Ten Years of Medicinal Chemistry (2005â2014) in the Journal

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Perspective

Ten Years of Medicinal Chemistry (2005-2014) in the Journal of Medicinal Chemistry: Country of Contributors, Topics and Public-Private Partnerships. Luca Costantino, and Daniela Barlocco J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.5b01349 • Publication Date (Web): 23 Mar 2016 Downloaded from http://pubs.acs.org on March 23, 2016

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Journal of Medicinal Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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Journal of Medicinal Chemistry

Ten Years of Medicinal Chemistry (2005-2014) in the Journal of Medicinal Chemistry: Country of Contributors, Topics and Public-Private Partnerships.

Luca Costantino*,† and Daniela Barlocco‡

†University

of Modena and Reggio Emilia, Dipartimento di Scienze della Vita, Via Campi 103,

41100 Modena (Italy); ‡University

of Milano, Dipartimento di Scienze Farmaceutiche, Via Mangiagalli 25, 20133 Milano

(Italy).

ABSTRACT This Perspective analyzes the articles that have appeared during the past ten years in the Journal of Medicinal Chemistry, the leading journal in the field of medicinal chemistry, to provide a picture of the changing trends in this research area. Our analysis involved the country of the corresponding author, assuming that he/she was the leader of the research group, the interaction between private and public sectors, and the research topics. This analysis provides information on the contributions to the journal of authors from each country and highlights the differences between the public and private sectors regarding the research topics pursued. Moreover, changes in the number of articles that describe work on hits, leads or clinical candidates during these years has been correlated with the affiliation of the contributors (public or private). An analysis of top-cited articles that have appeared in the journal has also been included. The data will provide the basis for understanding the evolution that is taking place in medicinal chemistry.

1 ACS Paragon Plus Environment


INTRODUCTION The world of drug discovery is changing. The past decade has been characterized by a decline in R&D biopharma efficiency1 despite the technical advances reported to date, creating strong pressure to evolve. Academia and other public institutions also participate in research in this field. Collaborations between these two groups (public-private partnerships or PPPs) have been suggested to be of high importance in developing innovative medicines.2 Moreover, in recent years, academic labs have been given investments to increase the ability of their drug discovery programs to progress to the clinical phases (data for USA2,3-5 and UK6,7). To date, however, no attempts have been made to establish a clear picture of the existing situation. The Journal of Medicinal Chemistry (J. Med. Chem.) is the leading journal in medicinal chemistry research. Graph 1 shows the trend of the impact factor during the period considered in comparison with top journals that publish analogous Ms (source: InCites,Web of Science®, Thomson Reuters8).

6

5

Journal Impact Factor

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J. Med. Chem.

4

ACS Med. Chem. Lett. Eur. J. Med. Chem. 3

Bioorg. Med. Chem. Bioorg. Med. Chem. Lett.

2

ChemMedChem J. Enzyme Inh. Med. Chem.

1

Med. Chem.

0 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Years


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Graph 1. Trend in the Impact Factors of the main journals that publish research articles in the field of medicinal chemistry. Data for the journal “Medicinal Chemistry Research” for 2013 are not available, and, owing to this, it was not included in the graph; in 2014, the impact factor was 1.402. Data for ACS Medicinal Chemistry Letters (ACS Med. Chem. Lett.), ChemMedChem and Medicinal Chemistry (Med. Chem.) are available only since 2011, 2007 and 2009, respectively. Other journals, that publish research in medicinal chemistry, but not as their main focus, or publish mainly “Reviews”, such as Nature, Angewandte Chemie Int. Ed., Current Medicinal Chemistry, etc. have not been included in this analysis.

The total number of citations for the Journal of Medicinal Chemistry each year has been both remarkable and constant. We considered the total citations during two years after the period studied to provide sufficient time for citations to occur. Thus, we were able to obtain data only for the years 2005-2012. During this period, the mean number of total citations was 8714 each year with a standard deviation (S.D.) of 985 (11%) (source: InCites, Web of Science®, Thomson Reuters8). At the same time, the total number of published manuscripts (Ms) increased, and articles published in 2005 are still cited to a remarkable extent in 2015; thus, the total citations increased from 35053 in 2005 to 63060 in 2014. Moreover, the number of Ms dealing with New Molecular Entities (NMEs) that received first time approval worldwide during 2005-2013 described in the “Annual Reports in Medicinal Chemistry” (2014 is not available yet) reported for the first time in J. Med. Chem. is remarkably greater than those reported in the journals examined in Graph 1 (Supplementary material Graph S2). A list of the 10 most-cited articles and 5 top-cited Perspectives published in the journal each year, classified on the basis of the number of citations obtained before October 13th, 2015, is reported in the Supplementary Material (Table S1).



