RESUMEN

Fluorinated trienoic acid analogues of the RXR selective modulator 1 (LG101506) were synthesized, and tested for their ability to bind RXRalpha and activate RXR homo and heterodimers. Potency and efficacy were observed to be dependent upon the position of fluorination, and improvement in pharmacological profile was demonstrated in some cases.

Asunto(s)

RESUMEN

Previous data have shown that RXR-selective agonists (e.g., 3 and 4) are insulin sensitizers in rodent models of non-insulin-dependent diabetes mellitus (NIDDM). Unfortunately, they also produce dramatic increases in triglycerides and profound suppression of the thyroid hormone axis. Here we describe the design and synthesis of new RXR modulators that retain the insulin-sensitizing activity of RXR agonists but produce substantially reduced side effects. These molecules bind selectively and with high affinity to RXR and, unlike RXR agonists, do not activate RXR homodimers. To further evaluate the antidiabetic activity of these RXR modulators, we have designed a concise and systematic structure-activity relationship around the 2E,4E,6Z-7-aryl-3-methylocta-2,4,6-trienoic acid scaffold. Selected compounds have been evaluated using insulin-resistant rodents (db/db mice) to characterize effects on glucose homeostasis. Our studies demonstrate the effectiveness of RXR modulators in lowering plasma glucose in the db/db mouse model.

Asunto(s)

RESUMEN

Propionic acid derivative 8, which was designed and synthesized based on putative pharmacophores of known PPARgamma- and PPARalpha-selective compounds, exhibits potent dual PPARalpha/gamma agonist activity as demonstrated by in vitro binding and dose overlap in the newly introduced EOB mouse model for glucose lowering and lipid/cholesterol homeostasis.

Asunto(s)

Asunto(s)

RESUMEN

DMP 811 exhibited high binding affinity for the angiotensin II subtype receptor AT1 in rat adrenal tissues with an IC50 of 6 nM, but not for the subtype receptor AT2. In the isolated rabbit aorta, DMP 811 inhibited the contractile response to angiotensin II selectively and noncompetitively with a KB value of 0.1 nM. In conscious renal hypertensive rats, DMP 811 decreased blood pressure with i.v. and p.o. ED30s of 0.005 and 0.03 mg/kg, respectively (p.o. ED30 for losartan = 0.59 mg/kg). In conscious furosemide-treated dogs, DMP 811 given either at 0.3 or 1 mg/kg p.o. decreased blood pressure. DMP 811 has oral bioavailabilities of 7 and 29% in rats and dogs, respectively, after a solution dose and 8 and 13%, respectively, after a suspension or capsule dosing. Our study indicates that DMP 811 is a selective and insurmountable AT1 receptor antagonist and is a 20-fold more potent orally-active antihypertensive agent than losartan.

Asunto(s)

RESUMEN

The possibility of receptor heterogeneity in the angiotensin II (AII) system has been suggested previously, based on differences in Kd values or sensitivity to thiol reagents. One of our earliest indications was the frequent observation of incomplete inhibition of the binding of AII to adrenal cortical membranes. Autoradiographic studies demonstrated that all of the labeling of the rat adrenal was blocked by unlabeled AII or saralasin, but not by DuP 753. The predominant receptor in the rat adrenal cortex (80%) is sensitive to dithiothreitol (DTT) and DuP 753, and is designated AII-1. The residual sites in the adrenal cortex and almost all of the sites in the rat adrenal medulla are insensitive to both DTT and DuP 753, but were blocked by EXP655. These sites have been confirmed by ligand binding studies and are designated AII-2. The rabbit adrenal cortex is unique in yielding a nonuniform distribution of AII-2 sites around the outer layer of glomerulosa cells. In the rabbit kidney, the sites on the glomeruli are AII-1, but the sites on the kidney capsule are AII-2. Angiotensin III appears to have a higher affinity for AII-2 sites since it inhibits the binding to the rabbit kidney capsule but not the glomeruli. Elucidation of the distribution and function of these diverse sites should permit the development of more selective and specific therapeutic strategies.

Asunto(s)

RESUMEN

DuP 753 and PD123177 are two nonpeptide angiotensin II (AII)-specific ligands, which show high affinities for two respective and distinct subtypes of AII binding sites, i.e., AII-1 and AII-2 sites, respectively, in the rat adrenal gland, brain and uterus. The objective of this study is to identify the functions of these subtype binding sites in the adrenal, sympathetic ganglia, brain and vascular smooth muscle. In conscious rats, DuP 753 at 1, 3 and 10 mg/kg i.v. but not PD123177 at 30 and 100 mg/kg i.v. inhibited the AII-induced aldosterone increase. In the isolated perfused rat adrenal gland, DuP 753 at 10(-6) and 10(-4) M but not PD123177 at 10(-3) M blocked the AII-induced epinephrine secretion. In control and chemically sympathectomized pithed rats, the pressor and tachycardiac responses to AII were blocked by DuP 753 at 10 mg/kg i.v. but not by PD123177 at 100 mg/kg i.v. In conscious rats, DuP 753 at 10 mg/kg s.c. but not PD123177 at 100 mg/kg s.c. inhibited the AII-induced water drinking. In the rabbit aorta, DuP 753 at 10(-6) M but not PD123177 at 10(-4) M inhibited the contractile effect of AII. In conscious renal artery-ligated hypertensive rats, DuP 753 but not PD123177 at 0.1 to 10 mg/kg i.v. lowered blood pressure. In summary, a function of the PD123177-sensitive AII binding site (AII-2) has not yet been identified. However, the DuP 753-sensitive site (AII-1) appears to mediate the AII-induced responses such as adrenal aldosterone and catecholamine secretion, release of catecholamine from sympathetic ganglia, drinking and vasoconstriction.

