RESUMO
A series of potent non-acetylinic negative allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5 NAMs) was developed starting from HTS screening hit 1. Potency was improved via iterative SAR, and physicochemical properties were optimized to deliver orally bioavailable compounds acceptable for in vivo testing. A lead molecule from the series demonstrated dose-dependent activity in the second phase of the rat formalin test from 30 mg/kg, and a preliminary PK/PD relationship was established.
Assuntos
Piridinas/síntese química , Receptor de Glutamato Metabotrópico 5/agonistas , Animais , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5/químicaRESUMO
An efficient total synthesis of the natural alkaloid (+)-dumetorine by using flow technology is described. The process entailed five separate steps starting from the enantiopure (S)-2-(piperidin-2-yl)ethanol 4 with 29% overall yield. Most of the reactions were carried out by exploiting solvent superheating and by using packed columns of immobilized reagents or scavengers to minimize handling. New protocols for performing classical reactions under continuous flow are disclosed: the ring-closing metathesis reaction with a novel polyethylene glycol-supported Hoveyda catalyst and the unprecedented flow deprotection/Eschweiler-Clarke methylation sequence. The new protocols developed for the synthesis of (+)-dumetorine were applied to the synthesis of its simplified natural congeners (-)-sedamine and (+)-sedridine.
Assuntos
Alcaloides/síntese química , Piperidinas/síntese química , Solventes/química , Alcaloides/química , Catálise , Ciclização , Estrutura Molecular , Piperidinas/química , Estereoisomerismo , Tecnologia , TemperaturaRESUMO
A continuous flow tubing reactor can be used to readily transform methyl or ethyl carboxylic esters into the corresponding hydroxamic acids. Flow rate, reactor volume, and temperature were optimized for the preparation of a small collection of hydroxamic acids. Synthetic advantages were identified as an increased reaction rate and higher product purity. This method was also successfully applied to the multistep preparation of suberoylanilide hydroxamic acid, a potent HDAC inhibitor used in anticancer therapy.
Assuntos
Ácidos Hidroxâmicos/síntese química , Ésteres/química , Micro-Ondas , VorinostatRESUMO
The synthesis and SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The introduction of a tricyclic [h]-fused benzazepine moiety on the recently disclosed scaffold of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines is reported. A full rat pharmacokinetic characterization is also reported.
Assuntos
Benzazepinas/síntese química , Benzazepinas/farmacologia , Antagonistas de Dopamina/síntese química , Antagonistas de Dopamina/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Benzazepinas/química , Técnicas de Química Combinatória , Antagonistas de Dopamina/química , Desenho de Fármacos , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
High-throughput screening resulted in the identification of a series of novel motilin receptor agonists with relatively low molecular weights. The series originated from an array of biphenyl derivatives designed to target 7-transmembrane (7-TM) receptors. Further investigation of the structure-activity relationship within the series resulted in the identification of compound (22) as a potent and selective agonist at the motilin receptor.
Assuntos
Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/química , Receptores de Neuropeptídeos/agonistas , Receptores de Neuropeptídeos/química , Animais , Sítios de Ligação , Membrana Celular/metabolismo , Química Farmacêutica/métodos , Técnicas de Química Combinatória , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Modelos Químicos , Estrutura Molecular , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Recombinantes/química , Relação Estrutura-AtividadeRESUMO
Optimisation of urea (5), identified from high throughput screening and subsequent array chemistry, has resulted in the identification of pyridine carboxamide (33) which is a potent motilin receptor agonist possessing favourable physicochemical and ADME profiles. Compound (33) has demonstrated prokinetic-like activity both in vitro and in vivo in the rabbit and therefore represents a promising novel small molecule motilin receptor agonist for further evaluation as a gastroprokinetic agent.
