse and monkey hair growth models after topical applications. It penetrates the skin according to the test in human cadaver skin mounted onto Franz diffusion chambers. The serum drug level of 5 is below the limit of quantification during tests in the bald stump-tailed macaques (Macaca arctoides). It is tested negative in the 3T3 neutral red uptake (NRU) phototoxicity test, indicating a low risk for causing photo-irritation. It is also rapidly metabolized according to the PK data, thus the systemic exposure is limited.


Asunto(s)
Alopecia/tratamiento farmacológico , Receptores de Hormona Tiroidea/agonistas , Triazinas/química , Administración Tópica , Animales , Células 3T3 BALB , Cabello/crecimiento & desarrollo , Humanos , Macaca , Ratones , Rojo Neutro/metabolismo , Receptores de Hormona Tiroidea/metabolismo , Absorción Cutánea , Triazinas/síntesis química , Triazinas/toxicidad
8.
Bioorg Med Chem Lett ; 20(16): 4932-5, 2010 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-20620058

RESUMEN

A series of aminomethylpyrazoles were prepared and evaluated using cell-based Smoothened beta-lactamase reporter assay and Smoothened binding assay. Potent Smoothened antagonists 10k and 10l were found to inhibit hair growth in vivo in the C3H/HeN mouse hair growth model. The more selective compound 10l was tested negative in the 3T3 NRU assay, indicating a low risk for causing photo-irritation and was efficacious using the C3H/HeN mouse hair growth model although it was slightly less efficacious than that of the reference compound eflornithine (7).


Asunto(s)
Azetidinas/química , Cabello/efectos de los fármacos , Pirazoles/química , Animales , Azetidinas/síntesis química , Azetidinas/farmacología , Eflornitina/farmacología , Cabello/crecimiento & desarrollo , Ratones , Ratones Noqueados , Pirazoles/síntesis química , Pirazoles/farmacología , Relación Estructura-Actividad
9.
J Med Chem ; 51(4): 835-41, 2008 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-18251495

RESUMEN

Quinazolinones 8 and pyrido[3,4-d]pyrimidin-4-ones 9 as orally active and specific matrix metalloproteinase-13 inhibitors were discovered for the treatment of osteoarthritis. Starting from a high-through-put screening (HTS) hit thizolopyrimidin-dione 7, we obtained two chemotypes, 8 and 9, using computer-aided drug design (CADD) and methodical structure-activity relationship (SAR) studies. They occupy the unique S 1'-specificity pocket and do not bind to the Zn(2+) ion. Some pyrido[3,4-d]pyrimidin-4-ones, such as 10a, possess favorable absorption, distribution, metabolism, and elimination (ADME) and safety profiles. 10a effectively prevents cartilage damage in rabbit animal models of osteoarthritis without inducing musculoskeletal side effects when given at extremely high doses to rats.


Asunto(s)
Inhibidores de la Metaloproteinasa de la Matriz , Osteoartritis/tratamiento farmacológico , Piridinas/síntesis química , Pirimidinas/síntesis química , Quinazolinonas/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Masculino , Piridinas/farmacocinética , Piridinas/farmacología , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Quinazolinonas/farmacocinética , Quinazolinonas/farmacología , Conejos , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
10.
Org Lett ; 10(13): 2897-900, 2008 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-18533675

RESUMEN

Cyclodehydration using the Burgess reagent provided a novel approach toward the synthesis of N-bridged 5,6-bicylic pyridines including pyrolo-, imidazo-, and triazolopyridines under mild and neutral conditions. The methodology tolerates acid-sensitive functional groups. A novel addition product was observed between the resulting pyrrolo- or imidazopyridine and an additional equivalent of the Burgess reagent, producing the corresponding sulfonylcarbamate adduct.


