RESUMO
Starting from screening hit, (4S,7R)-1,7,8,8-tetramethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (7), we optimized the potency and pharmacokinetic properties. This led to the identification of compounds with good in vivo activity in a mouse pharmacodynamic model of inhibition of 11ßHSD1.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Cânfora/química , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Pirazolonas/síntese química , Pirazolonas/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Animais , Ativação Enzimática/efeitos dos fármacos , Feminino , Hidrocortisona/sangue , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , RatosRESUMO
Benzimidazole and indane are the two key fragments in our potent and selective MCH-1 receptor (MCHR1) antagonists. To identify novel linkers connecting the two fragments, we investigated diamino-cycloalkane-derived analogs and discovered highly potent antagonists with cis-1,4-diaminocyclohexane as a unique spacer in this chemical class. Structural overlay suggested that cis-1-substituted-4-aminocyclohexane functions as a bioisostere of 4-substituted-piperidine and that the active conformation adopts a U-shaped orientation.
Assuntos
Cicloexanos/química , Indanos/química , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Animais , Benzimidazóis/química , Meia-Vida , Indanos/metabolismo , Indanos/farmacocinética , Isomerismo , Camundongos , Ligação Proteica , Ratos , Receptores do Hormônio Hipofisário/metabolismoRESUMO
From a series of N-acyl 4-(3-pyridonyl)phenylalanine derivatives of 4, the trifluoromethyl derivative 28 was identified as a potent, dual acting alpha4 integrin antagonist with activity in primate models of allergic asthma. Investigation of a series of prodrug esters led to the discovery of the morpholinopropyl derivative 48 that demonstrated good intestinal fluid stability, solubility and permeability. Compound 48 gave high blood levels of 28 when dosed orally in cynomolgus monkeys. Surprisingly, hydrolysis of 48 was rapid in liver microsomes from the pharmacological species, mouse, rat and monkey, but slow in dog and human; in vivo studies also indicated there was prolonged exposure to unchanged prodrug in dogs.
Assuntos
Integrina alfa4beta1/antagonistas & inibidores , Integrinas/antagonistas & inibidores , Fenilalanina/análogos & derivados , Animais , Cães , Ésteres/sangue , Ésteres/farmacologia , Humanos , Camundongos , Fenilalanina/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , RatosRESUMO
N-Acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives of type 4 were designed to replace the 2,6-dichlorobenzoylamine portion of compound 1 in order to identify novel compounds with improved potency against α4-integrins. Several derivatives were identified as very potent dual-acting α4-integrin, α4ß1 and α4ß7 antagonists. Investigation of a limited number of prodrug esters led to the discovery of the ethyl ester prodrug 42, which demonstrated good intestinal fluid stability and good permeability. Despite low solubility, 42 gave acceptable blood levels of 30 when dosed orally in non-human primates. Additionally, 42 had an overall excellent profile and was selected for clinical trials. Investigation of N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives led to the discovery of several very potent dual-acting α4-integrin antagonists. Ethyl ester prodrug 42 advanced to human clinical trials based on the excellent intestinal fluid stability, good permeability and superior efficacy in non-human primates.
Assuntos
Integrina alfa4beta1/antagonistas & inibidores , Integrinas/antagonistas & inibidores , Fenilalanina/análogos & derivados , Pirimidinas/farmacologia , Animais , Cães , Ésteres/química , Ésteres/farmacocinética , Ésteres/farmacologia , Humanos , Macaca fascicularis , Camundongos , Fenilalanina/farmacocinética , Fenilalanina/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Pirimidinas/química , Pirimidinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
IMPORTANCE OF THE FIELD: Small molecule glucokinase activators (GKAs) continue to represent a potential strategy to treat type 2 diabetes (T2D). Glucokinase (GK) primarily exerts its effect through modulatory actions in pancreatic ß-cells and hepatocytes. It couples insulin secretion in the pancreas with plasma glucose concentration and improves glucose utilization in the liver, thus, affecting two key aspects of glucose homeostasis. There has been an intense interest in GKAs within the pharmaceutical industry ever since the first report of a low molecular mass activator in 2003. The key drivers for this interest are the robust glucose lowering activity observed with GKAs in preclinical T2D animal models and early reports of efficacy in T2D patients. AREAS COVERED IN THIS REVIEW: The objective is to review GKA structures disclosed during the 2008 - 2010 period and classify them based on key structural features. For this purpose, only compound data from patent disclosures were used. WHAT THE READER WILL GAIN: The reader would gain a detailed view of structural diversity of the GKA field disclosed during the review period. TAKE HOME MESSAGE: There continues to be a high level of interest within the pharmaceutical industry in novel GKAs. Several new and highly potent structure types were reported for the first time in the past 3 years. Common features of all of them include a hydrogen bond donor-acceptor pair that makes contact with the backbone CO- and NH- bonds of Arg 63 residue on GK and two hydrophobic groups. During this review period, several GKAs progressed to Phase II clinical testing and the data on their safety and efficacy profiles are eagerly awaited.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucoquinase/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Desenho de Fármacos , Indústria Farmacêutica , Ativação Enzimática/efeitos dos fármacos , Glucoquinase/metabolismo , Humanos , Hipoglicemiantes/química , Patentes como AssuntoRESUMO
These two patent applications describe a subset of compounds previously claimed generically. Although both represent potentially exciting novel structural types, not previously associated with glucokinase activation, neither provides any relevant biological data to support their practical utility. Glucokinase activators from both Array Biopharma and Novo Nordisk (through their partner, Transtech Pharma) have entered the clinical development pipeline, but it is presently unknown whether the above patent applications cover any of these compounds.
