Novel polycyclic Compounds with Biological Activity

PI: Dr. Santiago Vázquez

Postdoc:

                Dr. Oscar Lozano Ventura

PhD students:

                Sandra Codony Gisbert (APIF-UB)

Beatrice E. Jora (FI-Doctorat Industrial)

                Eugènia Pujol Bech (APIF-IBUB)

Andreea L. Turcu (FPU)

Dr. Santi Vázquez studied Pharmacy (1986-91) and, under the direction of Professor Pelayo Camps, obtained his PhD in Organic and Medicinal Chemistry at the Universitat de Barcelona (UB) (1996, PhD Extraordinary Prize of the UB). After two years (1998-2000) in the Christopher Ingold Laboratories (University College London, London, UK) with Professor William B. Motherwell as a Marie Curie Research Fellow, he returned to Barcelona in 2000 as Assistant Professor. In 2001 he took up a researcher position as “Investigador Ramón y Cajal” and in 2005 he was promoted to his current permanent position as Associate Professor (“Professor Agregat”) at the Laboratori de Química Farmacèutica de la Universitat de Barcelona. Dr. Vázquez is a founder member of the Institut de Biomedicina de la Universitat de Barcelona (IBUB) and has over 25 years’ experience working on organic and medicinal chemistry, with focus on the synthesis of new compounds with potential biological activity.

 

Dr. Vázquez has participated as co-I in 16 research projects and as PI in 8 research projects from public funding agencies. Moreover, he has been the PI in 9 research contract with Spanish and international chemical and pharmaceutical companies. He is a regular consultor of Spanish chemical companies. He is also co-inventor in several patent and patent applications both in new chemical entities with biological activity (see below) and in new process for the manufacturing of generic active pharmaceutical ingredient (API). 

After working several years in pure organic chemistry -novel synthetic methodology, chemistry of polycyclic hydrocarbons-, more recently our research has focused on the synthesis of novel channel blockers -human NMDA and P2X7, M2 channel of influenza virus- and novel enzyme inhibitors, including 11b-HSD1 inhibitors and soluble epoxide hydrolase inhibitors. For our medicinal chemistry programs we have established successful collaborations with several computational (Prof. F. Javier Luque, UB) and biological groups in Europe (e. g., Prof. Erick DeClerck and Lieve Naesens, KU Leuven, Belgium; Prof. John M. Kelly, London School of Hygiene and Tropical Medicine, London, UK; Prof. Anna Moroni and Sabrina Gazzarrini,  University of Milano, Italy; Prof. Scott P. Webster, University of Edinburgh, UK; Prof. F. X. Sureda, Universitat Rovira i Virgili, Tarragona, Spain; Prof. Mercè Pallas, Prof. Manuel Vázquez-Carrera and Dr. David Soto, UB), the USA (e. g., Prof. William F. DeGrado, UCSF; Prof. Lawrence H. Pinto, Northwestern University; Prof. Bruce D. Hammock, UCD; Prof. Jun Wang, University of Arizona; Prof. Jon W. Johnson, University of Pittsburgh) and South Korea (Prof. Yong-Chul Kim, Laboratory of Drug Discovery of the Gwangju Institute of Science & Technology, Gwangju, South Korea). Below, there is a list of the main topics of our representative research.

 

1. Design, synthesis and evaluation of new polycyclic inhibitors of the M2 channel of the influenza A virus. 

 

Amantadine (Amt) and rimantadine (Rmt), have been in clinical use as anti-influenza A virus agents for decades. The mechanism of action of both drugs is based on the inhibition of the M2 proton channel of the influenza A virus. However, the efficacy of these two drugs dropped sharply in recent years due to the global distribution of mutant viruses carrying Amt resistance mutations. Detailed mutational studies indicated that several point mutations (i.e., L26F, V27A, and S31N) of the channel result in Amt-resistance.

In the last 8 years our group, in collaboration with the groups of W. F. DeGrado (UCSF), L. H. Pinto (Northwestern Univ.), L. Naesens (KU Leuven, Belgium), A. Moroni (Univ. Milano, Italy) and F. J. Luque (UB, Spain) has designed, synthesized, characterized and pharmacologically evaluated several series of M2 proton channel blockers able to simultaneously inhibit the wild-type (Amt-resistant) and the L26F and V27A M2 mutant channels. We were the first to report ring-contracted and ring-expanded analogs of Amt (a), the first to report dual inhibitors of the V27A and the L26F M2 mutant channels (b,c) and we provided computational (d) and experimental (e) evidences of the resistance mechanism. Finally, the observation that some of our M2 channel blockers were able to also target another viral protein, hemagglutinin, led to the recent discovery of a new family of anti-influenza agents targeting hemagglutinin (f).