Asunto(s)
Carbamatos/química , Compuestos Heterocíclicos con 2 Anillos/química , Piridinas/síntesis química , Compuestos de Azufre/química , Agua/química , Cristalografía por Rayos X , Ciclización , Modelos Moleculares , Estructura Molecular , Piridinas/química
11.
Nat Commun ; 8: 15912, 2017 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-28627513

RESUMEN

Synthetic methods inspired by Nature often offer unique advantages including mild conditions and biocompatibility with aqueous media. Inspired by an ergothioneine biosynthesis protein EgtB, a mononuclear non-haem iron enzyme capable of catalysing the C-S bond formation and sulfoxidation, herein, we discovered a mild and metal-free C-H sulfenylation/intramolecular rearrangement cascade reaction employing an internally oxidizing O-N bond as a directing group. Our strategy accommodates a variety of oxyamines with good site selectivity and intrinsic oxidative properties. Combining an O-N bond with an X-S bond generates a C-S bond and an S=N bond rapidly. The newly discovered cascade reaction showed excellent chemoselectivity and a wide substrate scope for both oxyamines and sulfenylation reagents. We demonstrated the biocompatibility of the C-S bond coupling reaction by applying a coumarin-based fluorogenic probe in bacterial lysates. Finally, the C-S bond coupling reaction enabled the first fluorogenic formation of phospholipids, which self-assembled to fluorescent vesicles in situ.

12.
Nat Commun ; 8: 14227, 2017 01 27.
Artículo en Inglés | MEDLINE | ID: mdl-28128196

RESUMEN

Ubiquitous tyrosinase catalyses the aerobic oxidation of phenols to catechols through the binuclear copper centres. Here, inspired by the Fischer indole synthesis, we report an iridium-catalysed tyrosinase-like approach to catechols, employing an oxyacetamide-directed C-H hydroxylation on phenols. This method achieves one-step, redox-neutral synthesis of catechols with diverse substituent groups under mild conditions. Mechanistic studies confirm that the directing group (DG) oxyacetamide acts as the oxygen source. This strategy has been applied to the synthesis of different important catechols with fluorescent property and bioactivity from the corresponding phenols. Finally, our method also provides a convenient route to 18O-labelled catechols using 18O-labelled acetic acid.


Asunto(s)
Catecoles/síntesis química , Iridio/química , Oxígeno/química , Fenoles/química , Acetamidas/química , Ácido Acético/química , Catálisis , Fluorescencia , Hidroxilación , Oxidación-Reducción , Isótopos de Oxígeno/química , Coloración y Etiquetado/métodos
13.
Org Lett ; 18(11): 2660-3, 2016 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-27172121

RESUMEN

2-Aminophenyl-1H-pyrazole was discovered as a removable bidentate directing group for copper-mediated aerobic oxidative C(sp(2)-H) bond amidation and sulfonamidation. When Cu(OAc)2 was employed as the copper source and 1,1,3,3-tetramethylguanidine as an organic base, the reaction, optimally carried out overnight in DMSO at 80 °C in open air, produced a variety of amides and sulfonamides in moderate to excellent yields. This directing group has proven to be particularly efficient in C-H sulfonamidation.

14.
Org Lett ; 4(13): 2201-3, 2002 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-12074667

RESUMEN

[reaction: see text] By taking advantage of the alpha- and gamma-activation of chloropyridines as well as palladium-mediated reactions, all four possible benzo[4,5]furopyridine tricyclic heterocycles, benzo[4,5]furo[2,3-b]pyridine, benzo[4,5]furo[2,3-c]pyridine, benzo[4,5]furo[3,2-c]pyridine, and benzo[4,5]furo[3,2-b]pyridine, are efficiently synthesized from 2-chloro-3-iodopyridine, 3-chloro-4-stannylpyridine, 4-chloro-3-iodopyridine, and 2-chloro-3-hydroxypyridine, respectively.


Asunto(s)
Benzofuranos/síntesis química , Piridinas/síntesis química , Catálisis , Cloro , Paladio/química , Piridinas/química
15.
Chem Commun (Camb) ; 50(81): 12135-8, 2014 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-25174413

RESUMEN

An efficient Rh(III)-catalyzed coupling reaction of N-phenoxyacetamides with α,ß-unsaturated aldehydes to give 1,2-oxazepines via C-H activation/[4+3] annulation has been developed. This transformation does not require oxidants and features C-C/C-N bond formation to yield seven-membered oxazepine rings at room temperature. Further derivation of 1,2-oxazepines leads to important chroman derivatives.


