Further studies on imidazo[4,5-b]pyridine AT1 angiotensin II receptor antagonists. Effects of the transformation of the 4-phenylquinoline backbone into 4-phenylisoquinolinone or 1-phenylindene scaffolds

Journal of Medicinal Chemistry

Volumn 49, Issue 22, 2006, Pages 6451-6464

  Cappelli, Andrea ^a   Mohr, Gal La Pericot ^a,d   Giuliani, Germano ^a   Galeazzi, Simone ^a   Anzini, Maurizio ^a   Mennuni, Laura ^b   Ferrari, Flora ^b   Makovec, Francesco ^b   Kleinrath, Eva M ^c   Langer, Thierry ^c   Valoti, Massimo ^a   Giorgi, Gianluca ^a   Vomero, Salvatore ^a  

^a UNIVERSITY OF SIENA   (Italy)

^b Rotta Research Laboratorium   (Italy)

^c UNIVERSITY OF INNSBRUCK   (Austria)

^d Medicinal Chemistry   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

1,2 DIHYDRO 4 [4 (5,7 DIMETHYL 2 ETHYL 3H IMIDAZO[4,5 B]PYRIDIN 3 YL)METHYL]PHENYL 2 METHYL 1 OXO 3 ISOQUINOLINECARBOXYLIC ACID; 1,2 DIHYDRO 4 [4 [(2 BUTYL 5,7 DIMETHYL 3H IMIDAZO[4,5 B]PYRIDIN 3 YL)METHYL]PHENYL] 2 METHYL 1 OXO 3 ISOQUINOLINECARBOXYLIC ACID; 3 [4 [(5,7 DIMETHYL 2 PROPYL 3H IMIDAZO[4,5 B]PYRIDIN 3 YL)METHYL]PHENYL] 1 ETHYL 1 HYDROXY 1H INDENE 2 CARBOXYLIC ACID; 3 [4 [(5,7 DIMETHYL 2 PROPYL 3H IMIDAZO[4,5 B]PYRIDIN 3 YL)METHYL]PHENYL] 2 HYDROXY 1 METHYL 1H INDENE 2 CARBOXYLIC ACID; ANGIOTENSIN 1 RECEPTOR ANTAGONIST; ANGIOTENSIN II; CARBOXYLIC ACID DERIVATIVE; CR 3210; CR 3588; IMIDAZO[4,5 B]PYRIDINE DERIVATIVE; LOSARTAN; POLYMER; PRODRUG; QUINOLINE DERIVATIVE; UNCLASSIFIED DRUG; VALSARTAN;

ANIMAL EXPERIMENT; ANIMAL TISSUE; AREA UNDER THE CURVE; ARTICLE; CELL STRAIN CACO 2; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG EXCRETION; DRUG HALF LIFE; DRUG PENETRATION; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG RELEASE; DRUG STRUCTURE; DRUG SYNTHESIS; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HUMAN; HUMAN CELL; KINETICS; MALE; NONHUMAN; PHARMACOPHORE; POLYMERIZATION; PREDICTION; PROTON NUCLEAR MAGNETIC RESONANCE; QUALITATIVE ANALYSIS; QUANTITATIVE ANALYSIS; RAT; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS; TEMPERATURE DEPENDENCE;

ANGIOTENSIN II TYPE 1 RECEPTOR BLOCKERS; ANIMALS; CACO-2 CELLS; COMPUTER SIMULATION; CRYSTALLOGRAPHY, X-RAY; HUMANS; HYDROGENATION; INDENES; INDICATORS AND REAGENTS; INTESTINAL ABSORPTION; ISOQUINOLINES; MAGNETIC RESONANCE SPECTROSCOPY; MALE; MODELS, MOLECULAR; PREDICTIVE VALUE OF TESTS; PURINES; QUINOLONES; RABBITS; RATS; RATS, SPRAGUE-DAWLEY; RATS, WISTAR; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33750488442     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0603163     Document Type: Article

References (40)