(a)    Duque, M. D.; Ma, C.; Torres, E.; Wang, J.; Naesens, L.; Juárez-Jiménez, J.; Camps, P.; Luque, F. J.; DeGrado, W. F.; Lamb, R. A.; Pinto, L. H.; Vázquez, S. (2011). Exploring the size limit of templates for inhibitors of the M2 ion chanel of influenza A virus. J. Med. Chem. 54, 2646-2657.

(b)    Rey-Carrizo, M.; Torres, E.; Ma, C.; Barniol-Xicota, M.; Wang, J.; Wu, Y.; Naesens, L.; DeGrado, W. F.; Lamb, R. A.; Pinto, L. H.; Vázquez, S. (2013). 3-Azatetracyclo[5.2.15,8.01,5]undecane derivatives: from wild-type inhibitors of the M2 ion channel of influenza A virus to derivatives with potent activity against the V27A mutant. J. Med. Chem. 56, 9265-9274

(c)     Rey-Carrizo, M.; Barniol-Xicota, M.; Ma, C.; Frigolé-Vivas, M.; Torres, E.; Naesens, L.; Llabrés, S.; Juárez-Jiménez, J.; Luque, F. J.; DeGrado, W.; Lamb, R.; Pinto, L.; Vazquez, S. (2014). Easily Accessible Polycyclic Amines that Inhibit the Wild-Type and Amantadine-Resistant Mutants of the M2 Channel of Influenza A Virus. J. Med. Chem. 57, 5738-5747.

(d)    Llabrés, S.; Juárez-Jiménez, J.; Masetti, M.; Leiva, R.; Vázquez, S.; Gazzarrini, S.; Moroni, A.; Cavalli, A.; Luque, F. J. (2016). Mechanism of the pseudoirreversible binding of amantadine to the M2 proton channel. J. Am. Chem. Soc. 138, 15345-15358.

(e)    Barniol-Xicota, M.; Gazzarrini, S.; Torres, E.; Hu, Y.; Wang, J.; Naesens, L.; Moroni, A.; Vázquez, S. (2017). Slow but steady wins the race: dissimilarities among new dual inhibitors of the wild-type and the V27A mutant M2 channels of influenza A virus. J. Med. Chem. 60, 3727-3738.

(f)      Leiva, R.; Barniol-Xicota, M.; Codony, S.; Ginex, T.; Vanderlinden, E.; Montes, M.; Luque, F. J.; Naesens, L.; Vázquez, S. (2018). Aniline-based inhibitors of influenza H1N1 virus acting on hemagglutinin-mediated fusion. J. Med. Chem. 61, 98-118.

 

2. Design, synthesis and evaluation of new polycyclic antagonist of the NMDA receptors.

 

Within this project we designed, synthesized and evaluated novel polycyclic compounds as analogs of the clinically approved NMDA receptor antagonists amantadine and memantine. First, we synthesized and fully characterized ring-contracted analogs of amantadine (a). Also, we were the first to report that oxa-analogs of amantadine were also antagonists of the NMDA receptors (b), and that novel polycyclic scaffolds, were also endowed with potent NMDA receptor antagonism (c,d).

a)       Camps, P.; Duque, M. D.; Vázquez, S.; Naesens, L.; DeClercq, E.; Sureda, F. X.; López-Querol, M.; Camins, A.; Pallàs, M.; Prathalingam, S. R.; Kelly, J. M.; Romero, V.; Ivorra, D.; Cortés, D. (2008). Synthesis and pharmacological evaluation of several ring-contracted amantadine analogs. Bioorg. Med. Chem. 16, 9925-9936.

b)      Duque, M. D.; Camp, P.; Profire, L.; Montaner, S.; Vázquez, S.; Sureda, F. X.; Mallol, J.; López-Querol, M.; Naesens, L.; DeClercq, E.; Prathalingam, S. R.; Kelly, J. M. (2009). Synthesis and pharmacological evaluation of (2-oxaadamant-1-yl)amines. Bioorg. Med. Chem. 17, 3198-3206.

c)       Valverde, E.; Sureda, F. X.; Vázquez, S. (2014). Novel benzopolycyclic amines with NMDA receptor antagonist activity. Bioorg. Med. Chem. 22, 2678-2683.

d)      Leiva, R.; Phillips, M. B.; Turcu, A. L.; Gratacòs-Batlle, E.; León-García, L.; Sureda, F. X.; Soto, D.; Johnson, J. W.; Vázquez S. (2018). Pharmacological and electrophysiological characterization of novel NMDA receptor antagonists. ACS Chem. Neurosci. 9, 2722-2730.

