| 1. |
- Andersson, H.O., et al.
(författare)
-
Optimization of P1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors
- 2003
-
Ingår i: European Journal of Biochemistry. - : Wiley. - 0014-2956 .- 1432-1033. ; 270:8, s. 1746-1758
-
Tidskriftsartikel (refereegranskat)abstract
- HIV-1 protease is an important target for treatment of AIDS, and efficient drugs have been developed. However, the resistance and negative side effects of the current drugs has necessitated the development of new compounds with different binding patterns. In this study, nine C-terminally duplicated HIV-1 protease inhibitors were cocrystallised with the enzyme, the crystal structures analysed at 1.8-2.3 Å resolution, and the inhibitory activity of the compounds characterized in order to evaluate the effects of the individual modifications. These compounds comprise two central hydroxy groups that mimic the geminal hydroxy groups of a cleavage-reaction intermediate. One of the hydroxy groups is located between the d-oxygen atoms of the two catalytic aspartic acid residues, and the other in the gauche position relative to the first. The asymmetric binding of the two central inhibitory hydroxyls induced a small deviation from exact C2 symmetry in the whole enzyme-inhibitor complex. The study shows that the protease molecule could accommodate its structure to different sizes of the P2/P2' groups. The structural alterations were, however, relatively conservative and limited. The binding capacity of the S3/S3' sites was exploited by elongation of the compounds with groups in the P3/P3' positions or by extension of the P1/P1' groups. Furthermore, water molecules were shown to be important binding links between the protease and the inhibitors. This study produced a number of inhibitors with Ki values in the 100 picomolar range.
|
|
| 2. |
- Wan, Y., et al.
(författare)
-
Design, synthesis, and biological evaluation of the first selective nonpeptide AT2 receptor agonist
- 2004
-
Ingår i: J Med Chem. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 47:24, s. 5995-6008
-
Tidskriftsartikel (refereegranskat)abstract
- The first druglike selective angiotensin II AT(2) receptor agonist (21) with a K(i) value of 0.4 nM for the AT(2) receptor and a K(i) > 10 microM for the AT(1) receptor is reported. Compound 21, with a bioavailability of 20-30% after oral administration and a half-life estimated to 4 h in rat, induces outgrowth of neurite cells, stimulates p42/p44(mapk), enhances in vivo duodenal alkaline secretion in Sprague-Dawley rats, and lowers the mean arterial blood pressure in anesthetized, spontaneously hypertensive rats. Thus, the peptidomimetic 21 exerts a similar biological response as the endogenous peptide angiotensin II after selective activation of the AT(2) receptor. Compound 21, derived from the prototype nonselective AT(1)/AT(2) receptor agonist L-162,313 will serve as a valuable research tool, enabling studies of the function of the AT(2) receptor in more detail.
|
|
| 3. |
|
|
| 4. |
- Wan, Y Q, et al.
(författare)
-
Dimethylformamide as a carbon monoxide source in fast palladium-catalyzed aminocarbonylations of aryl bromides
- 2002
-
Ingår i: Journal of Organic Chemistry. - Uppsala Univ, BMC, Dept Organ Pharmaceut Chem, SE-75123 Uppsala, Sweden. : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 67:17, s. 6232-6235
-
Tidskriftsartikel (refereegranskat)abstract
- Dimethylformamide (DMF) acts as an efficient source of carbon monoxide and dimethylamine in the palladium-catalyzed aminocarbonylation (Heck carbonylation) of p-tolyl bromide to provide the dimethylamide. Addition of amines to the reaction mixture in excess delivers the corresponding aryl amides in good yields. The amines employed, benzylamine, morpholine, and aniline, all constitute good reaction partners. The reaction proceeds smoothly with bromobenzene and more electron-rich aryl bromides, but electron-deficient aryl bromides fail to undergo aminocarbonylation. The reactions are conducted at 180-190 degreesC for 15-20 min with microwave heating in a reaction mixture containing imidazole and potassium tert-butoxide: the latter is required to promote decomposition of the DMF solvent at a suitable rate. The beneficial effects of controlled microwave irradiation as an energy source for the rapid heating of the carbonylation reaction mixture are demonstrated. The carbonylation procedure reported herein, which relies on the in situ generation of carbon monoxide, serves as a convenient alternative to other carbonylation methods and is particularly applicable to small-scale reactions where short reaction times are desired and the direct use of carbon monoxide gas is impractical.
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
- Andappan, Murugaiah M. S., et al.
