RESUMO
We have discovered novel benzofuran-based S1P1 agonists with excellent in vitro potency and selectivity. 1-((4-(5-Benzylbenzofuran-2-yl)-3-fluorophenyl)methyl) azetidine-3-carboxylic acid (18) is a potent S1P1 agonist with >1000× selectivity over S1P3. It demonstrated a good in vitro ADME profile and excellent oral bioavailability across species. Dosed orally at 0.3 mg/kg, 18 significantly reduced blood lymphocyte counts 24 h postdose and demonstrated efficacy in a mouse EAE model of relapsing MS.
RESUMO
In pursuit of a potent and highly selective sphingosine-1-phosphate receptor agonists with an improved in vivo conversion of the precursor to the active phospho-drug, we have utilized previously reported phenylamide and phenylimidazole scaffolds to identify a selectivity enhancing moiety (SEM) and selectivity enhancing orientation (SEO) within both pharmacophores. SEM and SEO have allowed for over 100 to 500-fold improvement in selectivity for S1P receptor subtype 1 over subtype 3. Utility of SEM and SEO and further SAR study allowed for discovery of a potent and selective preclinical candidate PPI-4955 (21b) with an excellent in vivo potency and dose responsiveness and markedly improved overall in vivo pharmacodynamic properties upon oral administration.
Assuntos
Amino Álcoois/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Administração Oral , Amino Álcoois/administração & dosagem , Animais , Camundongos , Relação Estrutura-AtividadeRESUMO
In pursuit of potent and selective sphingosine-1-phosphate receptor agonists, we have utilized previously reported phenylamide and phenylimidazole scaffolds to explore extensive side-chain modifications to generate new molecular entities. A number of designed molecules demonstrate good selectivity and excellent in vitro and in vivo potency in both mouse and rat models. Oral administration of the lead molecule 11c (PPI-4667) demonstrated potent and dose-responsive lymphopenia.
Assuntos
Amidas/síntese química , Imidazóis/síntese química , Receptores de Lisoesfingolipídeo/agonistas , Amidas/farmacologia , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Cloridrato de Fingolimode , Imidazóis/farmacologia , Camundongos , Propilenoglicóis/química , Propilenoglicóis/farmacologia , Subunidades Proteicas/agonistas , Subunidades Proteicas/fisiologia , Receptores de Lisoesfingolipídeo/fisiologia , Esfingosina/análogos & derivados , Esfingosina/química , Esfingosina/farmacologiaRESUMO
In the design of potent and selective sphingosine-1-phosphate receptor agonists, we were able to identify two series of molecules based on phenylamide and phenylimidazole analogs of FTY-720. Several designed molecules in these scaffolds have demonstrated selectivity for S1P receptor subtype 1 versus 3 and excellent in vivo activity in mouse. Two molecules PPI-4621 (4b) and PPI-4691 (10a), demonstrated dose responsive lymphopenia, when administered orally.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Amidas/química , Animais , Relação Dose-Resposta a Droga , Humanos , Imidazóis/química , Camundongos , Relação Estrutura-AtividadeRESUMO
A novel series of potent inhibitors of Ras farnesyl transferase possessing a 1,2,4-triazole pharmacophore is described. These inhibitors were discovered from a parallel synthesis effort and were subsequently optimized to in vitro IC(50) value of less than 1nM.
Assuntos
Inibidores Enzimáticos/síntese química , Farnesiltranstransferase/antagonistas & inibidores , Triazóis/síntese química , Sequência de Aminoácidos , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/genética , Genes ras , Modelos Moleculares , Conformação Molecular , Oligopeptídeos/química , Triazóis/farmacologiaRESUMO
Solid-phase synthesis of imidazolyl-beta-amino acid derivatives is described. Several analogs demonstrated moderate inhibition of geranylgeranyl protein transferase type I (GGPT I).
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Aminoácidos/síntese química , Aminoácidos/farmacologia , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Replacement of the 1-methylimidazol-5-yl moiety in the farnesyltransferase inhibitor ZARNESTRA series by a 4-methyl-1,2,4-triazol-3-yl group gave us compounds with similar structure-activity relationship profiles showing that this triazole is potentially a good surrogate to imidazole for farnesyltransferase inhibition.