 

3. Design, synthesis and evaluation of novel 11b-HSD1 inhibitors for neurodegenerative diseases.

 

In collaboration with the groups of Prof. Scott P. Webster (University of Edinburgh, UK), Prof. F. Javier Luque (UB) and Prof. Mercè Pallàs (UB) we have discovered a new family of 11b-HSD1 inhibitors that has been successfully tested in vivo in a broadly-used mouse model (SAMP8) of accelerated senescence and late-onset Alzheimer’s disease with very promising results.

a)       Leiva, R.; Griñan-Ferré, C.; Seira, C.; Valverde, E.; McBride, A.; Binnie, M.; Pérez, B.; Luque, F. J.; Pallàs, M.; Bidon-Chanal, A.; Webster, S. P.; Vázquez, S. (2017). Design, synthesis and in vivo study of novel pyrrolidine-based 11b-HSD1 inhibitors for age-related cognitive dysfunction. Eur. J. Med. Chem. 139, 412-428.

b)      Puigoriol-Illamola, D.; Griñan-Ferré, C.; Vasiolopoulou, F.; Leiva, R.; Vázquez, S.; Pallàs, M. (2018). 11b-HSD1 inhibition by RL-118 promotes autophagy and correlates with reduced oxidative stress and inflammation, enhancing cognitive performance in SAMP8 mouse model. Molecular Neurobiol. 55, 8904-8915.

 

 4. Organic chemistry projects.

 

In addition to our medicinal chemistry projects we keep working on synthetic organic chemistry, mainly related with the development of new synthetic methodology (a) and the synthesis of highly pyramidalized alkenes (b,c).

a) Barniol-Xicota, M.; Turcu, A. L.; Codony, S.; Escolano, C.; Vázquez, S. (2014). Direct reductive alkylation of amine hydrochlorides with aldehyde bisulfite adducts. Tetrahedron Lett. 55, 2548-2550.

b) Rey-Carrizo, M.; Barniol-Xicota, M.; Font-Bardia, M.; Vázquez, S. (2014). Dimerization of highly pyramidalized 3,4,8,9-tetramethyltetracyclo[4.4.0.03,9.04,8]dec-1(6)-ene to a hydrocarbon featuring four cyclohexane rings in boat conformation. Angew. Chem. Int. Ed. 53, 8195-8199.

c) Alonso, J. M.; Quiroga, S.; Codony, S.; Turcu, A. L.; Barniol-Xicota, M.; Pérez, D.; Guitián, E.; Vázquez, S.; Peña, D. (2018). Palladium-catalyzed cocyclotrimerization of arynes with a pyramidalized alkene. Chem. Commun. 54, 5996-5999. 

 

5. Patent applications. 

 

One of the main aims of our group is to generate Intellectual Property stemming from our research projects. Below there is a list of recent, selected patent and patent applications by our group. The titles give an idea of the wide range of topics of our group.

 

a)       Title: Analogs of adamantylureas as soluble epoxide hydrolase inhibitors.

Inventors: Santiago Vázquez, Elena Valverde, Rosana Leiva, Manuel Vázquez, Sandra Codony.

Patent application: WO2017/017048 (priority date: Jul 28, 2015).

b)      Title: New aza-tetracyclo derivatives.

Inventors: Santiago Vázquez, Rosana Leiva, Elena Valverde.

Patent application: WO2017/182464 (priority date: Apr 19, 2016).

c)       Title: Process for obtaining 3,14-diacetyloxymorphone from oripavine.

Inventors: Melville Mitchell, Santiago Vázquez, Andrés E. Lukach, Oscar Lozano, Joan Castañé.

Patent application: EP 3252055 B1 (priority date: May 31, 2016).

d)      Title: HRI activators useful for the treatment of metabolic diseases.

Inventors: Mohammad Zarei, Manuel Vázquez, Santiago Vázquez, Rosana Leiva, Eugènia Pujol.

Patent application: WO2018/010856 (priority date: Jul 13, 2016).

a) Financing administration: Fundació La Marató TV3 (Spain). 308/C/2018. 1 Apr 2019 to 31 Mar 2022.