(författare)
-
From the First Selective Non-Peptide AT(2) Receptor Agonist to Structurally Related Antagonists
- 2012
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:5, s. 2265-2278
-
Tidskriftsartikel (refereegranskat)abstract
- A para substitution pattern of the phenyl ring is a characteristic feature of the first reported selective AT(2) receptor agonist M024/C21 (1) and all the nonpeptidic AT(2) receptor agonists described so far. Two series of compounds structurally related to 1 but with a meta substitution pattern have now been synthesized and biologically evaluated for their affinity to the AT(1) and AT(2) receptors. A high AT(2)/AT(1) receptor selectivity was obtained with all 41 compounds synthesized, and the majority exhibited K-i ranging from 2 to 100 nM. Five compounds were evaluated for their functional activity at the AT(2) receptor, applying a neurite outgrowth assay in NG108-15 cells.. Notably, four of the five compounds, with representatives from both series, acted as potent AT(2) receptor antagonists. These compounds were found to be considerably more effective than PD 123,319, the standard AT(2) receptor antagonist used in most laboratories. No AT(2) receptor antagonists were previously reported among the derivatives with a para substitution pattern. Hence, by a minor modification of the agonist 1 it could be transformed into the antagonist, compound 38. These compounds should serve as valuable tools in the assessment of the role of the AT(2) receptor in more complex physiological models.
|
|
| 8. |
- Mahalingam, A. K., et al.
(författare)
-
Selective angiotensin II AT(2) receptor agonists with reduced CYP 450 inhibition
- 2010
-
Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 18:12, s. 4570-4590
-
Tidskriftsartikel (refereegranskat)abstract
- Structural alterations to the benzylic position of the first drug-like selective angiotensin II AT(2) receptor agonist (1) have been performed, with the emphasis to reduce the CYP 450 inhibitory property of the initial structure. The imidazole moiety, responsible for the CYP 450 inhibitory effect in 1, was replaced with various heterocycles. In addition, the modes of attachment of the heterocycles, that is, carbon versus nitrogen attachment, and introduction of carbonyl functionalities to the benzylic position have been evaluated. In all the three series, AT(2) receptor ligands with affinity in the lower nanomolar range were identified. None of the analogues, regardless of the substituents, exhibited any affinity for the AT(1) receptor. Compounds with substantially reduced inhibition of the CYP 450 enzymes were obtained. Among them the compound 60 was found to induce neurite elongation in NG 108-15 cells and served as potent AT(2) selective agonist.
|
|
| 9. |
- Murugaiah, A. M. S., et al.
(författare)
-
Selective angiotensin II AT(2) receptor agonists devoid of the imidazole ring system
- 2007
-
Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 15:22, s. 7166-7183
-
Tidskriftsartikel (refereegranskat)abstract
- A versatile parallel synthetic method to obtain three series of non-cyclic analogues of the first drug-like selective angiotensin II AT2 receptor agonist (1) has been developed. In analogy with the transformation of losartan to valsartan it was demonstrated that a non-cyclic moiety could be employed as an imidazole replacement to obtain AT2 selective compounds. In all the three series, AT2 receptor ligands with affinities in the lower nanomolar range were found. None of the analogues exhibited any affinity for the AT1 receptor. Four compounds, 17, 22, 39 and 51, were examined in a neurite outgrowth cell assay. All four compounds were found to exert a high agonistic effect as deduced from their capacity to induce neurite elongation in neuronal cells, as does angiotensin II.
|
|
| 10. |
- Shum, Michael, et al.
(författare)
-
Angiotensin II type 2 receptor promotes adipocyte differentiation and restores adipocyte size in high-fat/high-fructose diet-induced insulin resistance in rats
- 2013
-
Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 304:2, s. E197-E210
-
Tidskriftsartikel (refereegranskat)abstract
- Angiotensin II type 2 receptor promotes adipocyte differentiation and restores adipocyte size in high-fat/high-fructose diet-induced insulin resistance in rats. Am J Physiol Endocrinol Metab 304: E197-E210, 2013. First published November 13, 2012; doi:10.1152/ajpendo.00149.2012.-This study was aimed at establishing whether specific activation of angiotensin II (ANG II) type 2 receptor (AT2R) modulates adipocyte differentiation and function. In primary cultures of subcutaneous (SC) and retroperitoneal (RET) preadipocytes, both AT2R and AT1R were expressed at the mRNA and protein level. Cells were stimulated with ANG II or the AT2R agonist C21/M24, alone or in the presence of the AT1R antagonist losartan or the AT2R antagonist PD123,319. During differentiation, C21/M24 increased PPA gamma expression in both RET and SC preadipocytes while the number of small lipid droplets and lipid accumulation solely increased in SC preadipocytes. In mature adipocytes, C21/M24 decreased the mean size of large lipid droplets. Upon abolishment of AT2R expression using AT2R-targeted shRNAs, expressions of AT2R, aP2, and PPAR gamma remained very low, and cells were unable to differentiate. In Wistar rats fed a 6-wk high-fat/high-fructose (HFHF) diet, a significant shift toward larger adipocytes was observed in RET and SC adipose tissue depots. C21/M24 treatments for 6 wk restored normal adipocyte size distribution in both these tissue depots. Moreover, C21/M24 and losartan decreased hyperinsulinemia and improved insulin sensitivity impaired by HFHF diet. A strong correlation between adipocyte size area and glucose infusion rate during euglycemic-hyperinsulinemic clamp was observed. These results indicate that AT2R is involved in early adipocyte differentiation, while in mature adipocytes and in a model of insulin resistance AT2R activation restores normal adipocyte morphology and improves insulin sensitivity.
|
|
