Philippe Diaz
Professor
Contact
- Office
- SB479
- Phone
- (406) 243-4362
- Fax
- (406) 243-5228
- philippe.diaz@umontana.edu
- Website
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 老虎机攻略 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 a pharmaceutical spin-off of the 老虎机攻略. 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, PHAR421, PHAR444
Teaching Experience
BMED621, PHAR422, PHAR432, PHAR421, PHAR444
Research Interests
Neurodegenerative diseases
Pain
Dermatology
Projects
1R41AR078087-01A1 NIH/NCATS Title: Novel therapeutic target to combat cutaneous lupus.
5R44AR069416-03, NIH/NIAMS Title: Selective inhibition of CYP26A1 in the skin for the treatment of ichthyosis
5UT2GM130166-03 NIH/NIGMS Title: A novel therapeutic target to combat human autoinflammatory skin disease
1R41 NS105304-01A1, NIH/NINDS Title: Topical selective T-type blockers for the treatment of neuropathic pain
1R43AR076842-01, NIH/NIAMS Title: Topical selective T-type blockers for the treatment of pruritus
Field of Study
Neurodegenerative diseases
Pain
Dermatology
Selected Publications
31 patents and 40 publication in peer-reviewed journals
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. .
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. .
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. .
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. .
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. .
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. .
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. .
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. .
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. .
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. .
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. .
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. .
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. .
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. .
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. .
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. .
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.
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.
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.
28. 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.
29. 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., 6(2):277-87, 2015.
30. Development and characterization of novel and selective inhibitors of cytochrome P450 CYP26A1, the human liver retinoic acid hydroxylase. Diaz P.; Huang W.; Keyari C.M.; Buttrick B.; Price L.; Guilloteau N.; Tripathy S.; Sperandio V.G.; Astruc-Diaz F.; Isoherranen N. J.Med.Chem. 59(6): 2579-2595, 2016.
31. Identification of Tazarotenic Acid as the First Xenobiotic Substrate of CYP26A1 and CYP26B1 Using Homology Modeling and In Vitro Metabolite Characterization. Foti R.S.; Isoherranen N.; Zelter A.; Dickmann L.J.; Buttrick B.R.; Diaz P. and Douguet D. J Pharmacol Exp Ther 357(2): 281-292, 2016. Featured on cover page of issue.
32. 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. Foti, R. S. Diaz, P. Douguet, D. J Enzyme Inhib Med Chem. 2016 Jul 17:1-14.
33. Modified carbazoles destabilize microtubules and kill glioblastoma multiform cells. Diaz P; Horne E.; Xu C.; Hamel E.; Wagenbach M.; Petrov R.R. Uhlenbruck B.; Haas B.; Hothi P.; Wordeman L.; Gussio R.; Stella N.; European Journal of Medicinal Chemistry, 159(5): 74-89, 2018.
34. Definition of functionally and structurally distinct repressive states in the nuclear receptor PPARγ. Zahra Heidari, Ian M. Chrisman, Michelle D. Nemetchek, Scott J. Novick, Anne-Laure Blayo, Trey Patton, Desiree E. Mendes, Philippe Diaz, Theodore M. Kamenecka, Patrick R. Griffin & Travis S. Hughes; Nature Communications, volume 10, Article number: 5825, 2019.
35. Purified and specific cytoplasmic pollen extract, PureCyTonin®, a nonhormonal treatment for hot flushes, inhibits serotonin reuptake. Kurt Appel, Joachim Veit, Philippe Diaz, Santiago Palacios, Barbara Vega; Gynecological and Reproductive Endocrinology&Metabolism, 1(1):64-68, 2020.
36. Cav3.2 T-type calcium channels control acute itch in mice. Gadotti V. M., Kreitinger M. Joanna, Wageling B. Nicholas, Budke Dylan, Diaz Philippe, Gerald W. Zamponi Mol Brain, 13(1): 119, 2020.
37. Characterization of CYP26B1-Selective Inhibitor, DX314, as a Potential Therapeutic for Keratinization Disorders. Veit J. G. S.; De Glas V.; Balau B.; Liu H.; Bourlond F.; Paller A. S. ; Poumay Y.; Diaz. P. Journal of Investigative Dermatology 141(1): 72-83.e76, 2021.
38. A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis.Neuro-Oncology Advances. Eric A. Horne; Philippe Diaz; Patrick J Cimino;Erik Jung; Cong Xu; Ernest Hamel; Michael Wagenbach; Debra Kumasaka; Nicholas B Wageling; Daniel D Azorín; Frank Winkler; Linda G Wordeman; Eric C. Holland. Nephi Stella. Neuro-Oncology Advances, Vol. 3 Issue 1 Pages vdaa165, 2020.
39. Preclinical assessment of dual CYP26[A1/B1] inhibitor, DX308, as an improved treatment for keratinization disorders. Veit, J. G. S.; Poumay, Y.; Mendes, D.; Kreitinger, J.; Walker, L.; Paquet, A.; Menigot, C.; Zolezzi, F.; Paller, A. S.; Diaz, P., Skin Health Dis. 2021 Mar 26;1(2):e22. doi: 10.1002/ski2.22.
40. Cannabinoids activate the insulin pathway to modulate mobilization of cholesterol in C. elegans. Hernandez-Cravero B, Gallino S, Florman J, Vranych C, Diaz P, et al. (2022) Cannabinoids activate the insulin pathway to modulate mobilization of cholesterol in C. elegans. PLOS Genetics 18(11): e1010346. https://doi.org/10.1371/journal.pgen.1010346
Specialized Skills
Medicinal Chemistry, Drug design, Preclinical development, Investigational New Drug-enabling studies
Professional Experience
1992 – 1993 Military service French Air Force.
1996 – 1998 Team manager: Medicinal chemistry department, Galderma R&D, Sophia Antipolis, France.
1998 – 2001 Head of combinatorial chemistry department, Galderma R&D, Sophia Antipolis France.
2001 – 2004 Lecturer, Master FoQual, University of Nice.
2001 – 2006 Chemistry team leader and project monitor, Galderma R&D, Sophia Antipolis, France.
2006 – 2008 Senior research scientist, UT MD Anderson Cancer Center, Houston, Texas.
2008 – present Director of the Core Laboratory for Neuromolecular Production, The 老虎机攻略.
2010 – 2014 Research Associate Professor, The 老虎机攻略.
2014 – 2020 Associate Professor, The 老虎机攻略.
2013 – present CEO and co-founder Dermaxon LLC.
2020 – present Professor, The 老虎机攻略.
International Experience
Active collaborations with several foreign scientists (France, Canada and Argentina)
Honors / Awards
2020 NIH CAP Larta Commercialization Training Workshop fellow
2017 76th Society for Investigative Dermatology Annual Meeting 2016 Entrepreneur Shark Tank competition. 1st place award
2011-2012 Visiting Scholar at the Institute of Translational Health Sciences (ITHS) University of Washington.
2008 The Elmer Zsigmund Abstract Award, International Society for Anesthetic Pharmacology.
1993 – 1996 Fellowship Association Nationale de la Recherche Technique, Cifre Grant.
Hobbies
Music (Bassist for All Night Alibi), ski and outdoor activities