RESUMO
A ligand-based virtual screening exercise examining likely bioactive conformations of AM 580 (2) and AGN 193836 (3) was used to identify the novel, less lipophilic RARα agonist 4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid 5, which has good selectivity over the RARß, and RARγ receptors. Analysis of the medicinal chemistry parameters of the 3,5-substituents of derivatives of template 5 enabled us to design a class of drug-like molecules with lower intrinsic clearance and higher oral bioavailability which led to the novel RARα agonist 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid 56 that has high RARα potency and excellent selectivity versus RARß (2 orders of magnitude) and RARγ (4 orders of magnitude) at both the human and mouse RAR receptors with improved drug-like properties. This RARα specific agonist 56 has high oral bioavailability (>80%) in both mice and dogs with a good PK profile and was shown to be inactive in cytotoxicity and genotoxicity screens.
Assuntos
Aminobenzoatos/química , Benzoatos/química , Desenho de Fármacos , Receptor alfa de Ácido Retinoico/agonistas , Tetra-Hidronaftalenos/química , Administração Oral , Aminobenzoatos/farmacocinética , Aminobenzoatos/toxicidade , Animais , Benzoatos/farmacocinética , Benzoatos/toxicidade , Células COS , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Meia-Vida , Células Hep G2 , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Ratos , Receptores do Ácido Retinoico/agonistas , Receptores do Ácido Retinoico/metabolismo , Receptor alfa de Ácido Retinoico/metabolismo , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/farmacocinética , Tetra-Hidronaftalenos/toxicidade , Receptor gama de Ácido RetinoicoRESUMO
A 1,3,4-benzotriazepine was identified as a suitable lead in our effort toward obtaining a non-peptide parathyroid hormone-1 receptor (PTH1R) antagonist. A process of optimization afforded derivatives displaying nanomolar PTH1R affinity, a representative example of which behaved as a PTH1R antagonist in cell-based cyclic adenosine monophosphate (cAMP) assays, with selectivity over PTH2 receptors.
Assuntos
Benzazepinas/síntese química , Receptor Tipo 1 de Hormônio Paratireóideo/antagonistas & inibidores , Animais , Benzazepinas/química , Benzazepinas/farmacologia , Ligação Competitiva , Linhagem Celular , Linhagem Celular Tumoral , Cricetinae , Cricetulus , AMP Cíclico/biossíntese , Humanos , Camundongos , Ensaio Radioligante , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
Starting from a novel, achiral 1,3,4-benzotriazepine-based CCK2 receptor antagonist, a process of optimization has afforded further compounds of this type that maintain the nanomolar affinity for recombinant, human CCK2 receptors and high selectivity over CCK1 receptors observed in the initial lead but display more potent inhibition of pentagastrin-stimulated gastric acid secretion in vivo. Moreover, this has largely been achieved without altering their potency at wild-type canine and rat receptors, as judged by their displacement of [125I]-BH-CCK-8S in a radioligand binding assay and by their activity in an isolated, perfused rat stomach bioassay, respectively. 2-(5-Cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl)-N-(3-(5-oxo-2,5-dihydro- [1,2,4]oxadiazol-3-yl)-phenyl)-acetamide (47) was identified as the most effective compound stemming from this approach, proving to be a potent inhibitor of pentagastrin-stimulated gastric acid secretion in rats and dogs by intravenous bolus as well as by enteral administration.
Assuntos
Benzodiazepinas/síntese química , Ácido Gástrico/metabolismo , Pentagastrina/farmacologia , Receptor de Colecistocinina B/antagonistas & inibidores , Administração Oral , Animais , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Cães , Mucosa Gástrica/metabolismo , Humanos , Infusões Intravenosas , Injeções Intravenosas , Camundongos , Células NIH 3T3 , Ensaio Radioligante , Ratos , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
A series of 1,3,4-benzotriazepine-based CCK(2) antagonists have been devised by consideration of the structural features that govern CCK receptor affinity and the receptor subtype selectivity of 1,4-benzodiazepine-based CCK(2) antagonists. In contrast to the latter compounds, these novel 1,3,4-benzotriazepines are achiral, yet they display similar affinity for CCK(2) receptors to the earlier molecules and are highly selective over CCK(1) receptors.
Assuntos
Benzazepinas/síntese química , Receptor de Colecistocinina A/antagonistas & inibidores , Receptor de Colecistocinina B/antagonistas & inibidores , Animais , Benzazepinas/química , Benzazepinas/farmacologia , Benzodiazepinas/química , Linhagem Celular , Cricetinae , Cricetulus , Cristalografia por Raios X , Humanos , Camundongos , Estrutura Molecular , Ensaio Radioligante , Ratos , Receptor de Colecistocinina A/química , Receptor de Colecistocinina B/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Chemokine receptor 9 (CCR9), a cell surface chemokine receptor which belongs to the G protein-coupled receptor, 7-trans-membrane superfamily, is expressed on lymphocytes in the circulation and is the key chemokine receptor that enables these cells to target the intestine. It has been proposed that CCR9 antagonism represents a means to prevent the aberrant immune response of inflammatory bowel disease in a localized and disease specific manner and one which is accessible to small molecule approaches. One possible reason why clinical studies with vercirnon, a prototype CCR9 antagonist, were not successful may be due to a relatively poor pharmacokinetic (PK) profile for the molecule. We wish to describe work aimed at producing new, orally active CCR9 antagonists based on the 1,3-dioxoisoindoline skeleton. This study led to a number of compounds that were potent in the nanomolar range and which, on optimization, resulted in several possible preclinical development candidates with excellent PK properties.
Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Isoindóis/química , Receptores CCR/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Técnicas de Química Sintética , Quimiotaxia/efeitos dos fármacos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Isoindóis/administração & dosagem , Isoindóis/farmacocinética , Masculino , Camundongos Endogâmicos C57BL , Receptores CCR/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMO
A new molecular modeling approach has been used to derive a pharmacophore of the potent and selective cholecystokinin-2 (CCK(2)) receptor antagonist 5 (JB93182), based on features shared with two related series. The technique uses "field points" as simple and effective descriptions of the electrostatic and van der Waals maxima and minima surrounding a molecule equipped with XED (extended electron distribution) charges. Problems associated with the high levels of biliary elimination of 5 in vivo required us to design a compound with significantly lower molecular weight without sacrificing its nanomolar levels of in vitro activity. Two new series of compounds were designed to mimic the arrangement of field points present in the pharmacophore rather than its structural elements. In a formal sense, two of the three amides in 5 were replaced with either a simple pyrrole or imidazole, while some features thought to be essential for the high levels of in vitro activity of the parent compounds were retained and others deleted. These compounds maintained activity and selectivity for this receptor over CCK(1). In addition, the reduction in molecular weight coupled with lower polarities greatly reduced levels of biliary elimination associated with 5. This makes them good lead compounds for development of drug candidates whose structures are not obviously related to those of the parents and represents the first example of scaffold hopping using molecular field points.
Assuntos
Imidazóis/química , Modelos Moleculares , Pirróis/química , Receptor de Colecistocinina B/agonistas , Receptor de Colecistocinina B/antagonistas & inibidores , Animais , Ligação Competitiva , Córtex Cerebral/metabolismo , Desenho de Fármacos , Imidazóis/síntese química , Imidazóis/farmacologia , Técnicas In Vitro , Camundongos , Conformação Molecular , Pirróis/síntese química , Pirróis/farmacologia , Relação Quantitativa Estrutura-Atividade , Ensaio Radioligante , Receptor de Colecistocinina B/metabolismoRESUMO
The systematic optimization of the structure of a novel 2,4,5-trisubstituted imidazole-based cholecystokinin-2 (CCK(2)) receptor antagonist afforded analogues with nanomolar receptor affinity. These compounds were now comparable in their potency to the bicyclic heteroaromatic-based compounds 5 (JB93182) and 6 (JB95008), from which the initial examples were designed using a field-point based molecular modeling approach. They were also orally active as judged by their inhibition of pentagastrin stimulated acid secretion in conscious dogs, in contrast to the bicyclic heteroaromatic-based compounds, which were ineffective because of biliary elimination. Increasing the hydrophilicity through replacement of a particular methylene group with an ether oxygen, as in 3-{[5-(adamantan-1-yloxymethyl)-2-cyclohexyl-1H-imidazole-4-carbonyl]amino}benzoic acid (53), had little effect on the receptor affinity but significantly increased the oral potency. Comparison of the plasma pharmacokinetics and the inhibition of pentagastrin-stimulated acid output following bolus intraduodenal administration of both 53 and 6 indicated that 53 was well absorbed, had a longer half-life, and was not subject to the elimination pathways of the earlier series.
Assuntos
Imidazóis/síntese química , Pirróis/síntese química , Receptor de Colecistocinina B/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Córtex Cerebral/metabolismo , Cães , Feminino , Ácido Gástrico/metabolismo , Imidazóis/química , Imidazóis/farmacologia , Técnicas In Vitro , Infusões Intravenosas , Camundongos , Modelos Moleculares , Pentagastrina/administração & dosagem , Pentagastrina/farmacologia , Pirróis/química , Pirróis/farmacologia , Relação Quantitativa Estrutura-Atividade , Ensaio RadioliganteRESUMO
The syntheses and structures of three cyclophanes containing two (Z)-dehydrophenylalanine residues are reported; the length of the tethers between the two amino acid residues is easily altered and changing this parameter has a significant effect on the solid state structures of the cyclophanes.