Asunto(s)
Acetamidas/química , Aldehídos/química , Oxazepinas/química , Carbono/química , Catálisis , Cristalografía por Rayos X , Reacción de Cicloadición , Hidrógeno/química , Conformación Molecular , Nitrógeno/química , Rodio/química , Temperatura
16.
Org Lett ; 14(1): 214-7, 2012 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-22148911

RESUMEN

In the presence of AlMe(3), amines can be directly coupled with acids through dimethylaluminum amide intermediates to form the corresponding amides. A wide range of amines and acids including less nucleophilic amines, bulky amines, unprotected secondary amino acids, and acids with poor solubility were coupled smoothly to give the desired products in 55-98% yields.


Asunto(s)
Ácidos/química , Aluminio/química , Amidas/síntesis química , Aminas/química , Compuestos Organometálicos/química , Estructura Molecular
18.
J Med Chem ; 51(21): 7010-4, 2008 Nov 13.
Artículo en Inglés | MEDLINE | ID: mdl-18921992

RESUMEN

4-((1 R,2 R)-2-Hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile [PF-0998425, (-)- 6a] is a novel, nonsteroidal androgen receptor antagonist for sebum control and treatment of androgenetic alopecia. It is potent, selective, and active in vivo. The compound is rapidly metabolized systemically, thereby reducing the risk of unwanted systemic side effects due to its primary pharmacology. (-)- 6a was tested negative in the 3T3 NRU assay, validating our rationale that reduction of conjugation might reduce potential phototoxicity.


Asunto(s)
Antagonistas de Receptores Androgénicos , Ciclohexanoles/síntesis química , Ciclohexanoles/farmacología , Nitrilos/síntesis química , Nitrilos/farmacología , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/farmacología , Piel , Cristalografía por Rayos X , Ciclohexanoles/química , Diseño de Fármacos , Ligandos , Modelos Moleculares , Estructura Molecular , Nitrilos/química , Fármacos Fotosensibilizantes/química , Receptores Androgénicos/química , Receptores Androgénicos/metabolismo , Piel/efectos de los fármacos , Piel/metabolismo , Esteroides/química , Relación Estructura-Actividad
19.
J Org Chem ; 72(9): 3606-7, 2007 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-17417910

RESUMEN

A practical Buchwald-Hartwig amination of 2-bromopyridines with volatile amines is developed in sealed tubes. The method provides an expedient entry to a variety of secondary and tertiary aminopyridines that are otherwise not readily synthesized.


Asunto(s)
Aminas/química , Química Orgánica/métodos , Piridinas/química , Volatilización
20.
Bioorg Med Chem Lett ; 17(20): 5693-7, 2007 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-17766112

RESUMEN

A series of amino-pyridines were synthesized and evaluated for androgen antagonist activities. Among these compounds, (R)-(+)-6-[methyl-(1-phenyl-ethyl)-amino]-4-trifluoromethyl-nicotinonitrile was the most active example of this class. This compound displayed potent androgen receptor antagonist activity as well as favorable pharmacokinetic characteristics for a potential topical agent. It also demonstrated remarkable potency for stimulating hair growth in a male C3H mouse model as well as reducing sebum production in the male Syrian hamster ear model.


Asunto(s)
Aminopiridinas/química , Aminopiridinas/farmacología , Antagonistas de Receptores Androgénicos , Cabello/efectos de los fármacos , Cabello/crecimiento & desarrollo , Sebo/efectos de los fármacos , Sebo/metabolismo , Aminopiridinas/síntesis química , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos C3H , Modelos Moleculares , Estructura Molecular , Receptores Androgénicos/metabolismo , Relación Estructura-Actividad
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