RESUMO
A novel series of tricyclic tetrahydroquinolines were identified as potent and selective CRTh2 receptor antagonists. The agonism and antagonism switch was achieved through structure-based drug design (SBDD) using a CRTh2 receptor homologue model. The challenge of very low exposures in pharmacokinetic studies was overcome by exhaustive medicinal chemistry lead optimization through focused SAR studies on the tricyclic core. Further optimization resulted in the identification of the preclinical candidate 4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic acid (15c, MK-8318) with potent and selective CRTh2 antagonist activity and a favorable PK profile suitable for once daily oral dosing for potential treatment of asthma.
RESUMO
New synthetic methods were developed for the preparation of 2,3,6-trisubstituted 1-oxo-1,2-dihydroisoquinolines as CRTh2 antagonists. The isoquinolinone core could be constructed before the introduction of substitution groups or synthesized through a catalytic intramolecular cyclization reaction with desired substitution groups properly installed. These synthetic strategies have helped to accelerate the SAR development of this series, and potent lead compounds were identified in both the CRTh2 receptor binding assay and the CD11b biomarker assay.
Assuntos
Isoquinolinas/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Novel bicyclic adenosine A(2A) antagonists with an aminoquinazoline moiety were designed and synthesized. The optimization of the initial lead compound based on in vitro and in vivo activity has led to the discovery of a potent and selective class of adenosine A(2A) antagonists. The structure-activity relationships of this novel series of bicyclic aminoquinazoline derivatives as adenosine A(2A) antagonists are described in detail.
Assuntos
Antagonistas do Receptor A2 de Adenosina/química , Quinazolinas/química , Receptor A2A de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/farmacocinética , Animais , Sítios de Ligação , Desenho de Fármacos , Meia-Vida , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Quinazolinas/síntese química , Quinazolinas/farmacocinética , Ratos , Receptor A2A de Adenosina/metabolismo , Relação Estrutura-AtividadeRESUMO
A unified strategy was conceived and implemented to deliver conformationally constrained anilides based on their preferred cis-amide conformers. The imidazole/triazole mimicing amide bonds were designed, building upon an earlier discovery of a novel series of tricyclic lactams MK2 kinase inhibitors. This approach enabled rapid, modular synthesis of structurally novel analogs. The efficient SAR development led to the discovery of low molecular weight and potent MK2 non-ATP competitive inhibitors with good ligand efficiency, which led to improved permeability and oral exposure in rats.
Assuntos
Amidas/química , Azóis/farmacologia , Descoberta de Drogas , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Azóis/síntese química , Azóis/química , Relação Dose-Resposta a Droga , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Conformação Molecular , Permeabilidade/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
Diacylglycerol acyltransferase 1 (DGAT1) presents itself as a potential therapeutic target for obesity and diabetes for its important role in triglyceride biosynthesis. Herein we report the rational design of a novel class of DGAT1 inhibitors featuring a benzomorpholine core (23n). SAR exploration yielded compounds with good potency and selectivity as well as reasonable physical and pharmacokinetic properties. This class of DGAT1 inhibitors was tested in rodent models to evaluate DGAT1 inhibition as a novel approach for the treatment of metabolic diseases. Compound 23n conferred weight loss and a reduction in liver triglycerides when dosed chronically in mice with diet-induced obesity and depleted serum triglycerides following a lipid challenge.
RESUMO
Herein we report the design and synthesis of a series of novel bicyclic DGAT1 inhibitors with a carboxylic acid moiety. The optimization of the initial lead compound 7 based on in vitro and in vivo activity led to the discovery of potent indoline and quinoline classes of DGAT1 inhibitors. The structure-activity relationship studies of these novel series of bicyclic carboxylic acid derivatives as DGAT1 inhibitors are described.
Assuntos
Ácidos Carboxílicos/farmacologia , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Quinolonas/farmacologia , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Diacilglicerol O-Aciltransferase/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-AtividadeRESUMO
Isoxazoles are frequently used amide isosteres, as shown in the context of discovery of CRTh2 antagonists from amide 1 to isoxazole 2. However, persistent agonism and poor solubility in isoxazole series presented challenges to its further development. Based on the concept of quality by design (QbD), 5,5-disubstituted isoxazolines 3 were introduced. The chirality at 5 position of isoxazolines controlled the switch between two modes of actions, which led to a novel series of pure antagonists. This non-planar motif also conferred a change of shape of these molecules, which avoided flat structures and improved their physical properties.