1. De Gasparo, M.; Catt, K. J.; Inagami, T.; Wright, J. W.; Unger, T. International Union of Pharmacology. XXIII. The Angiotensin II Receptors. Pharmacol. Rev. 2000, 52, 415-472 and references therein.
2. Inoue, Y.; Nakamura, N.; Inagami, T. A Review of Mutagenesis Studies of Angiotensin II Type 1 Receptor, the Three-Dimensional Receptor Model in Search of the Agonist Binding Site and the Hypothesis of a Receptor Activation Mechanism. J. Hypertens. 1997, 15, 703-714.
3. (a) Wexler, R. R.; Greenlee, W. J.; Irvin, J. D.; Goldberg, M. R.; Prendergast, K.; Smith, R. D.; Timmermans, P. B. M. W. M. Nonpeptide Angiotensin II Receptor Antagonists: The Next Generation in Antihypertensive Therapy. J. Med. Chem. 1996, 39, 625-656.
4. (b) Schmidt, B.; Schieffer, B. Angiotensin II AT1 Receptor Antagonist. Clinical Implications of Active Metabolites. J. Med. Chem. 2003, 46, 2261-2270, and references therein.
5. (a) Mantlo, N. B.; Chakravarty, P. K.; Ondeyka, D. L.; Siegl, P. K. S.; Chang, R. S.; Lotti, V. J.; Faust, K. A.; Chen, T.-B.; Schorn, T. W.; Sweet, C. S.; Emmert, S. E.; Patchett, A. A.; Greenlee, W. J. Potent, Orally Active Imidazo[4,5-b]pyridine-Based Angiotensin II Receptor Antagonists. J. Med. Chem. 1991, 34, 2919-2922.
6. (b) Kim, D.; Mantlo, N. B.; Chang, R. S.; Kivlighn, S. D.; Greenlee, W. J. Evaluation of Heterocyclic Acid Equivalents as Tetrazole Replacements in Imidazopyridine-Based Nonpeptide Angiotensin II Receptor Antagonists. Bioorg. Med. Chem. Lett. 1994, 4, 41-44.
7. Mantlo, N. B.; Chang, R. S. L.; Siegl, P. K. S. Angiotensin II Receptor Antagonists Containing a Phenylpyridine Element. Bioorg. Med. Chem. Lett. 1993, 3, 1693-1696.
8. 1 Angiotensin II Receptor Antagonists Based on the 4-Phenylquinoline Structure. J. Med. Chem. 2004, 47, 2574-2586.
9. 1 Antagonist CR3210 in Biological Samples by HPLC. Il Farmaco. 2003, 58, 837-844.
10. 1 Antagonist in Biological Samples. J. Pharm. Biomed. Anal. 2004, 35, 321-329.
11. 1 receptor antagonists show limited oral bioavailability (eprosartan 13%, valsartan 25%, losartan 33%, candesartan 42%, telmisartan 50%, and irbesartan 60-80%). ((a) Israili, Z. H. Clinical Pharmacokinetics of Angiotensin II (AT1) Receptor Blockers in Hypertension. J. Hum. Hypertens. 2000, 14, S73-S86.
12. (b) Brunner, H. R. The New Angiotensin II Receptor Antagonist. Irbesartan. Am. J. Hypertens. 1997, 10, 311S-317S.)
13. Furthermore, losartan exhibiting highly variable oral bioavailability is transported by P-glycoprotein, whereas its carboxylic acid metabolite is not a P-glycoprotein substrate (Soldner, A.; Benet, L. Z.; Mutschler, E.; Christians, U. Active Transport of the Angiotensin-II Antagonist Losartan and Its Main Metabolite EXP 3174 Across MDCK-MDR1 and Caco-2 Cell Monolayers. Br. J. Pharmacol. 2000, 129, 1235-1243).
14. Krovat, E. M.; Langer, T. Non-Peptide Angiotensin II Receptor Antagonists: Chemical Feature Based Pharmacophore Identification. J. Med. Chem. 2003, 46, 716-726.