Assuntos
Carbono/química , Piridinas/química , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores de Neuropeptídeos/agonistas , Animais , Química Farmacêutica/métodos , Desenho de Fármacos , Gastrinas/química , Humanos , Concentração Inibidora 50 , Cinética , Modelos Químicos , Piridinas/síntese química , Piridinas/farmacologia , Coelhos , Ratos , Receptores dos Hormônios Gastrointestinais/química , Receptores de Neuropeptídeos/químicaRESUMO
Chemical modifications of dimiracetam, a bicyclic analogue of the nootropic drug piracetam, afforded a small set of novel derivatives that were investigated in in vivo models of neuropathic pain. Compounds 5, 7 and 8 displayed a very promising antihyperalgesic profile in rat models of neuropathic pain induced by both chronic constriction injury of the sciatic nerve and streptozotocin. The compounds completely reverted the reduction of pain threshold evaluated by the paw pressure test. Importantly these derivatives did not induce any behavioural impairment as evaluated by the rotarod test. These results suggest that compounds 5, 7 and 8 might represent novel and well-tolerated therapeutic agents for the relief of neuropathic pain.
Assuntos
Imidazóis/química , Imidazóis/farmacologia , Neuralgia/tratamento farmacológico , Pirróis/química , Pirróis/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Imidazóis/uso terapêutico , Limiar da Dor/efeitos dos fármacos , Pirróis/uso terapêutico , Ratos , Relação Estrutura-AtividadeRESUMO
Sugar- and lipid-derived aldehydes are reactive carbonyl species (RCS) frequently used as surrogate markers of oxidative stress in obesity. A pathogenic role for RCS in metabolic diseases of obesity remains controversial, however, partly because of their highly diffuse and broad reactivity and the lack of specific RCS-scavenging therapies. Naturally occurring histidine dipeptides (e.g., anserine and carnosine) show RCS reactivity, but their therapeutic potential in humans is limited by serum carnosinases. Here, we present the rational design, characterization, and pharmacological evaluation of carnosinol, i.e., (2S)-2-(3-amino propanoylamino)-3-(1H-imidazol-5-yl)propanol, a derivative of carnosine with high oral bioavailability that is resistant to carnosinases. Carnosinol displayed a suitable ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile and was determined to have the greatest potency and selectivity toward α,ß-unsaturated aldehydes (e.g., 4-hydroxynonenal, HNE, ACR) among all others reported thus far. In rodent models of diet-induced obesity and metabolic syndrome, carnosinol dose-dependently attenuated HNE adduct formation in liver and skeletal muscle, while simultaneously mitigating inflammation, dyslipidemia, insulin resistance, and steatohepatitis. These improvements in metabolic parameters with carnosinol were not due to changes in energy expenditure, physical activity, adiposity, or body weight. Collectively, our findings illustrate a pathogenic role for RCS in obesity-related metabolic disorders and provide validation for a promising new class of carbonyl-scavenging therapeutic compounds rationally derived from carnosine.
Assuntos
Carnosina , Diabetes Mellitus Experimental , Obesidade , Animais , Carnosina/análogos & derivados , Carnosina/farmacocinética , Carnosina/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Dipeptidases/metabolismo , Humanos , Masculino , Camundongos , Camundongos Mutantes , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
In the last decades, inhibitors of histone deacetylases (HDAC) have become an important class of anti-cancer agents. In a previous study we described the synthesis of spiro[chromane-2,4'-piperidine]hydroxamic acid derivatives able to inhibit histone deacetylase enzymes. Herein, we present our exploration for new derivatives by replacing the piperidine moiety with various cycloamines. The goal was to obtain highly potent compounds with a good in vitro ADME profile. In addition, molecular modeling studies unravelled the binding mode of these inhibitors.
Assuntos
Cromonas/farmacologia , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Modelos Moleculares , Compostos de Espiro/farmacologia , Cromonas/síntese química , Cromonas/química , Relação Dose-Resposta a Droga , Inibidores de Histona Desacetilases/química , Humanos , Estrutura Molecular , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
This review describes the patent applications and relevant scientific literature published during 2002 in the field of novel neurokinin receptor antagonists, with an emphasis on the medicinal chemistry of recent patent publications. A brief update on the development status of compounds including: the neurokinin-1 receptor antagonists aprepitant (Merck & Co Inc), vofopitant, ezlopitant (Pfizer Inc), R-673 (F Hoffmann-La Roche Ltd); the neurokinin-2 receptor antagonists nepadutant (Menarini Ricerche SpA), saredutant (Sanofi-Synthelabo), SR-144190 (Sanofi-Synthelabo) and UK-290795 (Pfizer Inc); and the neurokinin-3 receptor antagonists osanetant (Sanofi-Synthelabo) and talnetant (GlaxoSmithKline plc) will be given. The review also reports the recent published patent literature in the area of novel therapeutic uses and novel formulations and combinations claimed for neurokinin receptor antagonists.