Assuntos
Amidas/química , Desenho de Fármacos , Isoxazóis/química , Quinazolinonas/química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Animais , Cães , Meia-Vida , Haplorrinos , Humanos , Isoxazóis/síntese química , Isoxazóis/farmacocinética , Quinazolinonas/síntese química , Quinazolinonas/farmacocinética , Ratos , Ratos Wistar , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Solubilidade , Relação Estrutura-AtividadeRESUMO
A novel series of non-imidazole bicyclic and tricyclic histamine H3 receptor antagonists has been discovered. Compound 17 was identified as a centrally penetrant molecule with high receptor occupancy which demonstrates robust oral activity in rodent models of obesity. In addition compound 17 possesses clean CYP and hERG profiles and shows no behavioral changes in the Irwin test.
Assuntos
Antagonistas dos Receptores Histamínicos H3/química , Antagonistas dos Receptores Histamínicos H3/uso terapêutico , Obesidade/tratamento farmacológico , Animais , Antagonistas dos Receptores Histamínicos H3/metabolismo , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Humanos , Microssomos Hepáticos/metabolismo , Ratos , Receptores Histamínicos H3/metabolismoRESUMO
A novel series of benzimidazolone-containing histamine H3-receptor antagonists were prepared and their structure-activity relationship was explored. These benzimidazolone analogs demonstrate potent H3-receptor binding affinities, no P450 enzyme inhibition, and strong H3 functional activity. Compound 1o exhibits the best overall profile with H3Ki=0.95nM and rat AUC=12.9µMh.
Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Antagonistas dos Receptores Histamínicos H3/química , Antagonistas dos Receptores Histamínicos H3/farmacologia , Animais , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Sistema Enzimático do Citocromo P-450/metabolismo , Cobaias , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Humanos , Ratos , Receptores Histamínicos H3/metabolismo , Relação Estrutura-AtividadeRESUMO
The optimization of oxazole-based PDE4 inhibitor 1 has led to the identification of both oral (compound 16) and inhaled (compound 34) PDE4 inhibitors. Selectivity against PDE10/PDE11, off target screening, and in vivo activity in the rat are discussed.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Oxazóis/química , Prolina/análogos & derivados , Quinolinas/síntese química , Administração Oral , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Inalação , Oxazóis/síntese química , Oxazóis/farmacocinética , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacocinética , Prolina/síntese química , Prolina/química , Prolina/farmacocinética , Quinolinas/química , Quinolinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Conformation restriction of linear N-alkylanilide MK2 inhibitors to their E-conformer was developed. This strategy enabled rapid advance in identifying a series of potent non-ATP competitive inhibitors that exhibited cell based activity in anti-TNFα assay.
Assuntos
Anilidas/química , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Lactamas/química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Anilidas/síntese química , Anilidas/metabolismo , Ligação Competitiva , Avaliação Pré-Clínica de Medicamentos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lactamas/síntese química , Lactamas/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The structure-activity relationship studies of a novel series of carboxylic acid derivatives of pyridine-carboxamides as DGAT-1 inhibitors is described. The optimization of the initial lead compound 6 based on in vitro and in vivo activity led to the discovery of key compounds 10j and 17h.
Assuntos
Amidas/farmacologia , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Piridinas/farmacologia , Animais , Diacilglicerol O-Aciltransferase/metabolismo , Inibidores Enzimáticos/química , Humanos , Camundongos , Relação Estrutura-AtividadeRESUMO
In an attempt to further improve overall profiles of the oxadiazine series of GSMs, in particular the hERG activity, conformational modifications of the core structure resulted in the identification of fused oxadiazepines such as 7i which had an improved hERG inhibition profile and was a highly efficacious GSM in vitro and in vivo in rats. These SAR explorations offer opportunities to identify potential drugs to treat Alzheimer's disease.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/metabolismo , Azepinas/síntese química , Descoberta de Drogas , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Animais , Azepinas/química , Azepinas/farmacologia , Canal de Potássio ERG1 , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
A detailed structure-activity relationship study of a novel series of pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of the PK profile of this series led to the discovery of compound 11g, which demonstrated in vivo potency ip in a lethal fungal infection model.
