title: Pyrazole derivatives as potent inhibitors of c-Jun N-terminal kinase: synthesis and SAR studies.
abstract: Mitogen activated protein kinases including c-Jun N-terminal kinase play an indispensable role in inflammatory diseases. Investigation of reported JNK-1 inhibitors indicated that diverse heterocyclic compounds bearing an amide group rendered potent JNK-1 inhibitory activity which prompted us to synthesize new JNK-1 inhibitors containing a pyrazole heterocyclic group. A DABCO mediated 1,3-dipolar cycloaddition reaction in neat resulted in pyrazole carboxylic acid which was converted to desired amides. Upon confirmation of the structures, all the compounds were screened for JNK-1 inhibitory activity and in vivo anti-inflammatory activity. Several synthesized analogues have exhibited JNK-1 inhibitory activity less than 10 μM, in particular compounds 9 c, 10 a and 10 d were found to be potent among all the compounds.
authors.affiliation: University College of Pharmaceutical Sciences, Kakatiya University, Warangal 506009, Andhra Pradesh, India.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Doma
authors.affiliation: University College of Pharmaceutical Sciences, Kakatiya University, Warangal 506009, Andhra Pradesh, India.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Kulkarni
authors.affiliation: D-206/B, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 50067, India.
authors.forename: Radhakrishna
authors.initials: R
authors.lastname: Palakodety
authors.affiliation: Centre for Molecular Modeling, Indian Institute of Chemical Technology, Hyderabad 50067, India.
authors.forename: G Narahari
authors.initials: GN
authors.lastname: Sastry
authors.affiliation: Centre for Molecular Modeling, Indian Institute of Chemical Technology, Hyderabad 50067, India.
authors.forename: Janardhan
authors.initials: J
authors.lastname: Sridhara
authors.affiliation: University College of Pharmaceutical Sciences, Kakatiya University, Warangal 506009, Andhra Pradesh, India. Electronic address: achaiah_g@yahoo.co.in.
authors.forename: Achaiah
authors.initials: A
authors.lastname: Garlapati
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D004487:Edema / Q000188:drug therapy; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000893:Anti-Inflammatory Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D048031:JNK Mitogen-Activated Protein Kinases
keywords: IC(50); Inflammation; JNK-1; Pyrazoles