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Due to the importance of the journal, analyzing the published Ms during the past ten years may help to highlight the changing trends in the medicinal chemistry field, offering a representative picture of the research that has been performed during this time. We assumed that all the Ms published have the same relevance, and our analysis used the country of the author marked with an asterisk, assuming that he/she is the project leader, the interaction between the private and public sectors, and the research topics covered by the private or public institutions. This analysis provides information on contribution of each country to research in medicinal chemistry, and may be useful for governments to determine whether resources have been provided to this field in an effective way. While our analysis is relevant to the leading research in medicinal chemistry, it may not be relevant to approved drugs, because a drug approval involves many different factors. Nevertheless, basic science makes a strong contribution to the discovery of new drugs; thus, these data help provide a view of drugs in development. Moreover, policies regarding the publication of results can vary between research centers of public institutions vs. industry, and delays in submitting work for publication can arise because of patenting and licensing considerations. Although there is significant pressure for scientists that belong to public institutions to publish, scientists working in industry often publish Ms that discuss compounds only when they are approaching Phase 2 studies, or they are allowed to publish after a project closes. Nevertheless, the timeframe of the analysis should compensate for this issue. The Ms that appeared in J. Med. Chem. during the 10 years from 2005 to 2014 (7728 Ms), excluding “Perspectives” (336 Ms) or “Viewpoints” (24 Ms) have been analyzed based on the following aspects: 1) The country of the corresponding author(s) (assuming that this author was the project leader) was considered to provide a picture of the contributions of different countries to medicinal chemistry research published in the journal. Moreover, a similar analysis was


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performed that considered only Ms published by collaborators from the public and private sectors, to obtain a picture of the interactions between these two groups. 2) The affiliation of the research team that published the Ms was considered, to highlight differences in the number of Ms published by public institutions and industry, as well as extent and changing trends in partnerships between these two groups. Thus, Ms were classified on the basis of the affiliation of the research team, whether it from companies (one or more), from public institution(s), or from a public-private collaboration. In the latter case, the Ms were classified based on the affiliation of the corresponding author (industry or public institutions). Classification by authors could be misleading as a paper describing a licensed product be submitted by a lead author who is a licensee, while the actual inventive or impactful work may have originated in the lab of the licensor. However, we believe that our approach is the most reliable way to classify research Ms. 3) An analysis was performed to determine whether authors from the private sector include more in vivo data (pharmacokinetics and pharmacodynamics) in the Ms. These data may indicate the completeness of the study performed, and the effort expended to discover clinical candidates. 4) J. Med. Chem. research Ms were classified according to their content (whether or not their content is focused on drug discovery). Ms focused on drug discovery were classified on the basis of the various stages of compounds development (hits, leads or clinical candidates). Separate graphs have been included for Ms submitted by research teams from industry or the public sectors. For Ms contributed by public-private collaborators, Ms were classified according to the affiliation of the corresponding author. 5) The research topic of each Ms was also noted. The Ms were classified based on 25 disease targets, by performing a visual inspection of the Ms contents, and we were guided by the biological assays included in the Ms. In many cases, we classified the Ms according to the goals stated by the authors in their introductory paragraphs. We kept in mind that a 5 ACS Paragon Plus Environment


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biological target may play a role in multiple diseases. For example, the enzyme gamma secretase, which was initially considered as a target for the development of drugs for Alzheimer’s disease, was recently shown to be relevant also for the development of antitumor drugs.9 Accordingly, Ms dealing with gamma secretase were classified as specified by the authors . Moreover, this analysis was also extended to the top 10 Ms with most citations in each year.