Assuntos
Antagonistas dos Receptores de Neurocinina-1 , Receptores da Neurocinina-2/antagonistas & inibidores , Receptores da Neurocinina-3/antagonistas & inibidores , Animais , Química Farmacêutica , Combinação de Medicamentos , Humanos , Peptídeos/farmacologiaRESUMO
Alkaloids extracted from the Papaverum somniferum are among the most powerfully acting and clinically used drugs for diseases of the central nervous system, in particular for pain. The basic ring system, common to these opiate alkaloids, is the morphinan skeleton, which in the last 50 years has been chemically manipulated to obtain compounds with improved potency and increased selectivity toward different populations of opioid receptors. Despite a huge amount of research, interest surrounding these compounds is still high. This review will discuss the patent applications published from January 2001 to June 2002, focusing on new chemical entities that could become drugs over the next few years, new chemical processes for the production of the morphinans currently used in therapy, novel formulations and combined compositions.
Assuntos
Morfinanos/química , Patentes como Assunto , Ligantes , Estrutura Molecular , Morfinanos/farmacologia , Antagonistas de Entorpecentes , Receptores Opioides/agonistas , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides kappa/agonistas , Receptor de NociceptinaRESUMO
Heat-shock protein 90 (Hsp90) is a molecular chaperone involved in the stabilization of key oncogenic signaling proteins, and therefore, inhibition of Hsp90 represents a new strategy in cancer therapy. 2-Amino-7-[4-fluoro-2-(3-pyridyl)phenyl]-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime is a racemic Hsp90 inhibitor that targets the N-terminal adenosine triphosphatase site. We developed a method to resolve the enantiomers and evaluated their inhibitory activity on Hsp90 and the consequent antitumor effects. The (S) stereoisomer emerged as a potent Hsp90 inhibitor in biochemical and cellular assays. In addition, this enantiomer exhibited high oral bioavailability in mice and excellent antitumor activity in two different human cancer xenograft models.
Assuntos
Antineoplásicos/química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Oximas/química , Quinazolinonas/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sítios de Ligação , Linhagem Celular Tumoral , Feminino , Células HCT116 , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Camundongos , Camundongos Nus , Microssomos/metabolismo , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Oximas/farmacologia , Oximas/uso terapêutico , Ligação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína , Estereoisomerismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In this account, we report the development of a series of substituted cinnamic anilides that represents a novel class of mitochondrial permeability transition pore (mPTP) inhibitors. Initial class expansion led to the establishment of the basic structural requirements for activity and to the identification of derivatives with inhibitory potency higher than that of the standard inhibitor cyclosporine-A (CsA). These compounds can inhibit mPTP opening in response to several stimuli including calcium overload, oxidative stress, and thiol cross-linkers. The activity of the cinnamic anilide mPTP inhibitors turned out to be additive with that of CsA, suggesting for these inhibitors a molecular target different from cyclophylin-D. In vitro and in vivo data are presented for (E)-3-(4-fluoro-3-hydroxy-phenyl)-N-naphthalen-1-yl-acrylamide 22, one of the most interesting compounds in this series, able to attenuate opening of the mPTP and limit reperfusion injury in a rabbit model of acute myocardial infarction.
