Novel DMARDs on the basis of a new concept of dual cytokine regulation, TNF-α suppression and IL-10 augmentation

Bioorganic and Medicinal Chemistry Letters

Volumn 10, Issue 9, 2000, Pages 881-884

  Hanano, Tokushi ^a   Adachi, Kunitomo ^b   Aoki, Yoshiyuki ^b   Morimoto, Hiroshi ^b   Naka, Yoichi ^b   Hisadome, Masao ^b   Fukuda, Tetsuko ^b   Sumichika, Hiroshi ^b  

^a Drug Discovery Laboratories   (Japan)

^b Drug Development Laboratories   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIRHEUMATIC AGENT; CYTOKINE; INTERLEUKIN 10; PIPERAZINE DERIVATIVE; TUMOR NECROSIS FACTOR ALPHA;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIINFLAMMATORY ACTIVITY; ARTICLE; CHEMICAL MODIFICATION; CYTOKINE RELEASE; DOSE RESPONSE; DRUG INDUCED DISEASE; DRUG INHIBITION; DRUG SYNTHESIS; MALE; MOUSE; NONHUMAN; RHEUMATOID ARTHRITIS;

ANIMALS; ANTIRHEUMATIC AGENTS; ARTHRITIS, EXPERIMENTAL; CENTRAL NERVOUS SYSTEM; DOSE-RESPONSE RELATIONSHIP, DRUG; FOOT; FREUND'S ADJUVANT; INTERLEUKIN-10; LIPOPOLYSACCHARIDES; MICE; PIPERAZINES; RATS; RATS, INBRED LEW; RECEPTORS, CYTOKINE; STRUCTURE-ACTIVITY RELATIONSHIP; TUMOR NECROSIS FACTOR-ALPHA;

ANIMALIA;

EID: 0034194352     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(00)00129-3     Document Type: Article

References (11)

1. (a) Macnaul, K. L.; Hutchinson, N. I.; Parsons, J. N.; Bayne, E. K.; Tocci, M. J. J. Immunol. 1990, 145, 4154.
2. (b) Brennan, F. M.; Gibbons, D. L.; Mitchell, T.; Cope, A. P.; Maini, R. N.; Feldmann, M. Eur. J. Immunol. 1992, 22, 1907.
3. Jackson C.G., Williams H.J. Drugs. 56:1998;337.
4. Hanano, T.; Adachi, K.; Aoki, Y.; Morimoto, H.; Naka, Y.; Hisadome, M.; Fukuda, T.; Sumichika, H. Bioorg. Med. Chem. Lett. 10, 875.
5. Compounds 2a-h, 6a-e, 11a-c, 15a-c, and 19a-c gave satisfactory analytical and spectroscopic data in accord with their assigned structures.
6. The log P values were calculated using the well authorized program, PROLOGP contained in the PALLAS 1.2 package, a product of CompuDrug Chemistry Ltd (Budapest, Hungary).
7. It has been reported that there is a good relationship between membrane permeability and log P in the following paper. Komiya, I.; Park, J. Y.; Kamani, A.; Ho, N. F. H.; Higuchi, W. I. Int. J. Pharm. 1980, 4, 249.
8. 3.
9. 3)]. We found that the enantiomers have no significant difference in the activity [TNF-α (% inhibition) (R)-8b: 80%, (S)-8b: 79%; IL-10 (% of control) (R)-8b: 499%, (S)-8b: 413%)].
10. Compound 17c showed no significant adverse effects at up to 100 mg/kg, po in toxicological studies using rats.
11. It is well known that steroids such as prednisolone have an excellent anti-inflammatory effect on various diseases but they often show adverse effects (e.g. rebound). It should be possible to use the dual cytokine regulators with steroids (at low doses where steroids do not show adverse effects) at the same time because these two agents have totally different mechanisms of action. For example, rebound has been observed in a collagen induced arthritis model in rats; see the following reference. Yamaki, K.; Nakagawa, H.; Tsurufuji, S. Ann. Rheum. Dis. 1987, 46, 543.