RESUMO
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.
Assuntos
Encéfalo , Desenho de Fármacos , Inibidores Enzimáticos , Metionina Adenosiltransferase , Metionina Adenosiltransferase/antagonistas & inibidores , Metionina Adenosiltransferase/metabolismo , Humanos , Animais , Relação Estrutura-Atividade , Ratos , Encéfalo/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/síntese química , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/química , Antineoplásicos/síntese química , Camundongos , Masculino , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
RESUMO
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.
RESUMO
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.
RESUMO
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.
RESUMO
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.
RESUMO
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.
Assuntos
Catecóis/síntese química , Irídio/química , Oxigênio/química , Fenóis/química , Acetamidas/química , Ácido Acético/química , Catálise , Fluorescência , Hidroxilação , Oxirredução , Isótopos de Oxigênio/química , Coloração e Rotulagem/métodosRESUMO
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.
RESUMO
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.
Assuntos
Acetamidas/química , Aldeídos/química , Oxazepinas/química , Carbono/química , Catálise , Cristalografia por Raios X , Reação de Cicloadição , Hidrogênio/química , Conformação Molecular , Nitrogênio/química , Ródio/química , TemperaturaRESUMO
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.
Assuntos
Ácidos/química , Alumínio/química , Amidas/síntese química , Aminas/química , Compostos Organometálicos/química , Estrutura MolecularRESUMO
Pharmacology of MMP13 and MMP13 selective inhibitors is reviewed.
Assuntos
Inibidores de Metaloproteinases de Matriz , Osteoartrite/tratamento farmacológico , Inibidores de Proteases/farmacologia , Sítio Alostérico , Animais , Cartilagem/metabolismo , Colágeno/química , Desenho de Fármacos , Regulação Enzimológica da Expressão Gênica , Humanos , Inflamação , Cinética , Camundongos , Camundongos Knockout , Inibidores de Proteases/química , RatosRESUMO
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).
Assuntos
Azetidinas/química , Cabelo/efeitos dos fármacos , Pirazóis/química , Animais , Azetidinas/síntese química , Azetidinas/farmacologia , Eflornitina/farmacologia , Cabelo/crescimento & desenvolvimento , Camundongos , Camundongos Knockout , Pirazóis/síntese química , Pirazóis/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Alopecia/tratamento farmacológico , Receptores dos Hormônios Tireóideos/agonistas , Triazinas/química , Administração Tópica , Animais , Células 3T3 BALB , Cabelo/crescimento & desenvolvimento , Humanos , Macaca , Camundongos , Vermelho Neutro/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Absorção Cutânea , Triazinas/síntese química , Triazinas/toxicidadeRESUMO
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.
Assuntos
Antagonistas de Receptores de Andrógenos , Cicloexanóis/síntese química , Cicloexanóis/farmacologia , Nitrilas/síntese química , Nitrilas/farmacologia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/farmacologia , Pele , Cristalografia por Raios X , Cicloexanóis/química , Desenho de Fármacos , Ligantes , Modelos Moleculares , Estrutura Molecular , Nitrilas/química , Fármacos Fotossensibilizantes/química , Receptores Androgênicos/química , Receptores Androgênicos/metabolismo , Pele/efeitos dos fármacos , Pele/metabolismo , Esteroides/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Carbamatos/química , Compostos Heterocíclicos com 2 Anéis/química , Piridinas/síntese química , Compostos de Enxofre/química , Água/química , Cristalografia por Raios X , Ciclização , Modelos Moleculares , Estrutura Molecular , Piridinas/químicaRESUMO
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.
Assuntos
Inibidores de Metaloproteinases de Matriz , Osteoartrite/tratamento farmacológico , Piridinas/síntese química , Pirimidinas/síntese química , Quinazolinonas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Masculino , Piridinas/farmacocinética , Piridinas/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Quinazolinonas/farmacocinética , Quinazolinonas/farmacologia , Coelhos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Aminopiridinas/química , Aminopiridinas/farmacologia , Antagonistas de Receptores de Andrógenos , Cabelo/efeitos dos fármacos , Cabelo/crescimento & desenvolvimento , Sebo/efeitos dos fármacos , Sebo/metabolismo , Aminopiridinas/síntese química , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C3H , Modelos Moleculares , Estrutura Molecular , Receptores Androgênicos/metabolismo , Relação Estrutura-AtividadeRESUMO
Synthesis, pharmacology, and pharmacokinetic profiles of (1R, 2S)-4-(2-cyano-cyclohexyl-oxy)-2-trifluoromethyl-benzonitrile are reported. This compound 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.
Assuntos
Antagonistas de Androgênios/farmacologia , Cabelo/crescimento & desenvolvimento , Hidrocarbonetos Fluorados/farmacologia , Nitrilas/farmacologia , Sebo , Animais , Cricetinae , Hidrocarbonetos Fluorados/farmacocinética , Masculino , Mesocricetus , Camundongos , Modelos Moleculares , Nitrilas/farmacocinéticaRESUMO
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.
Assuntos
Aminas/química , Química Orgânica/métodos , Piridinas/química , VolatilizaçãoRESUMO
Interleukin-8 modulation is implicated in many inflammatory and cancer diseases. Starting from a mass-screening hit, the synthesis and structure-activity relationship of 2-amino-3-heteroarylquinoxalines as non-peptide, small molecule interleukine-8 receptor antagonists have been developed. The optimized derivatives, PD 0210293 (13y) and PD 0220245 (13r), show inhibition of both IL-8 receptor binding and IL-8-mediated neutrophil chemotaxis.