Pyrazoloheteroaryls: Novel p38α MAP kinase inhibiting scaffolds with oral activity

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 2, 2006, Pages 262-266

  Revesz, Laszlo ^a   Blum, Ernst ^a   Di Padova, Franco E ^a   Buhl, Thomas ^a   Feifel, Roland ^a   Gram, Hermann ^a   Hiestand, Peter ^a   Manning, Ute ^a   Neumann, Ulf ^a   Rucklin, Gerard ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

Author keywords

Adjuvant induced arthritis; Anti inflammatory; Antiarthritic; Collagen induced arthritis; MAP kinase inhibition; p38 inhibition; Rheumatoid arthritis

Indexed keywords

MITOGEN ACTIVATED PROTEIN KINASE P38 INHIBITOR; PYRAZOLONE DERIVATIVE; ENZYME INHIBITOR; LIPOPOLYSACCHARIDE; MITOGEN ACTIVATED PROTEIN KINASE 14; PYRAZINE DERIVATIVE; PYRAZOLE DERIVATIVE; PYRAZOLO(3,4 B)PYRAZINE; PYRAZOLO(3,4 B)PYRIDINE; PYRAZOLO(3,4-B)PYRAZINE; PYRAZOLO(3,4-B)PYRIDINE; PYRAZOLO(3,4-D)PYRIMIDINE; PYRAZOLO[3,4 D]PYRIMIDINE; PYRIDINE DERIVATIVE; PYRIMIDINE DERIVATIVE; TUMOR NECROSIS FACTOR ALPHA;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DRUG ACTIVITY; DRUG POTENCY; ENZYME INHIBITION; FEMALE; MOUSE; NONHUMAN; RAT; RHEUMATOID ARTHRITIS; ANIMAL; ARTHRITIS; CHEMICAL STRUCTURE; CHEMISTRY; DISEASE MODEL; DRUG ANTAGONISM; METABOLISM; ORAL DRUG ADMINISTRATION; STRUCTURE ACTIVITY RELATION; SYNTHESIS;

ANIMALIA;

ADMINISTRATION, ORAL; ANIMALS; ARTHRITIS, EXPERIMENTAL; DISEASE MODELS, ANIMAL; ENZYME INHIBITORS; LIPOPOLYSACCHARIDES; MICE; MITOGEN-ACTIVATED PROTEIN KINASE 14; MOLECULAR STRUCTURE; PYRAZINES; PYRAZOLES; PYRIDINES; PYRIMIDINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; TUMOR NECROSIS FACTOR-ALPHA;

EID: 27944439591     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.10.015     Document Type: Article

References (15)

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9. Proposed binding mode of 18c to p38α: The proposed binding mode of pyrazoloheteroaryls to p38α implies that the pyrazolo nitrogen forms a crucial H-bridge to the NH of Met109 and the difluorophenyl ring accommodates in the specificity pocket near Thr106. Rigid basic substituents such as the 1-dimethylamino-2-propyne side chain in 18c increase binding affinity by forming a salt bridge to Asp168.
10. Eight-week-old female OF1 mice were dosed orally by gavage with solutions of the compounds in DMSO/cornoil. One hour after dosing, LPS (20 mg/kg) was injected iv for stimulation of TNF-α release into plasma. One hour later blood was collected and TNF-α was determined using a mouse-specific ELISA.
11. A phosphorylated form of His-p38α MAP kinase (10 ng/well) of murine origin was used and immobilised GST-ATF-2 as substrate in the presence of 120 μM cold ATP.
12. AIA: Adjuvant-induced arthritis. Female Wistar rats were immunized with Mycobacterium tuberculosis at day 0 and dosed with the compounds (2 × 25 mg/kg po per day) from day 14 to 20. Swelling of the joints was measured on day 20.
13. -1].
14. CIA: Collagen-induced arthritis. Female (WAGxBUF/F1) rats were immunized intradermally with bovine nasal septum type II collagen emulsified in Freund's incomplete adjuvant. Swelling started ∼10 days after immunization. Dosing of compounds started on day 13, when swelling was nearly maximal. Compounds were dosed po once (q.d.) daily for 10 days.
15. 50 or % inhibition at 10 μM for 9/18a/23b): JNK2 (100 μM/8.3 μM/>100 μM); CDK1: (0%/-16%/-13%); HER-1 (-43%/5.2 μM/0%); c-Abl (-23%/-58%/-42%); c-Src (-17%/-68%/-37%); Kdr (-12%/-55%/-12%); c-Met (-38%/1.5 μM/-17%); FGFR (-27%/10 μM/-5%); c-Kit (-31%/-37%/0%); IGF1R (0%/0%/-23%); HER-2 (-45%/5.0 μM/-0%); and c-Raf (n.t./0%/-14%).