RESUMEN
Structural variation of the endothelin A-selective antagonist (S)-3-methoxy-2-(4,6-dimethoxypyrimidin-2-yloxy)-3, 3-diphenylpropionic acid (LU 135252) led to analogues which retain ET(A) affinity but exhibit substantial ET(B) affinity as well. The most active derivative obtained is (S)-3-[2-(3, 4-dimethoxyphenyl)ethoxy]-2-(4,6-dimethylpyrimidin-2-yloxy)- 3, 3-diphenylpropionic acid (LU 302872), which can be prepared in enantiomerically pure form in eight steps via an acid-catalyzed transetherification. It has a K(i) = 2.15 nM for binding to the ET(A) receptor and a K(i) = 4.75 nM for binding to the ET(B) receptor, is orally available, and antagonizes the big ET-induced blood pressure increase in rats and the big ET-induced bronchospasm in guinea pigs each time at a dose of 10 mg/kg.
Asunto(s)
Antagonistas de los Receptores de Endotelina , Propionatos/síntesis química , Pirimidinas/síntesis química , Administración Oral , Animales , Presión Sanguínea/efectos de los fármacos , Broncoconstricción/efectos de los fármacos , Células CHO , Cricetinae , Cobayas , Masculino , Propionatos/administración & dosificación , Propionatos/química , Propionatos/farmacología , Pirimidinas/administración & dosificación , Pirimidinas/química , Pirimidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptor de Endotelina A , Receptor de Endotelina B , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel class of endothelin-A receptor ligands was discovered by high-throughput screening. Lead structure optimization led to highly potent antagonists which can be synthesized in a short sequence. The compounds are endothelin-A-selective, are orally available, and show a long duration of action.
Asunto(s)
Antagonistas de los Receptores de Endotelina , Endotelinas/toxicidad , Pirimidinas/síntesis química , Administración Oral , Animales , Compuestos de Dansilo/farmacología , Muerte Súbita , Diseño de Fármacos , Endotelinas/antagonistas & inhibidores , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Pirimidinas/farmacología , Ratas , Receptor de Endotelina A , Receptores de Endotelina/metabolismo , Relación Estructura-Actividad , Sulfonamidas/farmacologíaRESUMEN
The new endothelin (ET) receptor antagonist LU 127043 shows higher ETA affinity than BQ 123, Ro 46-2005, and BMS 182874, with a Ki of 6 nmol/L vs. 19, 28, and 57 nmol/L. ETA/ETB selectivity of LU 127043 of about 160 is comparable to that of BQ 123 (200) and is much greater than that of Ro 46-2005 (0.93) and SB 209670 (0.74). In rabbit aortic segments, LU 127043 shows ET antagonistic potency similar to that of BQ 123 and BMS 182874 (pA2 7.34 vs. 7.36 and 7.09), whereas SB 209670 is more potent (9.80). In rats, LU 127043 completely prevents the ET-1-induced sudden death due to coronary constriction, as indicated by a pronounced T-wave increase. With i.v. pretreatment, LU 127043 is as effective as SB 209670, whereas it is three times more active using 4 h oral pretreatment. Even 8 h after oral administration, LU 127043, in contrast to SB 209670, provides dose-dependent protection. Hence, LU 127043 is an example of a selective ETA antagonist with high oral availability and long duration of action. Because the in vivo efficacy of other high affinity ET antagonists is relatively low, further optimization for therapeutic use should concentrate on pharmacokinetic properties.
Asunto(s)
Muerte Súbita , Antagonistas de los Receptores de Endotelina , Endotelinas/antagonistas & inhibidores , Vasoconstricción/efectos de los fármacos , Animales , Células CHO , Cricetinae , Técnicas In Vitro , Indanos/metabolismo , Indanos/farmacología , Masculino , Péptidos Cíclicos/metabolismo , Péptidos Cíclicos/farmacología , Conejos , Ratas , Ratas Sprague-Dawley , Receptores de Endotelina/metabolismoRESUMEN
In a clinical controlled study involving more than 100 patients with nonarticular rheumatism, the nonsteroidal anti-inflammatory agent Ibuprofen Klinge 600 proved clinically effective. The test parameters were subjective pain considered separately as pain at rest, pain on movement, and tenderness, and the time to appearance of fatigue. All three categories of pain were ameliorated by the treatment, the time interval to appearance of fatigue doubling or tripling during the course of 3 weeks of treatment. This therapeutic success was coupled with good toleration of nonsteroidal anti-inflammatory drugs.