15. Natsugari, H.; Ikeura, Y.; Kiyota, Y.; Ishichi, Y.; Ishimaru, T.; Saga, O.; Shirafuji, H.; Tanaka, T.; Kamo, I.; Doi, T.; Otsuka, M. Novel, Potent, and Orally Active Substance P Antagonists: Synthesis and Antagonist Activity of N-Benzylcarboxamide Derivatives of Pyrido[3,4-b]pyridine. J. Med. Chem. 1995, 38, 3106-3120.
16. (a) Senanayake, C. H.; Fredenburgh, L. E.; Reamer, R. A.; Liu, J.; Roberts, F. E.; Humphrey, G.; Thompson, A. S.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J.; Shinkai, I. New Approach to the Imidazolutidine Moiety of MK-996. Heterocycles 1996, 42, 821-830.
17. (b) Chakravarty, P. K.; Greenlee, W. J.; Mantlo, N. B.; Patchett, A.-A.; Walsh, T. F. Substituted Imidazo-Fused 6-Membered Heterocycles as Angiotensin II Antagonists. U.S. Patent 5,332,744, 1994.
18. Cappelli, A.; Pericot Mohr, G.; Anzini, M.; Vomero, S.; Donati, A.; Casolaro, M.; Mendichi, R.; Giorgi, G.; Makovec, F. Synthesis and Characterization of a New Benzofulvene Polymer Showing a Thermoreversible Polymerization Behavior. J. Org. Chem. 2003, 68, 9473-9476.
19. Cappelli, A.; Anzini, M.; Vomero, S.; Donati, A.; Zetta, L.; Mendichi, R.; Casolaro, M.; Lupetti, P.; Salvatici, P.; Giorgi, G. New π-Stacked Benzofulvene Polymer Showing Thermoreversible Polymerization: Studies in Macromolecular and Aggregate Structures and Polymerization Mechanism. J. Polym. Sci., Part A: Polym. Chem. 2005, 43, 3289-3304.
20. (a) Chang, R. S. L.; Siegl, P. K. S.; Clineschmidt, B. W.; Mantlo, N. B.; Chakravarty, P. K.; Greenlee, W. J.; Patchett, A. A.; Lotti, V. J. In vitro Pharmacology of L-158,809. a New Highly Potent and Selective Angiotensin II Receptor Antagonists. J. Pharmacol. Exp. Ther. 1992, 262, 133-138.
21. (b) Robertoson, M. J.; Cunoosamy, M. P.; Clark, K. L. Effects of Peptidase Inhibition on Angiotensin Receptor Agonist and Antagonist Potency in Rabbit Isolated Thoracic Aorta. Br. J. Pharmacol. 1992, 106, 166-172.
22. Naphthalene derivative 4a was described in a patent application and resynthesized in our laboratory as a reference compound for our quinoline derivatives (Suzuki, K.; Fujiwara, S.; Machii, D.; Ochifuji, N.; Takai, H.; Oono, T.; Furuta, S.; Yamada, K. Preparation of Imidazopyridines and Analogs as Angiotensin II Antagonists. Jpn. Kokai Tokkyo Koho JP 06 92,939, 1994.
23. and Fujiwara, S.; Takai, H.; Mizukami, T.; Myaji, H.; Sato, S.; Oomori, T.; Nukui, E. Preparation of N-[4-(4-Quinolinyl)benzyl]benzimidazole Derivatives as Immunosuppressants. Jpn. Kokai Tokkyo Koho JP 06. 340,658, 1994.)
24. 1 Selective Angiotensin II Antagonists. J. Med. Chem. 1996, 39, 2197-2206.
25. Carini, D. J.; Duncia, J. V.; Aldrich, P. E.; Chiu, A. T.; Johnson, A. L.; Pierce, M. E.; Price, W. A.; Santella, J. B., III; Wells, G. J.; Wexler, R. R.; Wong, P. C.; Yoo, S.-E.; Timmermans, P. B. M. W. M. Nonpeptide Angiotensin II Receptor Antagonists: The Discovery of a Series of N-(Biphenylmethyl) imidazoles as Potent, Orally Active Antihypertensives. J. Med. Chem. 1991, 34, 2525-2547.
