RESUMO
Molecular modeling of unbound tricyclic guanine scaffolds indicated that they can serve as effective bioisosteric replacements of xanthines. This notion was further confirmed by a combination of X-ray crystallography and SAR studies, indicating that tricyclic guanine DPP4 inhibitors mimic the binding mode of xanthine inhibitors, exemplified by linagliptin. Realization of the bioisosteric relationship between these scaffolds potentially will lead to a wider application of cyclic guanines as xanthine replacements in drug discovery programs for a variety of biological targets. Newly designed DPP4 inhibitors achieved sub-nanomolar potency range and demonstrated oral activity in vivo in mouse glucose tolerance test.
Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Guanina/farmacologia , Xantinas/farmacologia , Animais , Glicemia/efeitos dos fármacos , Cristalografia por Raios X , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/química , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Guanina/análogos & derivados , Guanina/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Xantinas/administração & dosagem , Xantinas/químicaRESUMO
We have identified a series of novel insulin receptor partial agonists (IRPAs) with a potential to mitigate the risk of hypoglycemia associated with the use of insulin as an antidiabetic treatment. These molecules were designed as dimers of native insulin connected via chemical linkers of variable lengths with optional capping groups at the N-terminals of insulin chains. Depending on the structure, the maximal activation level (%Max) varied in the range of â¼20-70% of native insulin, and EC50 values remained in sub-nM range. Studies in minipig and dog demonstrated that IRPAs had sufficient efficacy to normalize plasma glucose levels in diabetes, while providing reduction of hypoglycemia risk. IRPAs had a prolonged duration of action, potentially making them suitable for once-daily dosing. Two lead compounds with %Max values of 30 and 40% relative to native insulin were selected for follow up studies in the clinic.
Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemia , Animais , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cães , Hipoglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Receptor de Insulina , Suínos , Porco Miniatura , Índice TerapêuticoRESUMO
The design of amide and heteroaryl amide isosteres as replacements for the carbamate substructure in previously disclosed 2,6-disubstituted piperidine N-arylsulfonamides is described. In several cases, amides lessened CYP liabilities in this class of gamma-secretase inhibitors. Selected compounds showed significant reduction of Abeta levels upon oral dosing in a transgenic murine model of Alzheimer's disease.
Assuntos
Amidas/química , Amidas/farmacologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Amidas/farmacocinética , Peptídeos beta-Amiloides/metabolismo , Animais , Carbamatos/química , Carbamatos/farmacocinética , Carbamatos/farmacologia , Inibidores das Enzimas do Citocromo P-450 , Compostos Heterocíclicos/farmacocinética , Camundongos , Oxidiazóis/química , Oxidiazóis/farmacocinética , Oxidiazóis/farmacologia , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/farmacologia , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
A novel methodology for parallel liquid-phase synthesis of carbamates suitable for the preparation of sterically hindered molecules is disclosed. The alcohols are converted to 4-nitrophenylcarbonates, followed by the reaction with amines. Side product 4-nitrophenol and the unreacted excess amines are scavenged by appropriately chosen cleanup resins, selected among Amberlyst A26 (hydroxide form) and macroporous sulfonic acid (MP-TsOH) or polystyrene isocyanate (PS-NCO) and polystyrene benzaldehyde (PS-PhCHO) resins. As a part of a medicinal chemistry program directed toward finding gamma-secretase inhibitors as prospective drug candidates for Alzheimer's disease, a 6 x 24 library of carbamates was prepared. Out of 144 library members, 133 had a purity for the targeted compound of 80% or better. The prepared compounds were assessed in the gamma-secretase inhibition assay and demonstrated activity with IC 50 values in the range from 1 microM to 5 nM, with the activity of 7 compounds being better than 10 nM.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Carbamatos , Técnicas de Química Combinatória , Inibidores Enzimáticos , Bibliotecas de Moléculas Pequenas , Precursor de Proteína beta-Amiloide/biossíntese , Precursor de Proteína beta-Amiloide/genética , Carbamatos/síntese química , Carbamatos/química , Carbamatos/farmacologia , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/enzimologia , Membrana Celular/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Estrutura Molecular , Mutação , Transição de Fase , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Soluções , Relação Estrutura-AtividadeRESUMO
The design and synthesis of a new series of tetrahydrobenzisoxazoles as modulators of γ-secretase activity and their structure-activity relationship (SAR) will be detailed. Several compounds are active γ-secretase modulators (GSMs) with good to excellent selectivity for the reduction of Aß42 in the cellular assay. Compound 14a was tested in vivo in a nontransgenic rat model and was found to significantly reduce Aß42 in the CNS compartment compared to vehicle-treated animals (up to 58% reduction of cerebrospinal fluid Aß42 as measured 3 h after an acute oral dosing at 30 mg/kg).
RESUMO
The design, synthesis, SAR, and biological profile of a substituted 4-morpholine sulfonamide series of γ-secretase inhibitors (GSIs) were described. In several cases, the resulting series of GSIs reduced CYP liabilities and improved γ-secretase inhibition activity compared to our previous research series. Selected compounds demonstrated significant reduction of amyloid-ß (Aß) after acute oral dosing in a transgenic animal model of Alzheimer's disease (AD).
