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1.
J Med Chem ; 64(6): 3299-3319, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33666424

RESUMO

Class B G-protein-coupled receptors (GPCRs) remain an underexploited target for drug development. The calcitonin receptor (CTR) family is particularly challenging, as its receptors are heteromers comprising two distinct components: the calcitonin receptor-like receptor (CLR) or calcitonin receptor (CTR) together with one of three accessory proteins known as receptor activity-modifying proteins (RAMPs). CLR/RAMP1 forms a CGRP receptor, CLR/RAMP2 forms an adrenomedullin-1 (AM1) receptor, and CLR/RAMP3 forms an adrenomedullin-2 (AM2) receptor. The CTR/RAMP complexes form three distinct amylin receptors. While the selective blockade of AM2 receptors would be therapeutically valuable, inhibition of AM1 receptors would cause clinically unacceptable increased blood pressure. We report here a systematic study of structure-activity relationships that has led to the development of first-in-class AM2 receptor antagonists. These compounds exhibit therapeutically valuable properties with 1000-fold selectivity over the AM1 receptor. These results highlight the therapeutic potential of AM2 antagonists.


Assuntos
Receptores de Adrenomedulina/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Descoberta de Drogas , Feminino , Humanos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Receptores de Adrenomedulina/metabolismo , Bibliotecas de Moléculas Pequenas/uso terapêutico , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo
2.
ACS Pharmacol Transl Sci ; 3(4): 706-719, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32832872

RESUMO

The hormone adrenomedullin has both physiological and pathological roles in biology. As a potent vasodilator, adrenomedullin is critically important in the regulation of blood pressure, but it also has several roles in disease, of which its actions in cancer are becoming recognized to have clinical importance. Reduced circulating adrenomedullin causes increased blood pressure but also reduces tumor progression, so drugs blocking all effects of adrenomedullin would be unacceptable clinically. However, there are two distinct receptors for adrenomedullin, each comprising the same G protein-coupled receptor (GPCR), the calcitonin receptor-like receptor (CLR), together with a different accessory protein known as a receptor activity-modifying protein (RAMP). The CLR with RAMP2 forms an adrenomedullin-1 receptor, and the CLR with RAMP3 forms an adrenomedullin-2 receptor. Recent research suggests that a selective blockade of adrenomedullin-2 receptors would be therapeutically valuable. Here we describe the design, synthesis, and characterization of potent small-molecule adrenomedullin-2 receptor antagonists with 1000-fold selectivity over the adrenomedullin-1 receptor, although retaining activity against the CGRP receptor. These molecules have clear effects on markers of pancreatic cancer progression in vitro, drug-like pharmacokinetic properties, and inhibit xenograft tumor growth and extend life in a mouse model of pancreatic cancer. Taken together, our data support the promise of a new class of anticancer therapeutics as well as improved understanding of the pharmacology of the adrenomedullin receptors and other GPCR/RAMP heteromers.

3.
Org Lett ; 16(19): 5228-31, 2014 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-25243507

RESUMO

A palladium-catalyzed asymmetric decarboxylative allylic alkylation of allyl 2,2-diphenylglycinate imines using (S,S)-f-binaphane as a chiral supporting ligand has been developed. This transformation allows for decarboxylative generation and enantioselective allylation of nonenolate α-imino (2-azaallyl anions) to afford α-aryl homoallylic imines.

4.
Chem Commun (Camb) ; 50(21): 2735-7, 2014 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-24473485

RESUMO

Functionalised cyclic enol ethers can be recovered with high levels of enantiocontrol after an asymmetric catalytic [1,3]-rearrangement reaction. These compounds can be further elaborated to a series of carbo- and heterocyclic products in good yield and with excellent levels of stereocontrol.

5.
Org Lett ; 11(19): 4378-81, 2009 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-19725522

RESUMO

Carpanone has been stereoselectively synthesized in 55% yield and six steps from sesamol. The key step of the synthetic sequence is the direct introduction of the propenyl side chain via a Suzuki-Miyaura cross-coupling reaction. The subsequent Pd(II)-catalyzed oxidative coupling yields carpanone as a single diastereoisomer independently of the geometric configuration of the starting precursor. A new mechanism is proposed for this transformation.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Catálise , Compostos Heterocíclicos de 4 ou mais Anéis/química , Estrutura Molecular , Oxirredução , Paládio/química , Estereoisomerismo
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