RESUMO
As a member of the Janus (JAK) family of non-receptor tyrosine kinases, TYK2 mediates the signaling of pro-inflammatory cytokines including IL-12, IL-23 and type 1 interferon (IFN), and therefore represents an attractive potential target for treating the various immuno-inflammatory diseases in which these cytokines have been shown to play a role. Following up on our previous report that ligands to the pseudokinase domain (JH2) of TYK2 suppress cytokine-mediated receptor activation of the catalytic (JH1) domain, the imidazo[1,2-b]pyridazine (IZP) 7 was identified as a promising hit compound. Through iterative modification of each of the substituents of the IZP scaffold, the cellular potency was improved while maintaining selectivity over the JH1 domain. These studies led to the discovery of the JH2-selective TYK2 inhibitor 29, which provided encouraging systemic exposures after oral dosing in mice. Phosphodiesterase 4 (PDE4) was identified as an off-target and potential liability of the IZP ligands, and selectivity for TYK2 JH2 over this enzyme was obtained by elaborating along selectivity vectors determined from analyses of X-ray co-crystal structures of representative ligands of the IZP class bound to both proteins.
RESUMO
Substituted pyrazoles, 1,2,4-triazoles, and tetrazoles are good surrogates for cis-amide bonds in a series of boronate ester thrombin inhibitors.
Assuntos
Amidas/farmacologia , Ácidos Borônicos/farmacologia , Pirazóis/farmacologia , Tetrazóis/farmacologia , Trombina/antagonistas & inibidores , Trombina/química , Triazóis/farmacologia , Amidas/química , Sítios de Ligação , Ácidos Borônicos/química , Cristalografia por Raios X , Indicadores e Reagentes , Modelos Moleculares , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Estereoisomerismo , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química , Triazóis/síntese química , Triazóis/químicaRESUMO
In search of antiinflammatory drugs with a new mechanism of action, U0126 was found to functionally antagonize AP-1 transcriptional activity via noncompetitive inhibition of the dual specificity kinase MEK with an IC50 of 0.07 microM for MEK 1 and 0.06 microM for MEK 2. U0126 can undergo isomerization and cyclization reactions to form a variety of products, both chemically and in vivo, all of which exhibit less affinity for MEK and lower inhibition of AP-1 activity than parent, U0126.
Assuntos
Butadienos/química , Inibidores Enzimáticos/química , Nitrilas/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Biotransformação , Butadienos/farmacocinética , Butadienos/farmacologia , Ciclização , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , NF-kappa B/antagonistas & inibidores , Nitrilas/farmacocinética , Nitrilas/farmacologia , Ratos , Fator de Transcrição AP-1/antagonistas & inibidoresRESUMO
AT1 and AT2 are the two major receptor subtypes for angiotensin II that have been pharmacologically defined by using the selective ligands losartan and PD123177, respectively. EXP597 (4-[(5-(2-benzoyl)benzyloxycarbonyl-4-ethyl-2-n-propylimidazole-1- yl)methyl]-3-fluoro-2'-isoamyloxycarbonylaminosulfonyl-[1,1']-biph enyl, potassium salt) is a nonpeptide angiotensin II receptor ligand which in the rat adrenal exhibits binding affinities (IC50) of 0.5 and 0.7 nM for angiotensin AT1 and AT2 receptor subtypes, respectively. Further, EXP597 is an insurmountable angiotensin II receptor antagonist in the isolated rabbit aorta and lowers blood pressure in renal hypertensive rats with i.v. and p.o. ED30 values of 0.05 and 0.9 mg/kg, respectively.
Assuntos
Córtex Suprarrenal/metabolismo , Medula Suprarrenal/metabolismo , Antagonistas de Receptores de Angiotensina , Aorta/metabolismo , Imidazóis/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sulfonamidas/metabolismo , Administração Oral , Córtex Suprarrenal/efeitos dos fármacos , Medula Suprarrenal/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Ligação Competitiva , Compostos de Bifenilo/metabolismo , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipertensão Renal/tratamento farmacológico , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Técnicas In Vitro , Injeções Intravenosas , Losartan , Masculino , Piridinas/metabolismo , Piridinas/farmacologia , Piridinas/uso terapêutico , Coelhos , Ensaio Radioligante , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Receptores de Angiotensina/metabolismo , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Tetrazóis/metabolismo , Tetrazóis/farmacologia , Tetrazóis/uso terapêuticoRESUMO
A new series of nonpeptide angiotensin II (AII) receptor antagonists has been prepared. These N-(biphenylyl-methyl)imidazoles, e.g. 2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloro-5- (hydroxymethyl)imidazole, differ from the previously reported N-(benzamidobenzyl)imidazoles and related compounds in that they produce a potent antihypertensive effect upon oral administration; the earlier series generally were active only when administered intravenously. It has been found that the acidic group at the 2'-position of the biphenyl is essential. Only ortho-substituted acids possess both high affinity for the AII receptor and good oral antihypertensive potency. The carboxylic acid group has been replaced with a variety of acidic isosteres, and the tetrazole ring has been found to be the most effective. The tetrazole derivative, DuP 753, is currently in development for the treatment of hypertension.