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Morfolinas/química , Morfolinas/farmacologia , Sulfonamidas/química , Doença de Alzheimer/tratamento farmacológico , Animais , Inibidores Enzimáticos/uso terapêutico , Feminino , Masculino , Camundongos , Morfolinas/uso terapêutico , Relação Estrutura-AtividadeRESUMO
In the present paper, we described the design, synthesis, SAR, and biological profile of a novel spirocyclic sulfone series of γ-secretase inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic ring system to stabilize the active chair conformation of the parent γ-secretase inhibitors. The resulting series is devoid of the CYP2C9 inhibition liability of MRK-560. A few representative analogs were assessed in a nontransgenic animal model of Alzheimer's disease (AD), demonstrating reduction of amyloid-ß (Aß) in the CNS after acute oral dosing. A spirocyclic phosphonate was identified as the optimal ring system for both potency and pharmacokinetics. Compared to GSIs studied in the clinic, representative spirocyclic phosphonate 18a(-) features improved selectivity for the inhibition of the PS-1 isoform of γ-secretase (33-fold vs PS-2), which may alleviate the adverse effect profile of the clinical GSIs.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Descoberta de Drogas/métodos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Disponibilidade Biológica , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Inibidores das Enzimas do Citocromo P-450/farmacologia , Inibidores Enzimáticos/farmacocinética , Células HEK293 , Humanos , Conformação Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/farmacologiaRESUMO
Cyclic hydroxyamidines were designed and validated as isosteric replacements of the amide functionality. Compounds with these structural motifs were found to be metabolically stable and to possess highly desirable pharmacokinetic profiles. These designs were applied in the identification of γ-secretase modulators leading to highly efficacious agents for reduction of central nervous system Aß(42) in various animal models.
Assuntos
Amidinas/síntese química , Secretases da Proteína Precursora do Amiloide/metabolismo , Oxidiazóis/síntese química , Oxazinas/síntese química , Amidinas/farmacocinética , Amidinas/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Cães , Células HEK293 , Humanos , Macaca fascicularis , Masculino , Oxidiazóis/farmacocinética , Oxidiazóis/farmacologia , Oxazinas/farmacocinética , Oxazinas/farmacologia , Fragmentos de Peptídeos/metabolismo , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Development of cis-2,4,6-trisubstituted piperidine N-arylsulfonamides as gamma-secretase inhibitors for the potential treatment of Alzheimer's disease (AD) is reported.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Citocromo P-450 CYP3A/efeitos dos fármacos , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Piperidinas/química , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
The development of a novel series of tetrahydroquinoline-derived gamma-secretase inhibitors for the potential treatment of Alzheimer's disease is described.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores de Proteases/química , Quinolinas/química , Sulfonamidas/química , Humanos , Inibidores de Proteases/síntese química , Quinolinas/síntese química , Relação Estrutura-Atividade , Sulfonamidas/síntese químicaRESUMO
The design and development of a new class of small 2,6-disubstituted piperidine N-arylsulfonamide gamma-secretase inhibitors is reported. Lowering molecular weight including the use of conformational constraint led to compounds with less CYP 3A4 liability compared to early leads. Compounds active orally in lowering Abeta levels in Tg CRND8 mice were identified as potential treatments for Alzheimer's disease.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Piperidinas/síntese química , Piperidinas/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Administração Oral , Peptídeos beta-Amiloides/biossíntese , Animais , Área Sob a Curva , Sistema Enzimático do Citocromo P-450/metabolismo , Desenho de Fármacos , Espectroscopia de Ressonância Magnética , Camundongos , Conformação Molecular , Peso Molecular , Oxirredutases/metabolismoRESUMO
Attachment of the cyclopropylcarbamate group to the piperidine core of gamma-secretase inhibitors leads to a dramatic increase of their in vitro potency. Strategies for subsequent improvement of the in vivo pharmacokinetic profile of the series are discussed. Resulting compounds significantly reduce Abeta levels in TgCRND8 mice after a single PO dosing at 30 mpk.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/biossíntese , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Área Sob a Curva , Cristalografia por Raios X , Inibidores Enzimáticos/farmacocinética , Humanos , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Conformação Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
A novel piperidine series of gamma-secretase inhibitors, potentially useful for the treatment of Alzheimer's disease, is disclosed. SAR investigation revealed the requirement for cis-stereochemistry of the substituents attached to the core, which resulted in the chair-like diaxial conformation of the piperidine ring. The series was optimized to provide inhibitors with IC(50)'s in the single-digit nanomolar range. Absolute stereochemistry of the active enantiomer was assigned.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Piperidinas/química , Inibidores de Proteases/química , Concentração Inibidora 50 , Piperidinas/síntese química , Inibidores de Proteases/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
In search of a PDE5 inhibitor for erectile dysfunction, an SAR was developed from a PDE1/PDE5 purine series of leads, which had modest PDE5 potency and poor isozyme selectivity. A compound (41) with PDE5 inhibition and in vivo activity similar to sildenafil was discovered from this effort. In addition, purine 41 demonstrated superior overall PDE isozyme selectivity when compared to the approved PDE5 inhibitors sildenafil, vardenafil, and tadalafil, which may result in a more favorable side-effect profile.
Assuntos
Disfunção Erétil/tratamento farmacológico , Fosfodiesterase I/metabolismo , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/metabolismo , Purinas/síntese química , Purinas/uso terapêutico , 3',5'-GMP Cíclico Fosfodiesterases , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Humanos , Masculino , Modelos Moleculares , Estrutura Molecular , Piperazinas/farmacologia , Purinas/química , Ratos , Citrato de Sildenafila , Relação Estrutura-Atividade , Sulfonas , Vasodilatadores/síntese química , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêuticoRESUMO
Development of structure-activity relationship of cyclic guanines I lead us to discovery of a potent and selective series of phosphodiesterase 5 inhibitors 52-59 (IC50=1.3-11.0 nM, PDE6/5=116-600).