RESUMO
Inhibition of leucine-rich repeat kinase 2 (LRRK2) kinase activity represents a genetically supported, chemically tractable, and potentially disease-modifying mechanism to treat Parkinson's disease. Herein, we describe the optimization of a novel series of potent, selective, central nervous system (CNS)-penetrant 1-heteroaryl-1H-indazole type I (ATP competitive) LRRK2 inhibitors. Type I ATP-competitive kinase physicochemical properties were integrated with CNS drug-like properties through a combination of structure-based drug design and parallel medicinal chemistry enabled by sp3-sp2 cross-coupling technologies. This resulted in the discovery of a unique sp3-rich spirocarbonitrile motif that imparted extraordinary potency, pharmacokinetics, and favorable CNS drug-like properties. The lead compound, 25, demonstrated exceptional on-target potency in human peripheral blood mononuclear cells, excellent off-target kinase selectivity, and good brain exposure in rat, culminating in a low projected human dose and a pre-clinical safety profile that warranted advancement toward pre-clinical candidate enabling studies.
Assuntos
Doença de Parkinson , Ratos , Humanos , Animais , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença de Parkinson/tratamento farmacológico , Indazóis/farmacologia , Indazóis/uso terapêutico , Leucócitos Mononucleares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/química , Encéfalo/metabolismo , Trifosfato de AdenosinaRESUMO
The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder whose current therapies are limited in scope and efficacy. In this report, we describe a rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated in the discovery of brain-penetrant, candidate-quality molecules as represented by compounds 22 and 24. These compounds exhibit remarkable selectivity against the kinome and offer good oral bioavailability and low projected human doses. Furthermore, they showcase the implementation of stereochemical design elements that serve to enable a potency- and selectivity-enhancing increase in polarity and hydrogen bond donor (HBD) count while maintaining a central nervous system-friendly profile typified by low levels of transporter-mediated efflux and encouraging brain penetration in preclinical models.
Assuntos
Antiparkinsonianos/síntese química , Antiparkinsonianos/farmacologia , Encéfalo/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/antagonistas & inibidores , Quinazolinas/síntese química , Quinazolinas/farmacologia , Antiparkinsonianos/farmacocinética , Disponibilidade Biológica , Desenho de Fármacos , Humanos , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacocinética , Relação Estrutura-AtividadeRESUMO
Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists are used to treat type 2 diabetes mellitus (T2DM). Widespread use of PPARgamma agonists has been prevented due to adverse effects including weight gain, edema, and increased risk of congestive heart failure. Selective PPARgamma modulators (SPPARgammaMs) have been identified that have antidiabetic efficacy and reduced toxicity in preclinical species. In comparison with PPARgamma full agonists, SPPARgammaM 6 (MK0533) displayed diminished maximal activity (partial agonism) in cell-based transcription activation assays and attenuated gene signatures in adipose tissue. Compound 6 exhibited comparable efficacy to rosiglitazone and pioglitazone in vivo. However, with regard to the induction of untoward events, 6 displayed no cardiac hypertrophy, attenuated increases in brown adipose tissue, minimal increases in plasma volume, and no increases in extracellular fluid volume in vivo. Further investigation of 6 is warranted to determine if the improvement in mechanism-based side effects observed in preclinical species will be recapitulated in humans.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacocinética , Indóis/farmacocinética , PPAR gama/agonistas , Animais , Volume Sanguíneo/efeitos dos fármacos , Líquidos Corporais/efeitos dos fármacos , Cães , Haplorrinos , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Indóis/efeitos adversos , Indóis/uso terapêutico , Pioglitazona , Ratos , Rosiglitazona , Relação Estrutura-Atividade , TiazolidinedionasRESUMO
Routine screening for human PPAR ligands yielded compounds 1 and 2, both of which were sub-micromolar hPPARgamma agonists. Synthetic modifications of these leads led to a series of potent substituted 3-benzyl-2-methyl indoles, a subset of which were noted to be selective PPARgamma modulators (SPPARgammaMs). SPPARgammaM 24 displayed robust anti-diabetic activity with an improved therapeutic window in comparison to a PPARgamma full agonist in a rodent efficacy model.
Assuntos
Mediadores da Inflamação/metabolismo , PPAR gama/agonistas , Animais , Benzoatos/síntese química , Benzoatos/farmacologia , Benzoatos/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Indóis/síntese química , Indóis/farmacologia , Indóis/uso terapêutico , Ligantes , Estrutura Molecular , PPAR gama/metabolismoRESUMO
A series of metabolically robust N-benzyl-indole selective PPARgamma modulators with either a 3-benzoyl or 3-benzisoxazoyl moiety have been identified. In vitro, these compounds are partial agonists and exhibit reduced adipogenesis in human adipocytes. In vivo, these SPPARgammaMs result in potent glucose lowering in db/db mice and attenuate increases in heart weight and brown adipose tissue that is typically observed in rats upon treatment with PPARgamma full agonists.