RESULTS Country of the corresponding author(s) (Point 1): Graph 2 reports the mean values for the country of the author(s) labelled with the asterisk. During 2005-2014, the counts for each country remained almost constant, except for Italy and China, which showed the greatest changes (Graph 3), though in opposite directions. It was not possible to correlate these findings with the level of public funding or private investments in R&D10-12 because, to the best of our knowledge, detailed data for single countries are not available. However, one report11 showed that there was a slight decrease in biomedical R&D expenditure (during 2007-2012) in Canada, USA and Europe, whereas there was an increase in the annual growth rate of biomedical R&D expenditure for Taiwan, Japan, India, Australia, Singapore, and S. Korea, with the largest increase occurring in China.11


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400

Counts (mean for 10 years)

350 300 250 200 150 100 50

Australia

India

Japan

Taiwan

P.R. China

Israel

S. Korea

Greece

Czech

Hungary

Italy

Switz.

Poland

Austria

Belgium

NL

DK

Ireland

Sweden

UK

Germany

Spain

France

Canada

USA

0

Country

Graph 2. Ms classification based on the country of the author(s) marked with an asterisk (period: 2005-2014). Countries with mean values of less than 10 were omitted from the graph for clarity.

180 160 140 120 100 80 60 40 20 0

Italy P.R. China

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Counts

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Year

Graph 3. Ms number trends for China and Italy.



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Comparison of the data obtained here with those from the published analysis that considered the years 1999-201012 shows that there are some differences for Germany, Japan, and the UK, which increased with respect to our data, and Italy, which significantly decreased. However, the analysis reported by S. Ahmadian et al.12 examined the total number of research publications, patents, and h-index values of each country in pharmacy-related fields present in Scopus®. h-Index value is a measure of both the productivity and citation impact of the publications of a scientist, a group of scientists or a country. The criteria for assessing the country of the Ms were not specified, and the Ms were not limited to the field of medicinal chemistry research. Nevertheless, there is general agreement between the two sets of data, and differences may be attributed to publications in journals other than J. Med. Chem.. Except for China, the trend observed in ref.12 was supported by research evaluating the allocation of the 252 new drugs that were approved by the US FDA between 1998 and 2007 according to the type of discovery organization (public or private).13 The high number of Ms from the USA is also reflected in the country of the 10 most-cited articles for each studied year (Graph 4). Because there are several Ms at the same level that possess the highest citation numbers, especially for the most recent years, (10 Ms for 2005 and 2006, 12 for 2007, 10 for 2008 and 2009, 12 for 2010, 11 for 2011 and 2012, 17 for 2013 and 20 for 2014, for a total of 123 articles, we show only the % of the most abundant country (USA) of the author marked by an asterisk. The analysis was performed on October 13th, 2015 (source: Web of Science®,Thomson Reuters14). Clearly, this ranking is not precise because the time available for citations varies if one article is published e.g., in January 2014 and the other is published in December 2014, with less time available for citations. Older articles possess a larger number of citations, and this effect is less pronounced.


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90 80 % of authors from USA

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70 60 50 40 30 20 10 0 2005

2006 2007

2008 2009 2010 2011 2012 2013 2014 Year

Graph 4. Percentage (%) of authors with asterisks from the USA for the top 10 most highly cited articles.

Affiliation of the research team that published the manuscript (Point 2): To understand the relative impact of the public vs. private sectors on the number of published Ms, a classification based on the affiliation of the research team (from the public or private sector) was performed, and the results were expressed in percentages of the total number of Ms (Graph 5). In the case of research performed in collaboration between public and private sectors, Ms were further classified as “Public+”, research teams with the corresponding author from the public sector, or “Private+”, research teams with the corresponding author from the private sector. In the case of two asterisks, where one person was from a public institution and the other from industry, the Ms was assigned as industry (leader) collaborating with a public institution. Since these percentages remain almost constant during the period under study (as can be seen from the standard deviation values), and changing trends are not clearly evident, we reported only average values.


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2005-2014 mean % Ms affiliation of the research team


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80 70 60 50 40 30 20 10 0 Public

Private

Public+

Private+

Affiliation of the corresponding author(s)

Graph 5. Percentage (%) of J. Med. Chem. Ms based on the affiliation of the research team (mean +/- S.D.). Public: public sector, Private: private sector; Public+: Ms contributed in partnerships by authors from the public and private sectors, with the corresponding author from the public sector; Private+: Ms contributed in partnership by authors from the public and private sectors, with the corresponding author from the private sector.

Regarding the affiliation of the research team of the 10 most-cited articles for each year, the results range from 67:33 (private sector:public sector, respectively) during 2005-2009, to 49:51 for 2010-2014. Ms of the research teams under public-private partnerships are present to a low extent (Public+, 3%, Private+, 6%) (source: Web of Science®, Thomson Reuters14).