Assuntos
Antifúngicos/química , Inibidores Enzimáticos/química , Glucosiltransferases/antagonistas & inibidores , Piridazinas/química , Sulfonamidas/química , Animais , Antifúngicos/farmacocinética , Antifúngicos/uso terapêutico , Candida/efeitos dos fármacos , Candidíase/tratamento farmacológico , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Glucosiltransferases/metabolismo , Meia-Vida , Camundongos , Testes de Sensibilidade Microbiana , Piridazinas/farmacocinética , Piridazinas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêuticoRESUMO
The structure-activity relationship studies of a novel sulfonylurea series of piperazine pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of PK profiles within the series led to the discovery of several compounds with improved pharmacokinetic profiles which demonstrated in vitro potency against clinically relevant strains. However, the advancement of compounds from this series into a non-lethal systemic fungal infection model failed to show in vivo efficacy.
Assuntos
Antifúngicos/química , Inibidores Enzimáticos/química , Glucosiltransferases/antagonistas & inibidores , Chumbo/química , Piperazinas/química , Piridazinas/química , Compostos de Sulfonilureia/química , Animais , Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Linhagem Celular , Inibidores Enzimáticos/farmacologia , Humanos , Estrutura Molecular , Piperazina , Piridazinas/farmacologia , Ratos , Relação Estrutura-Atividade , Compostos de Sulfonilureia/farmacologiaRESUMO
The introduction of A ring pyrazole modification to the hydrocortisone C-21 heteroaryl thioethers generated compounds with excellent transrepression potency (IL-8 inhibition) compared to their hydrocortisone analogs. However, the transcriptional transactivation activity of these compounds were considerably higher than the corresponding hydrocortisone analogs. Among all the compounds evaluated, a quinoxaline thioether modification demonstrated the best overall in vitro separation.
Assuntos
Receptores de Glucocorticoides/efeitos dos fármacos , Esteroides/química , Sulfetos/química , Humanos , Hidrocortisona , Pirazóis/química , Relação Estrutura-Atividade , Sulfetos/farmacologia , Ativação Transcricional/efeitos dos fármacosRESUMO
A structure-activity relationship study was undertaken to address the lack of oral exposure of the H3 antagonist 1, which incorporated an arylketone. Among a number of sub-series, the 4H-pyrido[1,2-a]pyrimidin-4-one analog 21 showed an improved PK profile in rat and mouse and was active in an obesity model. The pyrimidin-4-one proved to be a novel and useful ketone bioisostere.
Assuntos
Antagonistas dos Receptores Histamínicos H3/farmacocinética , Tiadiazóis/farmacologia , Administração Oral , Animais , Cetonas , Obesidade/tratamento farmacológico , Ratos , Relação Estrutura-Atividade , Tiadiazóis/farmacocinéticaRESUMO
Optimization of oxazole-based PDE4 inhibitors has led to the discovery of a series of quinolyl oxazoles, with 4-benzylcarboxamide and 5-α-aminoethyl groups which exhibit picomolar potency against PDE4. Selectivity profiles and in vivo biological activity are also reported.
Assuntos
Anti-Inflamatórios/síntese química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Oxazóis/síntese química , Inibidores da Fosfodiesterase 4/síntese química , Quinolinas/síntese química , Animais , Anti-Inflamatórios/farmacologia , Óxidos N-Cíclicos/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Descoberta de Drogas , Humanos , Modelos Moleculares , Oxazóis/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Ratos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
The synthesis and SAR of a novel series of 4-azabenzoxazole histamine H(3) antagonists is described. Introduction of substituted phenyl, pyridyl and fused heterocyclic groups to the 6-position of the 4-azabenzoxazole core gave a series of compounds with good H(3) antagonist activity in both ex vivo and in vivo assays.
Assuntos
Benzoxazóis/química , Benzoxazóis/farmacologia , Antagonistas dos Receptores Histamínicos H3/química , Antagonistas dos Receptores Histamínicos H3/farmacologia , Receptores Histamínicos H3/metabolismo , Animais , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacocinética , Compostos Aza/farmacologia , Benzoxazóis/síntese química , Benzoxazóis/farmacocinética , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Humanos , Camundongos , Ratos , Relação Estrutura-AtividadeRESUMO
Based on in house screening lead compound 1 for the NAR project, SAR studies have been focused on the modification of the C2 ethers of the pyrimidinedione core structure. In this effort, an unpredictable SAR trend was overcome in the alkyl ether and arylalkyl ether series to identify compound 24 with improved in vitro activity compared to nicotinic acid. More consistent and predictable SAR was achieved in the propargyl ether series. Lead compound 41 was identified with good in vitro and in vivo activity in rat, and much improved rat PK profile.