Assuntos
1-Naftilamina/análogos & derivados , Acrilamidas/química , Anilidas/química , Cinamatos/química , Proteínas de Transporte da Membrana Mitocondrial/antagonistas & inibidores , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , 1-Naftilamina/síntese química , 1-Naftilamina/química , 1-Naftilamina/farmacologia , Acrilamidas/síntese química , Acrilamidas/farmacologia , Anilidas/síntese química , Anilidas/farmacologia , Animais , Cálcio/metabolismo , Cinamatos/síntese química , Cinamatos/farmacologia , Feminino , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Hepáticas/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Dilatação Mitocondrial/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Coelhos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Histone Deacetylases (HDACs) have become important targets for the treatment of cancer and other diseases. In previous studies we described the development of novel spirocyclic HDAC inhibitors based on the combination of privileged structures with hydroxamic acid moieties as zinc binding group. Herein, we report further explorations, which resulted in the discovery of a new class of spiro[2H-(1,3)-benzoxazine-2,4'-piperidine] derivatives. Several compounds showed good potency of around 100 nM and less in the HDAC inhibition assays, submicromolar IC50 values when tested against tumour cell lines and a remarkable stability in human and mouse microsomes. Two representative examples exhibited a good pharmacokinetic profile with an oral bioavailability equal or higher than 35% and one of them studied in an HCT116 murine xenograft model showing a robust tumour growth inhibition. In addition, the two benzoxazines were found to have a minor affinity for the hERG potassium channel compared to their corresponding ketone analogues.
Assuntos
Antineoplásicos/farmacologia , Benzoxazinas/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Compostos de Espiro/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Benzoxazinas/síntese química , Benzoxazinas/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Células HeLa , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Células K562 , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Neoplasias Experimentais/patologia , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
A series of spiro[chromane-2,4'-piperidine] derivatives based on a previously published lead benzyl spirocycle 1 and bearing various N-aryl and N-alkylaryl substituents on the piperidine ring were prepared as novel histone deacetylase (HDAC) inhibitors. The compounds were evaluated for their abilities to inhibit nuclear HDACs, their in vitro antiproliferative activities, and in vitro ADME profiles. Based on these activities, 4-fluorobenzyl and 2-phenylethyl spirocycles were selected for further characterization. In vivo pharmacokinetic (PK) studies showed that both compounds exhibit an overall lower clearance rate, an increased half-life, and higher AUCs after intravenous and oral administration than spiropiperidine 1 under the conditions used. The improved PK behavior of these two compounds also correlated with superior in vivo antitumor activity in an HCT-116 xenograft model.
Assuntos
Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Piperidinas/química , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Proteínas Sanguíneas/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores das Enzimas do Citocromo P-450 , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/farmacocinética , Injeções Intravenosas , Taxa de Depuração Metabólica , Camundongos , Camundongos Nus , Estrutura Molecular , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The V-type H+ATPase is critical during the intraerythrocytic stage of the human malaria parasite Plasmodium falciparum. It is responsible for maintaining a near-neutral cytosolic pH (pH 7.3), an acidic digestive vacuole (pH 4.5-5.5) and the generation of an inside-negative plasma membrane potential (approximately -95 mV). Inhibition of this pump is therefore likely to result in profound physiological disturbances within the parasite and parasite death, as illustrated previously by the antiplasmodial activity of the potent and specific inhibitors of the V-type H+-ATPase, bafilomycin A(1) and concanamycin A. In this study we examined the antiplasmodial activity of a series of compounds previously designed, on the basis of the active structural constituents of bafilomycin A(1), to inhibit the osteoclast V-type H+-ATPase. The compounds were tested against up to 4 strains of P. falciparum with varying chloroquine sensitivities. Of the 30 novel compounds tested, 9 had sub-micromolar antiplasmodial IC(50) values, with the most active compound having an IC(50) of 160+/-20 nM. The activity of a number of these compounds was investigated in more detail. We show that these inhibitors acidify the parasite cytosol within seconds and that some inhibitors irreversibly kill the parasite within 0.5-4 h. The antiplasmodial activity of the V-type H+-ATPase inhibitors was strongly correlated with their ability to acidify the parasite cytosol (correlation coefficient 0.98). In combination studies, we show that the inhibitors act indifferently when combined with current antimalarials. Our data support the disruption of parasite pH regulation through inhibition of its V-type H+-ATPase as an antimalarial approach.
Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Indóis/química , Indóis/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Animais , Citosol/fisiologia , Concentração de Íons de Hidrogênio , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , ATPases Vacuolares Próton-Translocadoras/antagonistas & inibidoresRESUMO
A series of amidopropenyl hydroxamic acid derivatives were prepared as novel inhibitors of human histone deacetylases (HDACs). Several compounds showed potency at <100 nM in the HDAC inhibition assays, sub-micromolar IC(50) values in tests against three tumor cell lines, and remarkable stability in human and mouse microsomes was observed. Three representative compounds were selected for further characterization and submitted to a selectivity profile against a series of class I and class II HDACs as well as to preliminary in vivo pharmacokinetic (PK) experiments. Despite their high microsomal stability, the compounds showed medium-to-high clearance rates in in vivo PK studies as well as in rat and human hepatocytes, indicating that a major metabolic pathway is catalyzed by non-microsomal enzymes.
Assuntos
Antineoplásicos/síntese química , Inibidores de Histona Desacetilases/síntese química , Histona Desacetilases/química , Ácidos Hidroxâmicos/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacocinética , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacologia , Camundongos , Microssomos Hepáticos/metabolismo , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Relação Estrutura-AtividadeRESUMO
The histone deacetylases (HDACs) are able to regulate gene expression, and histone deacetylase inhibitors (HDACi) emerged as a new class of agents in the treatment of cancer as well as other human disorders such as neurodegenerative diseases. In the present investigation, we report on the synthesis and biological evaluation of compounds derived from the expansion of a HDAC inhibitor scaffold having N-hydroxy-3-phenyl-2-propenamide and N-hydroxy-3-(pyridin-2-yl)-2-propenamide as core structures and containing a phenyloxopropenyl moiety, either unsubstituted or substituted by a 4-methylpiperazin-1-yl or 4-methylpiperazin-1-ylmethyl group. The compounds were evaluated for their ability to inhibit nuclear HDACs, as well as for their in vitro antiproliferative activity. Moreover, their metabolic stability in microsomes and aqueous solubility were studied and selected compounds were further characterized by in vivo pharmacokinetic experiments. These compounds showed a remarkable stability in vivo, compared to hydroxamic acid HDAC inhibitors that have already entered clinical trials. The representative compound 30b showed in vivo antitumor activity in a human colon carcinoma xenograft model.
Assuntos
Acrilamidas/síntese química , Antineoplásicos/síntese química , Inibidores de Histona Desacetilases/síntese química , Acrilamidas/farmacologia , Antineoplásicos/farmacocinética , Derivados de Benzeno , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Estabilidade de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Células HeLa , Inibidores de Histona Desacetilases/farmacocinética , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Piridinas , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Amides of (2Z,4E)-5-[(5,6-dichloroindol-2-yl)]-2-methoxy-N-[3-[4-[3-(carboxymethoxy)phenyl)] piperazin-1-yl]propyl]-2,4-pentadienamide (1) and of 5-(5,6-dichloro-2-indolyl)-2-methoxy-2,4-pentadienoic acid (2) are strong inhibitors of the vacuolar ATPase located on the plasma membrane of osteoclasts. In order to understand which V-ATPase subunit is involved in the interaction with these novel inhibitors, analogues containing a photoactivable group and an iodine atom were designed. A series of alcohols or amines containing the photoactivable trifluoroaziridinophenyl or benzophenone moiety and an iodine atom were linked to the above acids via an ester or amide group. These compounds could be thereafter used as a radioactive photoprobe to label the protein. Whereas the compounds containing the photoactivable groups maintained good inhibitory activity, the introduction of the bulky iodine atom was generally detrimental, decreasing potency significantly. Better results were obtained by linking 3-(4-aminopiperidinomethyl)-3'-iodobenzophenone to 3-ethoxy-4-(2-(5,6-dichlorobenzimidazolyl))benzoic acid to give the corresponding amide 27, that inhibited vacuolar ATP-ase with a IC(50)=140 nM. The feasibility of introducing a radioactive 125I atom was ascertained by exchanging the iodine with a tributylstannyl group, that was again substituted by iodine.