Manuscripts containing in vivo data (Point 3): The analysis of Ms regarding in vivo data related to pharmacokinetics (PK) and/or pharmacodynamics (PD) is reported in Graph 6. From 2005 to 2014, there is a consistent trend in the Ms published in J. Med. Chem. that contain in vivo data. Although Ms published by the private 10 ACS Paragon Plus Environment

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sector almost always contain in vivo data, the public sector publishes more than three times the Ms than the private sector and reports more than three times fewer in vivo assays. However, both sectors are growing in this respect.

100 90 80 70 60 Ms %

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Public

50

Private

40

Public+

30

Private+

20 10 0 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Year

Graph 6. Percentage (%) of J. Med. Chem. Ms containing in vivo data (pharmacodynamics and/or pharmacokinetic evaluations) according to the affiliation of the research team: Public: public sector, Private: private sector; Public+: Ms contributed in partnership by authors from the public and private sectors, with the corresponding author from the public sector; Private+: Ms contributed in partnership by authors from the public and private sectors, with the corresponding author from the private sector.

Point 4: Drug discovery. Research articles published in J Med. Chem. have been first analyzed on the basis of their topics, highlighting those dealing with drug discovery (excluding prodrugs, radiopharmaceuticals, compounds for photodynamic therapy, diagnostics, tools). This amount remains almost constant during the period considered (mean 74.8%, S.D. 5.6). Ms dealing with drug discovery have been



then classified on the basis of their contents (hit, a molecule with known structure and a robust dose-response activity in a primary screen, or a representative of a series with activity via an acceptable mechanism of action and some preliminary structure-activity relationships; lead, a representative of a series with sufficient potential, measured

by potency, selectivity,

pharmacokinetics, physicochemical properties, to progress to a full development program; clinical candidate, compounds that progressed into the clinic. Ms were selected as “leads” if they describe leads or, at least, if the experimental settings adopted are adequate for lead selection. Ms were classified as containing clinical candidates on the basis of what has been specified in the Ms by the authors; in the case of the presence of a code, we checked on the web if the compound entered clinical trials). Analysis has been performed for the years 2005, 2006, 2008, 2010, 2012 and 2014. Data are expressed as percentage of Ms dealing with hits (Graph 7A), leads (Graph 7B) and clinical candidates (Graph 7C) with respect to the total number of Ms for each category (Public, Private, Public+ and Private+).

Hits (Graph 7A) 120 100 80 % Ms

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Public 60

Private

40

Public+

20

Private+

0 2005

2006

2008

2010

2012

2014

Years


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Leads (Graph 7B) 70 60

% Ms

50 40

Public

30

Private

20

Public+

10

Private+

0 2005

2006

2008

2010

2012

2014

Years

Clinical candidates (Graph 7C) 35 30 25 % Ms

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20

Public

15

Private

10

Public+

5

Private+

0 2005

2006

2008

2010

2012

2014

Years

Graphs 7 A-C. Percentage (%) of Ms on J. Med. Chem. that report work on various stages of drug discovery (excluding prodrugs, radiopharmaceuticals, compounds for photodynamic therapy, diagnostics, tools) with respect to the total number of Ms within each category (Public: public sector, Private: private sector, Public+: partnerships by authors from the public and private sectors,



with the corresponding author from the public sector; Private+: partnerships by authors from the public and private sectors, with the corresponding author from the private sector.

As can be seen, there is a strong prevalence of the Public sector when hits are considered, while the opposite is true for leads. Ms dealing with clinical candidates are limited to Private and Private+ categories. Then, in order to highlight the relative impact of public and private sectors on drug discovery (the number of Ms from public sector is three times higher with respect to the private sector) we performed the same analysis considering the total number of Ms dealing with drug discovery (leads, Graph 8; hits and clinical candidates, Graphs S1A,B, respectively, Supplementary material).

Leads 16 % Ms dealing with drug disc.

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14 12 10

Public

8

Private

6

Public+

4

Private+

2 0 2005

2006

2008

2010

2012

2014

Years

Graph 8. Percentage (%) of Ms on J. Med. Chem. dealing with lead discovery with respect to the total number of Ms dealing with drug discovery. These data are for the years 2005, 2006, 2008, 2010, 2012 and 2014. Public: public sector, Private: private sector, Public+: partnerships by authors from the public and private sectors, with the corresponding author from the public sector; Private+:


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partnerships by authors from the public and private sectors, with the corresponding author from the private sector.

