RESUMO
We have identified a novel PDE2 inhibitor series using fragment-based screening. Pyrazolopyrimidine fragment 1, while possessing weak potency (Kiâ¯=â¯22.4⯵M), exhibited good binding efficiencies (LBEâ¯=â¯0.49, LLEâ¯=â¯4.48) to serve as a start for structure-based drug design. With the assistance of molecular modeling and X-ray crystallography, this fragment was developed into a series of potent PDE2 inhibitors with good physicochemical properties. Compound 16, a PDE2 selective inhibitor, was identified that exhibited favorable rat pharmacokinetic properties.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Fosfodiesterase/química , Animais , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Meia-Vida , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Conformação Molecular , Simulação de Dinâmica Molecular , Inibidores de Fosfodiesterase/metabolismo , Inibidores de Fosfodiesterase/farmacocinética , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacocinética , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
An iterative analog library synthesis approach was employed in the exploration of a quinolone carboxylic acid series of selective M(1) positive allosteric modulators, and strategies for improving potency and plasma free fraction were identified.
Assuntos
Ácidos Carboxílicos/síntese química , Quinolinas/química , Receptor Muscarínico M1/metabolismo , Regulação Alostérica , Animais , Proteínas Sanguíneas/química , Proteínas Sanguíneas/metabolismo , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Humanos , Ligação Proteica , Ratos , Bibliotecas de Moléculas PequenasRESUMO
Herein we describe the discovery and optimization of a new series of 2,3-disubstituted and 2,3,6-trisubstituted muscarinic acetylcholine receptorâ 4 (M4 ) positive allosteric modulators (PAMs). Iterative libraries enabled rapid exploration of one-dimensional structure-activity relationships (SAR) and identification of potency-enhancing heterocycle and N-alkyl pyrazole substituents. Further optimization led to identification of the potent, receptor-subtype-selective, brain-penetrant tool compound 24 (7-[3-[1-[(1-fluorocyclopentyl)methyl]pyrazol-4-yl]-6-methyl-2-pyridyl]-3-methoxycinnoline). It is efficacious in preclinical assays that are predictive of antipsychotic effects, producing dose-dependent reversal of amphetamine-induced hyperlocomotion in rats and mice, but not in M4 knockout mice. Cholinergic-related adverse effects observed in rats treated with 24 at unbound plasma concentrations more than 3-fold higher than an efficacious dose in the hyperlocomotion assay were fewer and less severe than those observed in rats treated with the nonselective M4 agonist xanomeline, suggesting a receptor-subtype-selective PAM has the potential for an improved safety profile.
Assuntos
Descoberta de Drogas , Piridinas/química , Piridinas/farmacologia , Receptor Muscarínico M4/efeitos dos fármacos , Regulação Alostérica , Animais , Humanos , Ratos , Receptor Muscarínico M4/metabolismo , Relação Estrutura-AtividadeRESUMO
Hydroisoindoline 2 has been previously identified as a potent, brain-penetrant NK1 receptor antagonist with a long duration of action and improved profile of CYP3A4 inhibition and induction compared to aprepitant. However, compound 2 is predicted, based on data in preclinical species, to have a human half-life longer than 40 h and likely to have drug-drug-interactions (DDI), as 2 is a victim of CYP3A4 inhibition caused by its exclusive clearance pathway via CYP3A4 oxidation in humans. We now report 2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one (3) as a next generation NK1 antagonist that possesses an additional clearance pathway through glucuronidation in addition to that via CYP3A4 oxidation. Compound 3 has a much lower propensity for drug-drug interactions and a reduced estimated human half-life consistent with once daily dosing. In preclinical species, compound 3 has demonstrated potency, brain penetration, and a safety profile similar to 2, as well as excellent pharmacokinetics.
Assuntos
Isoindóis/síntese química , Antagonistas dos Receptores de Neurocinina-1/síntese química , Oxazóis/síntese química , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Interações Medicamentosas , Glucuronídeos/metabolismo , Humanos , Isoindóis/química , Isoindóis/farmacocinética , Isoindóis/farmacologia , Taxa de Depuração Metabólica , Antagonistas dos Receptores de Neurocinina-1/química , Antagonistas dos Receptores de Neurocinina-1/farmacocinética , Antagonistas dos Receptores de Neurocinina-1/farmacologia , Oxazóis/química , Oxazóis/farmacocinética , Oxazóis/farmacologia , Fragmentos de Peptídeos/farmacologia , Substância P/análogos & derivados , Substância P/farmacologiaRESUMO
3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one (17) is a high affinity, brain-penetrant, hydroisoindoline-based neurokinin-1 (NK(1)) receptor antagonist with a long central duration of action in preclinical species and a minimal drug-drug interaction profile. Positron emission tomography (PET) studies in rhesus showed that this compound provides 90% NK(1) receptor blockade in rhesus brain at a plasma level of 67 nM, which is about 10-fold more potent than aprepitant, an NK(1) antagonist marketed for the prevention of chemotherapy-induced and postoperative nausea and vomiting (CINV and PONV). The synthesis of this enantiomerically pure compound containing five stereocenters includes a Diels-Alder condensation, one chiral separation of the cyclohexanol intermediate, an ether formation using a trichloroacetimidate intermediate, and bis-alkylation to form the cyclic amine.