Title of the project: Discovery of innovative drugs for respiratory virus infections.

Goals: To design, synthesize and evaluate new compounds with activity against clinically relevant viruses: a) influenza virus; b) human coronavirus.

 

b) Financing administration: Ministerio de Economia y Competitividad (Spain). SAF2017-82771-R. 1 Jan 2018 to 31 Dec 2020

Title of the project: Synthesis of compounds with new mechanisms of action for neurodegenerative diseases.

Goals: To design, synthesize and fully characterized new compounds with putative activity on clinically relevant targets: a) soluble epoxide hydrolase inhibitors; b) P2X7 receptor antagonists; c) sigma-1 ligands; d) glutaminyl cyclase inhibitors.

 

c) Financing administration: University of Barcelona (Spain). FVal-2018-FBG-UB. 1 Jan 2018 to 31 Dec 2018

Title of the project: Therapeutic and prophylactic effects of soluble Epoxide Hydrolase Inhibitors in Acute Pancreatitis and in Endoscopic Retrograde Cholangiopancreatography-Induced Acute Pancreatitis.

Goals: To select a new soluble epoxide hydrolase inhibitor with in vivo efficacy in animal models of acute pancreatitis.

 

d) Financing administration: Ministerio de Economia y Competitividad (Spain) SAF2014-57094-R. 1 Jan 2014 to 31 Dec 2017.

Title of the project: Exploring new targets and multi-target strategies against infective and prevalent diseases

Goals: To design, synthesize and fully characterized new compounds with putative activity against clinically relevant targets: a) NMDA receptor antagonists; b) P2X7 receptor antagonists; c) influenza virus M2 channel blockers.

 

e) Financing Firm: Fundació Caixa de Pensions 'La Caixa'. Caixaimpulse Program (FBG308661). 1 Feb 2016 to 31 Jul 2017

Title of the project: Drugs for inflammatory & cardiovascular disorders.

Goals: To design, synthesize and fully characterized new compounds with anti-inflammatory activity as inhibitors of the enzyme soluble epoxide hydrolase.

 

f) Financing administration: European Institute of Innovation & Technology - EIT Health. Proof of concept Grant - FBG48075. 1 Oct 2016 to 30 Sep 2017

Title of the project: Efficacy and safety assessment of novel soluble epoxide hydrolase inhibitors for the prevention and treatment of acute pancreatitis (sEHIAP).

Goals: To design, synthesize and fully characterized new compounds with activity as inhibitors of the enzyme soluble epoxide hydrolase. To perform the in vivo proof of concept of a selected candidate in a model of acute pancreatitis.

 

g) Financing Firm: Eli Lilly and Company. Open Innovation Drug Discovery Program. 1 Jan 2017 to 31 Dec 2017

Title of the project: Drugs for inflammatory & cardiovascular disorders.

Goals: To synthesize and fully characterized new compounds for high-throughput drug screening against selected targets.

Dr. Xavier Pujol Ollé (PhD, 2001; currently head of R&D at Farmhispania).

 

Dr. Gisela Colet Español (PhD, 2001; currently Manager of the Research Support Department at the Institut Català de Investigació Química, ICIQ).

 

Dr. M. Rosa Muñoz Blasco (PhD, 2007).

 

Dr. Carles Ayats Rius (PhD, 2007 ; currently senior researcher at LEITAT Technological Center).

 

Dr. José A. Fernández Pareja (PhD, 2007).

 

Dr. M. Dolores Duque Toral (PhD, 2010).

 

Dr. Eva Torres Costa (PhD, 2013; PhD Extraordinary Prize of the UB; currently Raw Material Purchaser Manager at Ferrer International).

 

Dr. Matías Rey-Carrizo (PhD, 2014; PhD Extraordinary Prize of the UB; currently Scientific Writer at BCN Medical Writing).

 

Dr. Elena Valverde Murillo (PhD, 2015; currently Regulatory Affairs Technician at Farmhispania).

 

Dr. Marta Barniol-Xicota (PhD, 2017; PhD Extraordinary Prize of the UB; currently Marie Curie Research Fellow at KU Leuven, Leuven, Belgium).

 

Dr. Rosana Leiva Martínez (PhD, 2017; PhD Extraordinary Prize of the UB; currently Medical Scientific Liaison at Novartis).

Laboratori de Química Farmacèutica, Facultat de Farmàcia i Ciències de l’Alimentació, i Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, s/n; 08028 Barcelona (Spain).

Tel.: +34 934024533

E-mail: svazquez@ub.edu