As can be seen (Graph 8), there is a growing trend toward Ms dealing with leads contributed by the public sector with respect to the total number of Ms published in J. Med. Chem.. This could indicate an increased capability and interest of this sector in translational research, although an effect of the policy of the journal (editors’ criteria in the form of rejection) cannot be ruled out. The data suggests that in the future the public sector will contribute more significantly than now to the discovery of new clinical candidates.

Research topic (Point 5): The research topics were analyzed to identify possible differences between the public and private sectors. Because of the low number of Ms contributed in collaboration, we grouped these Ms. Graph 9 shows the target analysis considering the Ms with a research team belonging to the public sector or by authors from the public and private sectors in partnership, with the corresponding author from the public sector, and Graph 10 shows the Ms with the research team belonging to the private sector or by authors from the public and private sectors in partnership, with the corresponding author from the private sector. In the case of two asterisks, where one person was from a public institution and the other from industry, the Ms was assigned as industry (leader) collaborating with a public institution. The research topic was classified according to the following categories: 1) Basic (article topic not linked to a specific class of drugs or a specific disease area); 2) Disease status not well defined (articles addressing compounds designed to clarify the biological role of the target under examination or structure-activity relationship (SAR) among receptor subtypes);

3)

Imaging/diagnostic

compounds

(positron

emission

tomography

(PET), 15

ACS Paragon Plus Environment


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radiopharmaceuticals) independent of the target; 4) Tools (techniques or fluorescent compounds for use in, for example, surface plasmon resonance (SPR) assays); 5) Photodynamic therapy and other techniques; 6) Prodrugs/Antibody-Directed Enzyme Prodrug Therapy (ADEPT)/soft drugs that are independent from the target; 7) Ms that investigate delivery (interaction with transporters, ATPbinding cassette (ABC) transporters, and multi-drug resistance (MDR) systems); 8) Compound metabolism (cytochrome P450 (CYP) enzymes and other topics, such as drug metabolite studies); 9) Genetic diseases; 10) Antitumor; 11) Antiparasitic (protozoa); 12) Compounds for other parasitic diseases (worms, etc.); 13) Antimicrobial; 14) Antiviral and prion diseases; 15) Antimycobacterial; 16) Antifungal; 17) Compounds for the gastrointestinal (GI), respiratory and urogenital apparatus that are not included in other sections, including benign prostatic hypertrophia; 18) Compounds that address the endocrine apparatus (hormones, excluding compounds included in point 17 (obesity, diabetes, eating disorders, and cachessia) or 7 (antitumor drugs). This point includes compounds for estrogen receptor subtypes that have been not included in the antitumor drugs; 19) Compounds for immunity and inflammatory diseases (immunity, inflammation, autoimmune diseases, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease); 20) Obesity, diabetes, eating disorders, cachessia, and diabetic complications; 21) Compounds for the cardiovascular system (heart, coagulation, hypolipidemics, etc.); 22) Compounds for central nervous system diseases, including compounds that target the vanilloid receptor; 23) Compounds involved in cell protection (compounds for iron overload, free radical scavengers, etc.); 24) Compounds for diseases involving bones and cartilages; and 25) Other indications. For clarity, the following graphs report only the percentage of Ms in each disease area exceeding 3% (categories n° 1, 2, 3, 10, 11, 13, 14, 19-22).


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30.00

% Ms (Public and Public+)

25.00 2005 20.00

2006 2007

15.00

2008 2009

10.00

2010 2011

5.00

2012 2013

0.00

2014

Graph 9. Percentage (%) of Ms contributed by research teams from the public sector on selected therapeutic targets. 2012: J. Med. Chem. contains a thematic issue (Alzheimer’s disease; category 22); 2014: J. Med. Chem. contains another thematic issue (hepatitis C virus (HCV); category 14).

30.00 % Ms (Private and Private+)

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25.00

2005 2006

20.00

2007 15.00

2008

10.00

2009 2010

5.00

2011 2012

0.00

2013 2014



Graph 10. Percentage (%) of Ms contributed by research teams from the private sector on selected therapeutic targets. 2012: J. Med. Chem. published a thematic issue (Alzheimer’s disease; category 22); 2014: J. Med. Chem. published another thematic issue (HCV; category 14).

