People

Philippe Diaz

Associate Professor

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Personal Summary

After completing a M.Sc. in Chemistry at the University of Marseille (France) in 1992 and an engineering degree at the ENSSPICAM (now Ecole Centrale de Marseille), a National French school of engineering, Philippe received his Ph.D. in Chemistry under Dr. Lucien Stella from the University of Marseille and Dr. Charpentier from Galderma R&D in 1997. He received an accreditation to supervise research from the University of Montpellier in 2005. Philippe started his career at Galderma R&D where he held senior leadership roles in the drug discovery department. Philippe then decided to be more connected with patients and physicians to design new medicines that address significant unmet medical needs. He was senior scientist at the Department of Anesthesiology and Pain Medicine at MD Anderson Cancer Center in Houston where he became interested by the complexity of neuroscience and pain. Philippe joined the University of Montana in 2008 where he was promoted Research Associate Professor in 2010 and Associate Professor in 2014. He is co-inventor of more than 24 patents. Philippe is co-founder of DermaXon a pharmaceutical spin-off of the University of Montana. He is fluent in French, English and Spanish (plus little Italian) and he gather an international network in the fields of drug discovery, neurosciences and dermatology.

Research Interests

My research interests encompasses two somewhat distinct areas of research, pain and neurodegenerative diseases. The first focus of my laboratory centers on understanding the pharmacology of cannabinoids. The second area of investigation by my research group aims to define the therapeutic efficacy of cytochrome P450 CYP26 inhibitors, and their effect in regulating retinoic acid homeostasis.

Therapeutic potential of multi-target-directed cannabinoid ligands

Cannabinoid ligands that target CB1 and/or CB2 receptors possess therapeutic potential for the treatment of an ever growing numbers of disorders. Cannabinoids ligands promote apoptosis in tumor cells, decrease neuroinflammation or are effective in treating neuropathic pain. Currently, the diversity of cannabinoid ligands is very broad and continues to expand rapidly. Whether cannabinoid ligands exert their biological activities via a cannabinoid receptor-dependent or an off-target-mediated mechanism remains unclear. In our efforts to understand and to improve the therapeutic effects of cannabinoids, we design and synthesize cannabinoid ligands. In our initial lead compound set, we identified selective ligands for cannabinoid receptors but also selective T-type Ca2+ channel antagonists, a potent and selective CB2 receptor agonist (NTRX-07) with analgesic and anti-inflammatory properties, and compounds that kill human glioblastoma multiform cell lines. We are currently using a medicinal chemistry approach to decipher the complex pharmacology of cannabinoid ligands.

Therapeutic potential of retinoic acid metabolism inhibitors

Several studies have demonstrated that Retinoic acid (RA), a metabolite of vitamin A (also named retinol) has therapeutic benefit in the treatment of neurodegenerative diseases. RA is also used to treat skin conditions. One key limitation is that when RA is administered to humans, it induces its own metabolism, making it less effective for long-term treatment. The proteins mediating RA metabolism are named CYP26s. Of the CYP26s identified clearing RA, CYP26B1 appears to be the predominant brain isoform whereas CYP26A1 is the predominant skin isoform. Because RA has a poor fate when administered to human, a loss of activity is expected during long-term treatment explaining RA treatment resistance. Based on this evidence, we have designed a library of CYP26 inhibitors. We have discovered inhibitors of CYP26A1 and/or CYP26B1, making it possible to accurately and safely control RA concentrations for therapeutic benefit in patients. We are currently investigating the effect of our compounds in neurodegenerative diseases and ichthyosis.

Education

1990    B.S., Chemistry       University of Nice, France  
1992   Engineering degree ENSSPICAM. National school of engineering, France
1992   M.S. Organic Chemistry    University of Aix-Marseille III, France
1997   Ph.D. Organic Chemistry    University of Aix-Marseille III, France
 2005    Habilitation to supervise research University of Montpellier 2, France.

