RESUMO
Soluble guanylate cyclase (sGC) is a clinically validated therapeutic target in the treatment of pulmonary hypertension. Modulators of sGC have the potential to treat diseases that are affected by dysregulation of the NO-sGC-cGMP signal transduction pathway. This letter describes the SAR efforts that led to the discovery of CYR715, a novel carboxylic acid-containing sGC stimulator, with an improved metabolic profile relative to our previously described stimulator, IWP-051. CYR715 addressed potential idiosyncratic drug toxicity (IDT) liabilities associated with the formation of reactive, migrating acyl glucuronides (AG) found in related carboxylic acid-containing analogs and demonstrated high oral bioavailability in rat and dose-dependent hemodynamic pharmacology in normotensive Sprague-Dawley rats.
Assuntos
Ácidos Carboxílicos/química , Glucuronídeos/química , Hipertensão Pulmonar/tratamento farmacológico , Guanilil Ciclase Solúvel/metabolismo , Vasodilatadores/química , Administração Oral , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Glucuronídeos/administração & dosagem , Glucuronídeos/farmacocinética , Humanos , Masculino , Metaboloma , Modelos Moleculares , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ligação Proteica , Ratos Sprague-Dawley , Transdução de Sinais , Relação Estrutura-Atividade , Vasodilatadores/administração & dosagem , Vasodilatadores/farmacocinéticaRESUMO
A mild and operationally simple method to synthesize diphenylhexatriene (DPH) is reported. The method relies on the Pd-catalyzed dimerization of cinnamyl acetate and provides efficient access to DPH in a single step.
Assuntos
Cinamatos/química , Difenilexatrieno/síntese química , Compostos Organometálicos/química , Paládio/química , Catálise , Dimerização , Difenilexatrieno/química , Estrutura MolecularRESUMO
Density functional theory computations reproduce the surprisingly high regioselectivities in nucleophilic additions and cycloadditions to 4,5-indolynes and the low regioselectivities in the reactions of 5,6-indolynes. Transition-state distortion energies control the regioselectivities, activating the 5 and 6 positions over the 4 and 7 positions, leading to high preferences for 5- and 6-substituted products from 4,5- and 6,7-indolynes, respectively. Orbital and electrostatic interactions have only minor effects, producing low regioselectivities in the reactions of 5,6-indolynes. The distortion model predicts high regioselectivities with 6,7-indolynes; these have been verified experimentally. The regioselectivities found with other arynes are explained on the basis of distortion energies that are reflected in reactant geometries.
Assuntos
Hidrocarbonetos Aromáticos/química , Indóis/química , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Teoria Quântica , Estereoisomerismo , TermodinâmicaRESUMO
Efficient syntheses of 4,5-, 5,6-, and 6,7-indolyne precursors beginning from commercially available hydroxyindole derivatives are reported. The synthetic routes are versatile and allow access to indolyne precursors that remain unsubstituted on the pyrrole ring. Indolynes can be generated under mild fluoride-mediated conditions, trapped by a variety of nucleophilic reagents, and used to access a number of novel substituted indoles. Nucleophilic addition reactions to indolynes proceed with varying degrees of regioselectivity; distortion energies control regioselectivity and provide a simple model to predict the regioselectivity in the nucleophilic additions to indolynes and other unsymmetrical arynes. This model has led to the design of a substituted 4,5-indolyne that exhibits enhanced nucleophilic regioselectivity.
Assuntos
Simulação por Computador , Indóis/química , Indóis/síntese química , Estrutura MolecularRESUMO
In recent years, soluble guanylate cyclase (sGC, EC 4.6.1.2) has emerged as an attractive therapeutic target for treating cardiovascular diseases and diseases associated with fibrosis and end-organ failure. Herein, we describe our design and synthesis of a series of 4-hydroxypyrimidine sGC stimulators starting with an internally discovered lead. Our efforts have led to the discovery of IWP-051, a molecule that achieves good alignment of potency, stability, selectivity, and pharmacodynamic effects while maintaining favorable pharmacokinetic properties with once-daily dosing potential in humans.