An analysis of the topic of research for the 10 most cited articles each year was also performed, and the results are expressed as percentage values (Graph 11). Antitumor compounds were always in the first position, followed by articles investigating basic science or antivirals. Compounds designed to treat metabolic diseases were reported for Type 2 diabetes, and the majority of articles studying antiviral compounds that were signed by researchers in industry focused on HCV (6 Ms), whereas only one Ms on this topic was from a public institution. Among the compounds relevant for cardiovascular disease, all the Ms described anticoagulants (source: Web of Science®,Thomson Reuters14).

45 40 35 30 % Ms

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25 20 15

Private/Private+

10

Public/Public+

5 0

Graph 11. Primary disease areas of the top 10 cited Ms for the entire period of 2005-2014.


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DISCUSSION During the past decade, the USA has remained the largest contributor of Ms published in J. Med. Chem., consistent with its position as the leading country in medicinal chemistry research. During the decade covered by our analysis, the main changes were a significant decrease in the number of corresponding authors from Italy and a large increase in those from China (Graph 3). This is in accordance with the rapid growth of China’s pharmaceutical industry.15 The literature data indicate that up to 24% of FDA-approved compounds during the period of 1998-2007 (24%) were based on university discoveries that were subsequently developed by companies.13 Given the importance of public institutions in drug discovery, it has been suggested that a remedy for the decline in biopharma R&D efficiency may be expansion of partnerships between the public and private sectors.16 Our analysis shows that from 2005 to 2014 the percentage of Ms contributed in collaboration between public/private sectors remains almost constant (Graph 5). Recently there was an increase in the capabilities of academic research institutions for drug discovery. Thus, many investigational new drug applications have been filed, and several compounds have been approved.2 Academic institutions in the USA2,3-5 and the UK6,7 (data are available for these two countries only) have been given investments to increase the capability of their drug discovery programs for the progression of early stage opportunities. A large portion of their drug discovery group members have some industry experience.4,6,7 However, while nearly all the Ms signed by authors from industry contain in vivo data, that could indicate an effort to fully characterize the preclinical characteristics of the compounds with a view to a clinical translation. The analysis performed here shows that few Ms published by the public sector contain these data, although the number of Ms containing leads is increasing.



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Targets considered in the public and private sectors differ significantly (Graphs 9 and 10, respectively). In particular, Ms dealing with parasitic diseases, antibacterials and compounds not directed toward a specific target are lower for the private sector than those of the public sector. The percentage of Ms relating to basic science is well represented by the private sector, contributing significantly to the advancement of basic knowledge in this field. Comparing the New Chemical Entities (NCE), which recently entered clinical trials (source: clinicaltrials.gov, reported in ref. 17-19, the top three indications were as follows: in 2011, 1) Diabetes, 2) Hepatitis C virus (HCV), and 3) COPD; in 2012, the same; in 2013: 1) Diabetes, 2) Breast cancer, and 3) HCV (fourth: COPD and rheumatoid arthritis (same points)), for which the data reported in Graphs 9 and 10 showed a better correlation with Ms classified by topic within the industry sector (Graph 10) (antiviral, compounds for immunity and inflammatory diseases and compounds for metabolic disorders, such as obesity, diabetes, eating disorders, cachessia, and diabetic complications; classified under categories 14, 19 and 20) than within the public sector (Graph 9). Thematic issues (2012, Alzheimer’s disease; classified under category 22; 2014, HCV; classified under category 14) significantly increase in the number of Ms addressing these two “hot topics”, but only within the private sector (Graph 10). Analysis of the topic of researches for the top 10 Ms with most citations in each year (Graph 11) showed a similar trend.

CONCLUSIONS While several studies appeared recently dealing with analyses of research contributions to FDA-approved drugs20, to the best of our knowledge this Perspective provides the first analysis that deals with medicinal chemistry at the research level. This research may or may not result in new drugs, but the advancement of science is in any case of value in the drug discovery process. The analysis performed here is based on the research that has been published in the Journal of Medicinal Chemistry, the leading journal in this field of research. During 2005-2014, there were few changes 20 ACS Paragon Plus Environment