 

Courses Taught

BMED621, PHAR422, PHAR432, PHAR632

Teaching Experience

BMED621, PHAR422, PHAR432, PHAR632

Research Interests

Neurodegenerative diseases

Pain

Dermatology

Field of Study

Neurodegenerative diseases

Pain

Dermatology

Selected Publications

26 patents and 32 publication in peer-reviewed journals

Link to the publication list in Pubmed

Publications

1. Synthesis of bridged bicyclic β-trifluoromethyl β-amino acid derivatives by an original Dakin-West/ Diels-Alder Tandem Sequence. Cufos T.; Diaz P.; Stella L. Synlett. 1995, 1, 101-102.
2. Chemoenzymatic synthesis of enantiomers of a new retinoid to investigate the role of chirality in the biological response. Charpentier B.; Bernardon J.M.; Diaz P.; Vion M.; Millois C.; Bernard B.; Shroot B.  Bioorg. Med. Chem. Lett. 1995, 5, 2801-2804.
3. Synthesis and biological activities of new heterocyclic aromatic retinoids. Diaz P.; Michel S.; Stella L.; Charpentier, B. Bioorg. Med. Chem. Lett. 1997, 7, 2289-2294.
4. New Synthetic Retinoids obtained by a Tandem Cyclisation-Anion Capture Process. Diaz P.; Gendre F. ; Stella L.; Charpentier B. Tetrahedron. 1998, 54, 4579-4590.
5. New Selenium-Containing Acetylenic Retinoids by Direct Coupling of Alkynylsilanes with Selenylhalides. Diaz P. ; Gendre F. ; Bernardon J.M. Tetrahedron Lett. 1998, 39, 9003-9006.
6. Coupling reaction of chalcogenyl halides with alkynes on solid support. Synthesis of new selenium-containing retinoids. Gendre F.; Diaz P. Tetrahedron Lett. 2000, 41, 5193-5197.
7. Solution-Phase Synthesis of Diaryl Selenides using Polymer Supported Borohydride. Millois C.; Diaz P. Org. Lett. 2000, 2 (12), 1705-1708. PMID:10880206.
8. Palladium-catalyzed cascade allylation / carbopalladation / cross coupling: a novel three-component reaction for the synthesis of 3,3-disubstituted-2,3-dihydrobenzofurans. Szlosek-Pinaud M.; Diaz P.; Martinez J.; Lamaty F. Tetrahedron Lett. 2003, 44, 8657–8659.
9. Solid-phase synthesis of diaryl sulfides: Direct coupling of solid supported aryl halides with thiols using an insoluble polymer supported reagent. Gendre F.; Yang M.; Diaz P. Org. Lett. 2005, 7 (13), 2719–2722. PMID:15957930.
10. Efficient synthetic approach to heterocycles possessing the 3,3-disubstituted-2,3-dihydrobenzofuran skeleton via diverse palladium-catalyzed tandem reactions. Szlosek-Pinaud M.; Diaz P.; Martinez J.; Lamaty F. Tetrahedron. 2007, 63, 3340–3349.
11. Design and synthesis of a novel series of N-alkyl isatin acylhydrazone derivatives that act as selective CB2 agonists for the treatment of neuropathic pain. Diaz P.; Xu J.J.; Astruc Diaz F.; Pan H.M.; Brown D.L.; Naguib M. J.Med.Chem. 2008, 51, 4932–4947. PMID:18666769.
12. MDA7, a novel selective cannabinoid receptor 2 agonist preventing allodynia in rats with neuropathic pain. Naguib M.; Diaz P.; Xu J.J.; Astruc-Diaz F.; Craig S.; Brown D.L. Br.J.Pharmacol. 2008, 155 (7), 1104-1116. PMID:18846037.
13. 6-Methoxy-N-alkyl Isatin Acylhydrazone Derivatives as a Novel Series of Potent Selective Cannabinoid Receptor 2 Inverse Agonists: Design, Synthesis, and Binding Mode Prediction. Diaz P.; Phatak S.S.; Xu J.J.; Astruc Diaz F.; Cavasotto C.N.; Naguib M. J.Med.Chem. 2009, 52 (2), 433-444. PMID:19115816.
14. 2,3-dihydro-1-benzofuran derivatives as a Novel Series of Potent Selective Cannabinoid Receptor 2 Agonists: Design, Synthesis, and Binding Mode Prediction. Diaz P.; Phatak S.S.; Xu J.J.; Fronczek F.R.; Astruc-Diaz F.; Cavasotto C.N.; Naguib M. ChemMedChem. 2009, 4, 1615-1629. Featured on cover page of issue. PMID:19637157.
15. Pharmacological Characterization of a Novel Cannabinoid Ligand, MDA19, for Treatment of Neuropathic Pain. Xu J.; Diaz P.; Astruc-Diaz F.; Craig S.; Munoz E.; and Naguib M. Anesth. Analg. 2010, 111 (1), 99-109. PMID:20522703.