26. Catalyst, version 4.7 (software package): Accelrys, Inc. (previously known as Molecular Simulations, Inc.): San Diego, CA 2002.
27. (a) Artursson, P. Epithelial Transport of Drugs in Cell Culture. 1: A Model for Studying the Passive Diffusion of Drugs over Intestinal Absorptive (Caco-2) Cells. J. Pharm. Sci. 1990, 79, 476-482.
28. (b) Artursson, P.; Karlsson, J. Correlation between Oral Drug Absorption in Humans and Apparent Drug Permeability Coefficients in Human Intestinal Epithelial (Caco-2) Cells. Biochem. Biophys. Res. Commun. 1991, 175, 880-885.
29. Ribadeneira, M. D.; Aungst, B. J.; Eyermann, C. J.; Huang, S.-M. Effects of Structural Modifications on the Intestinal Permeability of Angiotensin II Receptor Antagonists and the Correlation of In Vitro, In Situ, and In Vivo Absorption. Pharm. Res. 1996, 13, 227-233.
30. m) of compound 4b is 7-fold higher than that shown by 2a (Valoti, M. Personal communication). Interestingly, other authors reported that the absence of 2a glucuronide in the hepatocyte and its presence in the bile suggest that its rate of formation is much slower than its rate of transport out of the cell (see ref 23).
31. (a) Colletti, A. E.; Krieter, P. A. Disposition of Angiotensin II Receptor Antagonist L-158,809 in Rats and Rhesus Monkeys. Drug Metab. Disp. 1994, 22, 183-188.
32. (b) Huskey, S. W.; Miller, R. R.; Chiu, S.-H. L. N-Glucuronidation Reactions. 1. Tetrazole N-Glucuronidation of Selected Angiotensin II Receptor Antagonists in Hepatic Microsome from Rats, Dogs, Monkeys, and Humans. Drug Metab. Dispos. 1993, 21, 792-799 and references therein.
33. (a) Greer, S. C. Physical Chemistry of Equilibrium Polymerization. J. Phys. Chem. B 1998, 102, 5413-5422.
34. (b) Ishizone, T.; Ohnuma, K.; Okazawa, Y.; Hirao, A.; Nakahama, S. Anionic Polymerization of Monomers Containing Functional Groups. 12. Anionic Equilibrium Polymerization of 4-Cyano-α-methylstyrene. Macromolecules 1998, 31, 2797-2803.
35. (c) Iwatsuki, S.; Itoh, T.; Higuchi, T.; Enomoto, K. Equilibrium Polymerization of 7,8-Dibenzoyl-, 7.8-Diacetyl-, and 7,8-Dibutoxycarbonyl-7,8- dicyanoquinodimethane and Their Copolymerization with Styrene: a New Concept on the Mechanism of Alternating Copolymerization. Macromolecules, 1988, 21, 1571-1579.
36. Dainton, F. S.; Ivin, K. J. Reversibility of the Propagation Reaction in Polymerization Processes and Its Manifestation in the Phenomenon of a 'Ceiling Temperature'. Nature 1948, 162, 705-707.
37. 1 Receptor Antagonists. J. Med. Chem. 2006, 49, 1526-1535.
38. Sheldrick, G. M. SHELXS-97, Rel. 97-2, A Program for Automatic Solution of Crystal Structures: University of Göttingen: Göttingen, Germany, 1997.
39. Sheldrick, G. M. SHELXL-97, Rel. 97-2, A Program for Crystal Structure Refinement; University of Göttingen: Göttingen, Germany, 1997.
40. ISIS/Draw, version 2.1; MDL Information Systems: San Diego, CA 1990-1996.