Assuntos
Éteres Cíclicos/química , Éteres Cíclicos/síntese química , Fenilalanina/análogos & derivados , Fenilalanina/química , Fenilalanina/síntese química , Cristalografia por Raios X , Conformação Molecular , Estrutura MolecularRESUMO
The conformationally constrained analogues of phenylalanine, tetrahydroisoquinoline-3-carboxylic acid (Tic), Sic, Hic and Nic, and the new amino acid Xic have been incorporated into a potent and highly selective cholecystokinin-2 (CCK(2)) receptor antagonist (2) in place of the phenylalanine residue, producing compounds 15a-e. High selectivities for CCK(2) over CCK(1) were observed for compounds 15a-e. The in vitro profile of the analogue containing the Nic residue (15d) was identical to that of compound 2, whereas the alternative conformational constraints resulted in a significant loss of affinity. The apparent advantage of Nic in the context of these CCK(2) ligands was subsequently demonstrated to be statistically significant.
Assuntos
Compostos Heterocíclicos com 2 Anéis/síntese química , Fenilalanina/química , Receptores da Colecistocinina/antagonistas & inibidores , Tetra-Hidroisoquinolinas , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Mucosa Gástrica/metabolismo , Cobaias , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Técnicas In Vitro , Isoquinolinas/química , Ligantes , Camundongos , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Ratos , Receptor de Colecistocinina B , Estômago/efeitos dos fármacosRESUMO
There has been an effort towards the design and preparation of non-peptide antagonists of the CCK(2) receptor going back for over fifteen years. However, as no obvious unmet medical need for this type of molecule has emerged, the interest has somewhat declined. A number of comprehensive reviews have been written where much of the early work is described and so this article focuses on the information generated in the last five years. It is to be hoped that the area will regain some impetus following the recent disclosure of clinical trial data demonstrating the possible utility of a CCK(2) antagonist in pancreatic cancer. When considering non-peptide agonists for the CCK(2) receptor, traditionally, much less work has been reported in the area. However, recent suggestions of possible clinical utility in the treatment of diabetes, functionally different subtypes of the receptor and molecular models of receptor-ligand interactions should act as a spur for work towards potent small molecule ligands.
Assuntos
Desenho de Fármacos , Receptor de Colecistocinina B/agonistas , Receptor de Colecistocinina B/antagonistas & inibidores , Animais , Humanos , Ligantes , Peptídeos/metabolismo , Receptor de Colecistocinina B/metabolismoRESUMO
This review generally describes work in the area of CCK2 or gastrin receptor agonists and antagonists before focussing on highlights of studies in these areas carried out at the James Black Foundation over the last dozen years. Thus, an alanine scan of BOC-tetragastrin coupled with a bioassay in the isolated mouse stomach led to new insights as to the nature of the function of the various residues of the peptide. This in turn produced molecules such as the peptoid, JB 90118 which was an antagonist in all in vitro systems explored but was found to be CCK1 selective and an agonist still in vivo. We then go on to describe attempts to mimic a putative 3(10) helical conformation for BOC-tetragastrin which had been suggested by fluorescence studies. Structures based on the dibenzobicylo[2.2.2]octane skeleton appeared to fulfil the requirements of the pharmacophore and promising initial results were obtained after the requisite molecules were synthesised. Optimisation of this series led to compounds with affinities in the nanomolar range but which were lacking in consistency when examined in vivo. Further manipulation, this time of the skeleton, led to molecules such as JB 93182 which were of equivalent affinity but with a better profile of action in vivo. It was found during exploration of the SAR of this new series that even relatively small alterations to the structure could give rise to molecules which behaved as agonists. Attempts to improve the oral bioavailability of JB 93182 by reduction of its molecular weight were aided by a molecular modelling approach which ultimately gave rise to another new series, some imidazole derivatives, exemplified by JB 98248.
Assuntos
Gastrinas , Animais , Gastrinas/agonistas , Gastrinas/antagonistas & inibidores , Indóis/química , Indóis/farmacologia , Camundongos , Modelos Moleculares , Ratos , Relação Estrutura-AtividadeRESUMO
omega-(1H-Imidazol-4-yl)alkane-1-sulfonamides were prepared and found to be potent histamine H(3) receptor antagonists. High receptor affinity and a low difference in the data between the bioassays were achieved with 5-(1H-imidazol-4-yl)pentane-1-sulfonic acid 4-chlorobenzylamide (16). Good in vitro profiles were also obtained for 2-hydroxysulfonamide and vinylsulfonamide analogues. This complements and completes the existing set of imidazole-based sulfonamides and sulfamides.
Assuntos
Compostos de Benzil/química , Compostos de Benzil/farmacologia , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Receptores Histamínicos H3/efeitos dos fármacos , Animais , Bioquímica/métodos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Cobaias , Relação Estrutura-AtividadeRESUMO
Amino alcohols have been used to introduce non-racemic chirality into macrocycles using a modular approach that relies on a Heck macrocyclisation reaction. A wide variety of macrocycles have been synthesised, and their structures studied using X-ray crystallography and molecular modelling. A fragmentation reaction encountered during the use of (S)-1,1-dimethylvalinol revealed that carboxylic acids generate acylals under reaction conditions often used for Heck reactions.