Assuntos
Ativação Enzimática/efeitos dos fármacos , Glucoquinase/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/enzimologia , Glucoquinase/metabolismo , Humanos , Patentes como AssuntoRESUMO
This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and safety.
Assuntos
Indanos/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Amidas/química , Amidas/farmacocinética , Amidas/farmacologia , Animais , Benzimidazóis/química , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Cristalografia por Raios X , Humanos , Indanos/química , Indanos/farmacocinética , Cinética , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Somatostatina/química , Receptores de Somatostatina/metabolismo , Relação Estrutura-AtividadeRESUMO
Starting with a cyclic peptide of moderate potency as a VLA-4 antagonist, highly potent and conformationally defined cyclic peptides were developed incorporating a constrained tyrosine and an achiral Asp-Pro spacer. N-Acyl phenylalanine derivatives were also discovered to have VLA-4 antagonist activity. During the course of development of this series, we found that the active acylphenylalanines mimic the pharmacophores present in the cyclic peptides and hypothesized that they bind to the same site on VLA-4. This insight guided our optimization strategy. Based on the emerging SAR, as well as insights from the recent X-ray crystal structure of the integrin alphavbeta3 bound to a RGD containing cyclic peptide, we propose a binding model for these compounds.
Assuntos
Integrina alfa4beta1/antagonistas & inibidores , Humanos , Concentração Inibidora 50 , Mimetismo Molecular , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Relação Estrutura-AtividadeRESUMO
Nuclear magnetic resonance (NMR) methods were employed to study the interaction of the cytokine Interleukin-2 (IL-2) with the alpha-subunit of its receptor (IL-2Ralpha), and to help understand the behavior of small molecule inhibitors of this interaction. Heteronuclear (1)H-(15)N HSQC experiments were used to identify the interaction surface of (15)N-enriched Interleukin-2 ((15)N-IL-2) in complex with human IL-2Ralpha. In these experiments, chemical shift and line width changes in the heteronuclear single-quantum coherence (HSQC) spectra upon binding of (15)N-IL-2 enabled classification of NH atoms as either near to, or far from, the IL-2Ralpha interaction surface. These data were complemented by hydrogen/deuterium (H/D) exchange measurements, which illustrated enhanced protection of slowly-exchanging IL-2 NH protons near the site of interaction with IL-2Ralpha. The interaction surface defined by NMR compared well with the IL-2Ralpha binding site identified previously using mutagenesis of human and murine IL-2. Two low molecular weight inhibitors of the IL-2/IL-2Ralpha interaction were studied: one (a cyclic peptide derivative) was found to mimic a part of the cytokine and bind to IL-2Ralpha; the other (an acylphenylalanine derivative) was found to bind to IL-2. For the interaction between IL-2 and the acylphenylalanine, chemical shift perturbations of (15)N and (15)NH backbone resonances were tracked as a function of ligand concentration. The perturbation pattern observed for this complex revealed that the acylphenylalanine is a competitive inhibitor-it binds to the same site on IL-2 that interacts with IL-2Ralpha.
Assuntos
Interleucina-2/metabolismo , Receptores de Interleucina/metabolismo , Subunidade alfa de Receptor de Interleucina-2 , Ligantes , Espectroscopia de Ressonância Magnética , Pichia/metabolismoRESUMO
A systematic structure-activity relationship investigation of the lead compound 1 resulted the identification of several N-[(substituted alkyl)cycloalkanoyl]-4-[((2,6-dichlorophenyl)carbonyl)amino]-L-phenylalanine derivatives as potent VCAM/VLA-4 antagonists. The data are consistent with a model of these compounds in which these alkanoylphenylalanines reside in a compact gauche (-) bioactive conformation.
Assuntos
Integrina alfa4beta1/antagonistas & inibidores , Fenilalanina/análogos & derivados , Molécula 1 de Adesão de Célula Vascular/efeitos dos fármacos , Cristalografia por Raios X , Cicloparafinas/síntese química , Cicloparafinas/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Fenilalanina/farmacologia , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
A series of N-benzoyl-4-[(2,6-dichlorobenzoyl)amino]-L-phenylalanine derivatives was prepared in order to optimize the substitution on the N-benzoyl moiety for VCAM/VLA-4 antagonist activity. Disubstitution in the 2- and 6-positions is favored and a range of small alkyl and halogen are tolerated. A model of the bioactive conformation of these compounds is proposed.
Assuntos
Integrina alfa4beta1/antagonistas & inibidores , Fenilalanina/análogos & derivados , Molécula 1 de Adesão de Célula Vascular/efeitos dos fármacos , Compostos Heterocíclicos/química , Humanos , Hidrocarbonetos Aromáticos , Concentração Inibidora 50 , Modelos Moleculares , Mimetismo Molecular , Fenilalanina/farmacologia , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
A structure-based focused library approach was employed in an effort to identify more lipophilic replacements for the N-benzylpyroglutamyl group of the VCAM/VLA-4 antagonist 2. This effort led to the discovery of two new classes of potent antagonists characterized by the N-(alpha-phenylcyclopentanoyl- and the N-(2,6-dimethylbenzoyl)-derivatives 60 and 64.