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in the Ms numbers classified by country, except for Italy and China. A change in focus in the therapeutic areas can be clearly observed only in the public sector research (Graph 9). However, because of the lower number of Ms from the private sector (30% with respect to the public sector), the trends are more difficult to determine for this group of Ms (Graph 10). Of the top ten articles during these years, a shift from private sector dominance to near balance between the two sectors was observed, as well as a significantly lower number (approximately one third) of Ms published by industry. This underlines the importance of research performed by both private and public sectors. On the whole, the majority of the Ms published in J. Med. Chem. deal with drug discovery. The private sector appears to be more oriented towards translation, as can be seen in the supplementary Graph S1B (percentage of Ms dealing with clinical candidates within private and public sector); however, there is an increase in Ms dealing with lead discovery by the public sector (Graphs 7B and 8). Concerning the topics of all the Ms during 2005-2014, there are significant differences in the top 10 articles between the public and private sectors, reflecting the importance that HCV and Type 2 diabetes have gained in recent years. It is possible that expanding collaborations between the public and private sectors will increase the productivity of the drug discovery process. However, these changes remain difficult to detect based on the articles published in J. Med. Chem. during 2005-2014. Academia and the private sector differ in another aspect: some research topics pursued in academia may not be of high interest to the Pharma industry, although they are important for world health (for example, imaging/diagnostic agents, or compounds for parasitic diseases). This is consistent with the number of Ms on these topics published in J. Med. Chem. by the private and public sectors. A recent analysis suggests that academia will play an increasingly important role in drug discovery.20 Another article21 illustrates the changes in the ways in which new medicines are discovered, highlighting the gradual withdrawal of the biopharmaceutical industry from early-stage R&D. New models of integration between public and private sectors have been proposed, and several 21 ACS Paragon Plus Environment


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approaches have been described.21,22 These, together with the data shown here at the research level, can lead to conclude that public and private sectors can interact fruitfully if a close collaboration can be established between these two sectors.

Notes The authors declare no competing financial interests.

Supplementary material. A list of the most-cited 10 articles for each year, and of the 5 top-cited Perspectives is reported in Table S1. A graph that relates percentages of Ms on J. Med. Chem. dealing with hits and clinical candidates discovery with respect to the total number of Ms dealing with drug discovery for each category (Public, Private, Public+ and Private+) is reported in Graphs S1A and S1B, respectively. Table S2 reports the raw data related to Graphs 7A-C, 8 and S1. Graph S2 reports the number of Ms dealing with New Molecular Entities (NMEs) that received first time approval worldwide during 2005-2013 reported for the first time in J. Med. Chem., in comparison with the other journals reported in Graph 1.

Corresponding author information: E.mail: [email protected]; Phone +39-0592058572

Biographies Luca Costantino earned his degree in Pharmacy (1981) from the University of Modena and Reggio Emilia (Italy). He became Researcher at the University of Modena and R.E., Faculty of Pharmacy, 22 ACS Paragon Plus Environment

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in 1983 and associate professor at the University of Modena in 1998. His main research interests are addressed to the design of small molecules as enzyme inhibitors and

to the design of

nanoparticles as drug carriers for CNS.

Daniela Barlocco earned her degree in Pharmacy (1969) and in Chemistry (1977) from the University of Pavia (Italy). She became Researcher at the University of Milan, Faculty of Pharmacy, in 1980 and associate professor at the University of Modena in 1992. She got the title of full professor at the University of Milan in 2000. Her main research interests are addressed to the design of small molecules as enzyme inhibitors and to the comprehension of the protein-protein interactions.

ACKNOWLEDGEMENTS We thank Dott. Nicola De Bellis (University of Modena e R.E.) for the helpful discussion and suggestions about the bibliometric analysis here performed.

Abbreviations used: Ms: manuscript; PPPs: public-private partnerships; R&D: research and development; HCV: hepatitis C virus; COPD: chronic obstructive pulmonary disease.

REFERENCES (1) Scannell, J.W.; Blanckley, A.; Warrington, B. Diagnosing the decline in pharmaceutical R&D efficiency. Nat Rev. Drug Disc. 2012, 11, 191-200.



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Drug Disc. Today 2015, 20, 1288-1292. (22) Frye, S.V.; Arkin, M.R.; Arrowsmith, C.H.; Conn, P.J.; Glicksman, M.A.; Hull-Ryde, E.A.; Slusher, B.S. Tackling reproducibility in academic preclinical drug discovery. Nat. Rev. Drug Disc. 2015, 14, 733-734.



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Table of Contents graphic


Ten Years of Medicinal Chemistry (2005â2014) in the Journal

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