16. Design and evaluation of a novel fluorescent CB2 ligand as probe for receptor visualization in immune cells. Petrov R.R.; Ferrini M.E.; Jaffar Z.; Thompson C.M.; Roberts K.; Diaz P. Bioorg. Med. Chem. Lett. 2011, 21, 5859-5862. PMID:21855337.
17. Suzuki–Miyaura cross-coupling of benzylic bromides under microwave conditions. McDaniel S. W.; Keyari C.M.; Rider K.C.; Natale N.R.; Diaz P. Tetrahedron Lett. 2011, 52, 5656-5658. PMID:21966033.
18. Neuroinflammation, Alzheimer’s Disease-Associated Pathology, and Down-Regulation of the Prion-Related Protein in Air Pollution Exposed Children and Young Adults. Calderón-Garcidueñas L.; Kavanaugh M.; Block M.; D'Angiulli A.; Delgado-Chávez R.; Torres-Jardón R.; González-Maciel A.; Reynoso-Robles R.; Osnaya N.; Villarreal-Calderon R.; Guo R.; Hua Z.; Zhu H.; Perry G.; Diaz P. J. Alzheimers Dis. 2012, 28 (1), 93-107. PMID:21955814.
19. Functional characterization and analgesic effects of mixed cannabinoid receptor/T-type channel ligands. You H.; Gadotti V.M.; Petrov R.R.; Zamponi G.W.; Diaz P. Mol. Pain. 2011, 7:89. PMID:22093952.
20. Prevention of Paclitaxel-Induced Neuropathy Through Activation of the Central Cannabinoid Type 2 Receptor System. Naguib M.; Xu J.J.; Diaz P.; Brown D.L.; Cogdell D.; Bie B.; Hu J.; Craig S.; Hittelman W.N. Anesth. Anal. 2012, 114(5), 1104-1120. PMID:22392969.
21. In vivo efficacy of enabling formulations based on hydroxypropyl-β-cyclodextrins, micellar preparation and liposomes for the lipophilic cannabinoid CB2 agonist, MDA7. Astruc-Diaz F.; McDaniel SW.; Xu JJ.; Parola S.; Brown DL.; Naguib M.; Diaz P. J. Pharm. Sci. 2013, 102(2):352-64. PMID:23192786.
22. Synthesis of New Quinolinequinone Derivatives and Preliminary Exploration of their Cytotoxic Properties. Keyari C.; Kearns A.; Duncan N.; Eickholt E.; Abbott G.; Beall H.; Diaz P. J.Med.Chem. 2013, 56(10):3806-3819. PMID:23574193.
23. Analgesic effect of a mixed T-type channel inhibitor/CB2 receptor agonist. Gadotti VM.; You H.; Petrov RR.; Berger ND.; Diaz P.; and Zamponi GW. Mol.Pain. 2013, 9:32. PMID:23815854.
24. Mastering tricyclic ring systems for desirable functional cannabinoid activity. Petrov R.R.; Knight L.; Chen S.R.; Wager-Miller J.; McDaniel S.W.; Diaz F.; Barth F.; Pan H.L.; Mackie K.; Cavasotto C.N.; Diaz P. Europ.J.Med.Chem. 69:881-907. 2013. PMCID: PMC3909471.
25. Up-regulation of mRNA ventricular cellular prion protein PrPC in air pollution highly exposed young urbanites: Endoplasmic reticulum stress and the impact of nano size particles. Villarreal-Calderon R.; Franco-Lira M.; González-Maciel A.; Reynoso-Robles R.; Harritt L.; Pérez-Guillé B.; Ferreira-Azevedo L.; Drecktrah D.; Zhu H.; Sun Q.; Torres-Jardón R.; Diaz P.; Calderón-Garcidueñas L. Int. J. Mol. Sci. 14(12):23471-91. 2013. PMCID: PMC3876057
26. Novel Di-Aryl-Substituted Isoxazoles act as Noncompetitive Inhibitors of the System XC- Cystine/Glutamate Exchanger. Newell J.L.; Keyari, C.M.; Diaz P.; Natale N.R.; Patel S.A, Bridges R.J. Neurochemistry International. pii: S0197-0186(13)00309-4, 2013. PMID: 24333322
27. Spinal gene expression profiling and pathways analysis of a CB2 agonist (MDA7)-targeted prevention of paclitaxel-induced neuropathy. Xu J.J; Diaz P.; Bie B.; Astruc-Diaz F.; Wu J.; Yang H.; Brown D.L.; Naguib M. Neuroscience. Neuroscience. 260:185-94. 2014. PMID: 24361916
28. Characterization of novel cannabinoid based T-type calcium channel blockers with analgesic effects. Bladen C.; McDaniel S.W.; Gadotti V.M.; Petrov R.R.; Berger N.D.; Diaz P. (corresponding author); Zamponi G. ACS Chem. Neurosci., Just Accepted.
29. NMP-7 inhibits chronic inflammatory and neuropathic pain via block of Cav3.2 T-type calcium channels and activation of CB2 receptors. Berger N.D.; Gadotti V.M.; Petrov R.R.; Chapman K.; Diaz P.; and Zamponi G.W. Molecular Pain. 2014 Dec 6;10:77.  PMCID: PMC4271433