Asunto(s)

RESUMEN

The novel anticancer drug candidate brequinar sodium [DuP 785, NSC 368390, 6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinoline carboxylic acid sodium salt] inhibits dihydroorotate dehydrogenase, the fourth enzyme in the de novo pyrimidine biosynthetic pathway leading to the formation of UMP. Sixty-nine quinoline 4-carboxylic acid analogs were analyzed as inhibitors of L1210 dihydroorotate dehydrogenase. This structure-activity relationship study identified three critical regions of brequinar sodium and its analogs, where specific substitutions are required for the inhibition of the activity of dihydroorotate dehydrogenase. The three principal regions are: (i) the C(2) position where bulky hydrophobic substituents are necessary, (ii) the C(4) position which has a strict requirement for the carboxylic acid and its corresponding salts, and (iii) the benzo portion of the quinoline ring with appropriate substitutions. These results will be useful in the elucidation of the precise nature of the interaction between brequinar sodium and dihydroorotate dehydrogenase.

Asunto(s)

RESUMEN

Two types of angiotensin II (AII) receptor (AII-1 and AII-2) have been identified in rat adrenal cortex by means of two highly specific, but structurally dissimilar, nonpeptide AII receptor antagonists, DuP753 and EXP655, and by the discriminatory effect of dithiothreitol (DTT). Using radioligand-receptor binding techniques, DuP753 was found to be highly specific for AII-1 sites, displaying an inhibitory potency value of 1.2 x 10(-8) M. This type of AII receptor was particularly sensitive to inactivation by DTT. EXP655 possessed no affinity for the AII-1 sites, but was highly selective for the AII-2 sites exhibiting an inhibitory potency value of approx 10(-7). The AII-2 receptors were found resistant to DTT inactivation. A limited survey of the tissue distribution of these receptor subtypes indicates that AII-1 sites are exclusively found in vascular tissues, whereas AII-2 sites are highly enriched in adrenal medulla and brain.

Asunto(s)

RESUMEN

We have demonstrated the existence of two distinct subtypes of the angiotensin II receptor in the rat adrenal gland using radioligand binding and tissue section autoradiography. The identification of the subtypes was made possible by the discovery of two structurally dissimilar, nonpeptide compounds, DuP 753 and EXP655, that show reciprocal selectivity for the two subtypes. In the rat adrenal cortex, DuP 753 inhibited 80% of the total AII binding with an IC50 value on the sensitive sites of 2 x 10(-8) M, while EXP655 displaced only 20%. In the rat adrenal medulla, EXP655 gave 90% inhibition of AII binding with an IC50 value of 3.0 x 10(-8) M, while DuP 753 was essentially inactive. The combination of the two compounds completely inhibited AII binding in both tissues.

Asunto(s)

RESUMEN

A novel, substituted 4-quinolinecarboxylic acid (NSC 339768) demonstrated antitumor activity against L1210 leukemia and B16 melanoma in the National Cancer Institute's Developmental Therapeutics Program. An extensive analogue synthesis program was initiated; over 200 derivatives were synthesized and tested for anticancer activity. One of these compounds, 6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid sodium salt, NSC 368390 (DuP-785), was selected for further investigation because of its efficacy against a spectrum of human solid tumors and its water solubility. In initial studies with L1210 leukemia, the compound caused an increase in life span of greater than 80%. The activity was schedule dependent, and the compound was equally efficacious when administered i.p., i.v., s.c., or p.o. In tests against human tumors xenografted under the renal capsule of nude mice, NSC 368390 when injected i.p. in doses of 20-40 mg/kg daily for 9 days inhibited the growth of the MX-1 breast, LX-1 lung, BL/STX-1 stomach, and CX-1 colon carcinomas by greater than 90%. NSC 368390 also inhibited the growth of three distinct human colon carcinomas, the HCT-15, clone A, and DLD-2 tumors, growing s.c. in nude mice. An i.p. dose of 25 mg/kg given daily for 9 days inhibited the growth of the DLD-2 colon cancer by 98%. 1-beta-D-Arabinofuranosylcytosine and Adriamycin were ineffective, and fluorouracil was only moderately effective against these colon tumors. Because of its good activity against human colon tumors and other human carcinomas and its water solubility, NSC 368390 (DuP-785) is being developed as a Phase 1 anticancer agent.

Asunto(s)