RESUMO
Described in this paper is the synthesis and pharmacological activity of five metabolites of the angiotensin II antagonist tasosartan (1). Of particular interest is the effect of the additional acidic group of the enol metabolite (8) on activity. As suggested by the structural-activity relationship of other angiotensin II antagonist series, a second acidic group can improve receptor binding activity but decrease in vivo activity after oral dosing. The metabolic introduction of a second acidic group in tasosartan bypasses this problem and contributes to the excellent profile of the compound. A molecular modeling study provides a rationale for the role of the enol group of 8 in AT1 receptor binding.
Assuntos
Angiotensina II/antagonistas & inibidores , Modelos Moleculares , Piridonas/síntese química , Pirimidinas/síntese química , Pirimidinas/metabolismo , Tetrazóis/metabolismo , Administração Oral , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Angiotensina II/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Bloqueadores do Receptor Tipo 2 de Angiotensina II , Antagonistas de Receptores de Angiotensina , Animais , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/fisiopatologia , Técnicas In Vitro , Injeções Intravenosas , Fígado/efeitos dos fármacos , Fígado/metabolismo , Conformação Molecular , Piridonas/administração & dosagem , Piridonas/química , Piridonas/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina , Receptores de Angiotensina/metabolismo , Relação Estrutura-AtividadeRESUMO
A structurally novel series of adenosine 5'-triphosphate-sensitive potassium (K(ATP)) channel openers is described. As part of our efforts directed toward identifying novel, bladder-selective potassium channel openers (KCOs) targeted for urge urinary incontinence (UUI), we found that bioisosteric replacement of the N-cyanoguanidine moiety of pinacidil (1, Figure 1) with a diaminocyclobutenedione template afforded squaric acid analogue 2, the prototype of a novel series of K(ATP) channel openers with unique selectivity for bladder smooth muscle in vivo. Further modification of the heterocyclic ring to give substituted aryl derivatives (3) afforded potent KCOs that possessed the desired detrusor selectivity when administered orally. The effects of these potassium channel agonists on bladder contractile function was studied in vitro using isolated rat detrusor strips. Potent relaxants were evaluated in vivo in a rat model of bladder instability. Lead compounds were evaluated concomitantly in normotensive rats for their effects on mean arterial blood pressure (MAP) and heart rate as a measure of in vivo bladder selectivity. (R)-4-[3,4-Dioxo-2-(1,2, 2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzo nitrile (79) met our potency and selectivity criteria and represents an attractive development candidate for the treatment of UUI. Electrophysiological studies using isolated rat bladder detrusor myocytes have demonstrated that compound 79 produces significant hyperpolarization which is glyburide-reversed, thus consistent with the activation of K(ATP). The design, synthesis, structure-activity relationships (SAR), and pharmacological activity associated with this series of novel KCOs will be discussed.
Assuntos
Ciclobutanos/síntese química , Nitrilas/síntese química , Canais de Potássio/agonistas , Bexiga Urinária/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Ciclobutanos/química , Ciclobutanos/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/citologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Nitrilas/química , Nitrilas/farmacologia , Técnicas de Patch-Clamp , Cloreto de Potássio/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Bexiga Urinária/citologia , Bexiga Urinária/fisiologia , Incontinência Urinária/tratamento farmacológicoRESUMO
A novel series of benzylamine, potassium channel openers (KCOs) is presented as part of our program toward designing new, bladder-selective compounds for the treatment of urge urinary incontinence (UUI). We have found that the in vitro potency of (R)-4-[3,4-dioxo-2-(1,2, 2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzo nitrile 1 in the relaxation of precontracted rat detrusor strips can also be obtained with cyanobenzylamine derivative 4 (IC(50) = 0.29 microM) (Figure 3). Addition of a 2-Cl substituted benzylamine moiety and changing the alkylamino substituent of 4 to a t-Bu amine gives 31 (IC(50) = 0.14 microM)-a compound with similar in vitro potency as 4 as well as relaxant activity on bladder smooth muscle in vivo when administered orally (31, ED(50) = 3 mg/kg) in a rodent model of bladder instability. Further modifications, particularly the replacement of the t-Bu amino substituent with a tert-amylamine, gave a similarly active compound 60 (IC(50) = 0.10 microM) which shows excellent in vivo efficacy (ED(50) = 0.6 mg/kg). Moreover, 60, 3-(2,4-dichloro-6-methyl-benzylamino)-4-(1, 1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (WAY-151616), shows excellent tissue selectivity for bladder K channels over arterial tissue (60, MAP ED(20) = 100 mg/kg; selectivity: MAP ED(20)/bladder ED(50) = 166). Other manipulations of the benzylamino cyclobutenediones, acylation of the benzylamine, conversion of the benzylamine substituent to a benzamide, homologation of the benzylamine to a phenethylamine, and incorporation of a methyl group at the benzyl carbon, all led to substantial loss of in vitro activity, although some in vivo activity was maintained in the acylated analogues. Compound 60 represents an attractive candidate for development in the treatment of UUI.
Assuntos
Benzilaminas/síntese química , Ciclobutanos/síntese química , Canais de Potássio/agonistas , Bexiga Urinária/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Benzilaminas/química , Benzilaminas/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Ciclobutanos/química , Ciclobutanos/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Cloreto de Potássio/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Bexiga Urinária/fisiologia , Incontinência Urinária/tratamento farmacológicoRESUMO
The synthesis, physical properties, and antitumor activity of the cis-, d,l-trans-, d-trans-, and l-trans- stereoisomers of 1,2-diaminocyclohexane tetrachloroplatinum(IV) are described. The objective of the study was to produce a platinum complex with activity against cisplatin-resistant tumor cells and with suitable pharmaceutical properties for formulation development. The isomers had the following solubilities in saline: cis-, 2 mg/ml; d,l-trans-, 6.5 mg/ml; and d-trans- and l-trans-, 15-16 mg/ml. The four complexes showed slightly better activity than cisplatin against the ip implanted murine L1210 leukemia. In contrast to cisplatin, all complexes produced significant increases in life span against L1210/cisplatin, a subline of L1210 with acquired resistance to cisplatin. However, the cis- isomer was less active against L1210/cisplatin. The d,l-trans- isomer (tetraplatin) was selected for further studies based on greater ease for large-scale synthesis. It showed superior activity to cisplatin against P388/cisplatin and like cisplatin showed significant and reproducible activity against the ip implanted B16 melanoma, ip implanted M5076 sarcoma, ip implanted P388 leukemia, and MX-1 human breast xenograft implanted under the renal capsule. Purity and stability (greater than 24 hours in saline) were evaluated by high-performance liquid chromatography and found to be suitable for development of a parenteral dosage form. Preliminary studies in a rat model (to be reported elsewhere) showed it to be less nephrotoxic than cisplatin on a molar basis and worthy of further study.