30. Bladen C, McDaniel SW, Gadotti VM, Petrov RR, Berger ND, Diaz P, Zamponi GW. Characterization of novel cannabinoid based T-type calcium channel blockers with analgesic effects. ACS Chem Neurosci. 2015 Feb 18;6(2):277-87. doi: 10.1021/cn500206a. PubMed PMID: 25314588; PubMed Central PMCID: PMC4372069.

31. Foti RS, Diaz P, Douguet D. Comparison of the ligand binding site of CYP2C8 with CYP26A1 and CYP26B1: a structural basis for the identification of new inhibitors of the retinoic acid hydroxylases. J Enzyme Inhib Med Chem. 2016;31(sup2):148-161. PubMed PMID: 27424662.

32. Diaz P, Huang W, Keyari CM, Buttrick B, Price L, Guilloteau N, Tripathy S, Sperandio VG, Fronczek FR, Astruc-Diaz F, Isoherranen N. Development and Characterization of Novel and Selective Inhibitors of Cytochrome P450 CYP26A1, the Human Liver Retinoic Acid Hydroxylase. J Med Chem. 2016 Mar 24;59(6):2579-95. doi: 10.1021/acs.jmedchem.5b01780. PubMed PMID: 26918322; PubMed Central PMCID: PMC4836378.

33. Foti RS, Isoherranen N, Zelter A, Dickmann LJ, Buttrick BR, Diaz P, Douguet D. Identification of Tazarotenic Acid as the First Xenobiotic Substrate of Human Retinoic Acid Hydroxylase CYP26A1 and CYP26B1. J Pharmacol Exp Ther. 2016 May;357(2):281-92. doi: 10.1124/jpet.116.232637. PubMed PMID: 26937021; PubMed Central PMCID: PMC4851321.


 

Professional Experience

1996-1998    Team manager: Medicinal chemistry department, Galderma R&D, France.
1998-2001   Head of combinatorial chemistry department, Galderma R&D, France.
2001-2004    Lecturer, Master FoQual, University of Nice. France.
2001-2006   Chemistry team leader and project monitor, Galderma R&D, France.
2005-2007   Lecturer, Master in Medicinal chemistry, University of Montpellier. France.
2006-2008   Sr. research scientist, UT MD Anderson Cancer Center, Houston, Texas.
2008-present  Manager, Core Laboratory for Neuromolecular Production, U of Montana.
2010-2014   Research Associate Professor, The Univ of Montana
2014-present  Associate Professor, The University of Montana.
2013-present  co-Founder and CSO, DermaXon LLC, Missoula MT 59802

International Experience

Chair of the International students committee BMED

Active collaborations with several foreign scientists (France, Canada and Argentina)

Advisor of two graduate students who were awarded prestigious Chateaubriand Fellowships to conduct research abroad

Hobbies

Music (Bassist for All Night Alibi), ski and outdoor activities