Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide (BMS-582949), a Clinical p38α MAP Kinase Inhibitor for the Treatment of Inflammatory Diseases

2010 ◽  
Vol 53 (18) ◽  
pp. 6629-6639 ◽  
Author(s):  
Chunjian Liu ◽  
James Lin ◽  
Stephen T. Wrobleski ◽  
Shuqun Lin ◽  
John Hynes ◽  
...  
Keyword(s):  
Map Kinase ◽  
Kinase Inhibitor ◽  
Inflammatory Diseases ◽  
P38α Map Kinase

Modelling Flexible Protein-Ligand Binding in p38α MAP Kinase using the QUBE Force Field

2019 ◽  
Author(s):  
Joshua Horton ◽  
Alice Allen ◽  
Daniel Cole
Keyword(s):  
Quantum Mechanics ◽  
Force Field ◽  
Map Kinase ◽  
Binding Free Energy ◽  
Quantum Mechanical ◽  
Enhanced Sampling ◽  
Relative Binding ◽  
Stringent Test ◽  
Flexible Protein ◽  
P38α Map Kinase

<div><div><div><p>The quantum mechanical bespoke (QUBE) force field is used to retrospectively calculate the relative binding free energy of a series of 17 flexible inhibitors of p38α MAP kinase. The size and flexibility of the chosen molecules represent a stringent test of the derivation of force field parameters from quantum mechanics, and enhanced sampling is required to reduce the dependence of the results on the starting structure. Competitive accuracy with a widely-used biological force field is achieved, indicating that quantum mechanics derived force fields are approaching the accuracy required to provide guidance in prospective drug discovery campaigns.</p></div></div></div>

scholarly journals POS0083 USEFUL EXPERIENCE OF RHEUMATOLOGISTS FOR UNDERSTANDING OF THE DISEASE ORIGIN AND APPROACHES TO THERAPY IN FIBRODYSPLASIA OSSIFICANS PROGRESSIVA

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 249.2-250
Author(s):  
I. Nikishina ◽  
S. Arsenyeva ◽  
V. Matkava ◽  
A. Arefieva ◽  
M. Kaleda ◽  
...  
Keyword(s):  
Heterotopic Ossification ◽  
Kinase Inhibitor ◽  
Inflammatory Diseases ◽  
Clinical Manifestations ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Rapid Progression ◽  
Time Duration ◽  
Long Term Follow Up ◽  
Vertebral Bodies ◽  
The One

Background:Many monogenic genetic conditions, such as auto-inflammatory diseases (AIDs), have similar clinical manifestations and immunopathogenesis to “classic” rheumatic diseases (RD). Such cases may include Fibrodysplasia ossificans progressiva (FOP), an extremely rare genetic disease, which, according to our previous study and data from other authors1, may represent an example of AID with catastrophic heterotopic ossification due to a mutation in the ACVR1 gene. it seems that the experience of rheumatologists, especially children’s ones, will be useful in the treatment of FOP.Objectives:To analyzed the dynamics of clinical manifestations and to therapy approaches including target anti-inflammatory drug Tofacitinib (TOFA) in the one of the world’s largest groups of patients (pts) with FOP.Methods:The study was based on the analysis retrospective and prospective observation of the 35 pts (17 males and 18 females) with a verified diagnosis of FOP for the period from 1998 to 2020. In 9 pts with severe course of FOP TOFA administration were evaluated.Results:In all 35 pts the diagnosis was verified by “classic” FOP phenotype: malformed great toes in 33 pts (94,3%); short malformed thumbs-8 (22.8%); peripheral osteochondromas-20 (57.1%); abnormalities of the cervical spine-32 (91.4%), multiple heterotopic ossifications-32 (91,4%). Genetic tests were done in 26, it confirmed mutation in the ACVR1 gene in 100%. Long term follow-up detected a lot of spondyloarthritis-like signs similar to the manifestation of RD: ankylosis of the facet joints and vertebral bodies (by the type of syndesmophytes) in most pts, sacroiliitis, confirmed by radiological methods (X-ray, CT, MRI), gradual ankylosis in the peripheral joints in 18 (56.4%), synovitis in large joints in 8 (25%) pts (knee and hip mostly). In 9 pts with the most difficult course with rapid progression of ossification due to continuous flares despite the NSAIDs and steroids intake, we tried to use TOFA after the approval of the local Ethic Committee. We use the similar dose to randomized trial for JIA (up to 5 mg twice a day). The first patient was 16 y.o. at the time of TOFA administration in December 2019, the age of the other pts was from 2 to 12 y.o. By present time duration of TOFA therapy is from 6 to 15 mo. For the previous 6 months before TOFA initiation the number of flares was in average 8 per patient. After 6 months of TOFA treatment the number of new flares decreased to 0-1, except youngest patient of 2 y.o. in whom the number of flares decreased from 10 to 4 per the same period. In all 9 pts we minimize the dose or completely stop the steroids. New nodes formation stopped immediately in most pts and also the significant motion improvement of large (shoulder) joints were established. Drug tolerance was good in all pts, no AE were registered. But despite the good clinical effect without new heterotopic ossification in our first patient, we found continuous intraskeletal ossification between vertebral bodies, facet and sacroiliac joints in MRI.Conclusion:We are confident that the processes of heterotopic ossification in FOP are very similar to new born formation phenomenon in spondyloarthritis and reliable suppression of inflammation can interrupt the progression of the disease. We used similar justifications to our colleagues for the use of anti-cytokine drugs, but used a JAK-kinase inhibitor, it was extremely important the oral rout of drug administration and possibility to escape any injections in FOP. TOFA demonstrated positive effect and safety in children with severe course of FOP. It showed their advantages over the use of steroids and possibility to inhibit the rate of progression.References:[1]R.Haviv et al. Is fibrodysplasia ossificans progressiva aninterleukin-1 driven auto-inflammatory syndrome? Pediatric Rheumatology (2019) 17:84 //doi.org/10.1186/s12969-019-0386-6Disclosure of Interests:None declared.

N-Phenyl-N-purin-6-yl ureas: The design and synthesis of p38α MAP kinase inhibitors

2003 ◽  
Vol 13 (6) ◽  
pp. 1191-1194 ◽  
Author(s):  
Zehong Wan ◽  
Jeffrey C. Boehm ◽  
Michael J. Bower ◽  
Shouki Kassis ◽  
John C. Lee ◽  
...  
Keyword(s):  
Map Kinase ◽  
Kinase Inhibitors ◽  
Design And Synthesis ◽  
P38α Map Kinase
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