Crop Protection Discovery: Is Being the First Best? - Journal of

Subscriber access provided by University of South Dakota

Perspective

Crop Protection Discovery – Is Being the First Best? Thomas C. Sparks, James E Hunter, Beth A. Lorsbach, Greg Hanger, Roger Gast, Greg Kemmitt, and Robert J Bryant J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.8b03484 • Publication Date (Web): 11 Sep 2018 Downloaded from http://pubs.acs.org on September 13, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

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.

Page 1 of 40

Journal of Agricultural and Food Chemistry

For: Journal of Agricultural and Food Chemistry Review

Crop Protection Discovery – Is Being the First Best? Thomas C. Sparks*, James E. Hunter, Beth A. Lorsbach, Greg Hanger, Roger E. Gast, Greg Kemmitt, Robert J. Bryant** Corteva Agrisciences™, Agriculture Division of DowDuPont™, Dow AgroSciences. Discovery Research 9330 Zionsville Road, Indianapolis, IN 46268 **Agranova, Orpington, Kent BR6 9AP UK

*Corresponding Author: Ph: 317-337-3064 Fax 317-337-3205 E-mail: [email protected]

ACS Paragon Plus Environment


1

ABSTRACT

2

Current crop protection chemicals span an array of chemistry classes and modes of

3

action.

4

active ingredients competing with each other for market position. In this competition,

5

the first product to market in a new class or mode of action may or may not have an

6

advantage depending on a number of parameters including relative efficacy against the

7

target pests, pest resistance, regulatory pressures, synthetic complexity, and marketing

8

effectiveness.

9

protection compounds has been declining, and patenting strategies have gotten more

10

sophisticated, making it more challenging to break into an existing area of chemistry.

11

One result is new classes of chemistry tend to be smaller, making first to market more

12

beneficial than in the past.

13

chemistry has the opportunity to set positioning and expectations.

14 15 16 17

Keywords Agrochemical discovery, Crop protection compounds, Pesticide

18 19 20 21 22 23 24 25 26 27

Typically, within each chemistry class there are multiple chemically distinct

The number of companies involved in the discovery of new crop

Additionally, the first into a market with a new class of

Abbreviations used ALS - acetolactate synthase inhibitor DMI – demethylase Inhibitor EPSPS - enolpyruvyl-3-shikimate phosphate synthase FRAC – Fungicide Resistance Action Committee GM – genetically modified HRAC –Herbicide Resistance Action Committee IRAC – Insecticide Resistance Action Committee MoA - mode of action SDHI - succinate dehydrogenase inhibitors


Page 2 of 40

Page 3 of 40


28

29

INTRODUCTION

30

The increasing global population1 requires expanded production of food to feed the

31

additional two billion people expected on this planet by 2050.

32

pathogens and weeds that negatively impact crop productivity remains an ongoing,

33

essential component to successful and economical food production. However, pest and

34

pathogen resistance to existing commercial pesticides continues to expand3,4 and

35

escalating regulatory and environmental requirements4,5 limit the utility of many

36

established classes of chemistry. Thus, there remains a need for new and novel crop

37

protection products creating opportunities for innovation to address grower and

38

consumer needs.

Controlling insects,

39 40

Although there has been substantial consolidation in the crop protection agrochemical

41

industry, especially among companies involved in the basic research and development

42

of new crop protection products,4,5 new active ingredients

43

and developed (Figure 1)6 representing a range of classes. A long standing and central

44

approach in crop protection discovery programs is the utilization of competitor patents

45

as a source of inspiration for new agrochemcials as well as the further evolution of a

46

chemical class by the originating company seeking to expand the spectrum and

47

utility.4,7,8 This enduring approach in discovery programs9 has led to a long line of crop

48

protection active ingredients belonging to common chemical families and manifesting

49

their bioactivity via the same mode of action.

50

introduction of the once revolutionary organophosphate insecticide, parathion, in the

continue to be discovered

For example, the discovery and



Page 4 of 40

51

1940’s, lead to a diverse range of organophosphate insecticides10 over the next 70

52

years with an excess of 150 different active ingrediants.11 Similar, but less extreme

53

examples exist for a range of existing chemical classes of insecticides (N-methyl

54

carbamates, cyclodienes, pyrethroids, neonicotinoids), fungicides (triazoles, strobilurins)

55

and herbicides (aryloxyphenoxys, sulfonyl ureas / sulfonamides).

56

the first molecule that becomes a product in a particular agrochemical class remained

57

the primary molecule in that class and market in spite of numerous other chemically

58

analogous products being introduced.

59

neonicotinoid developed and has maintained its sales lead for more than 20 years, in

60

spite of the introduction of several other neonicotinoids (Table 1).

61

leading product of some classes emerged only after the first molecule was introduced.

62

This was the case for the α-cyano-pyrethroids, cypermethrin and deltamethrin, which

63

quickly displaced permethrin,12 one of the very first photostable pyrethroids

64

commercialized.

In some instances

Imidacloprid, for example, was the first

Conversely, the

65 66

Slightly more than half of global pesticide sales are derived from active ingredients

67

introduced since 1991, about evenly divided between fungicides, herbicides and

68

insecticides (Figure 2), clearly demonstrating the value of newer products in the

69

marketplace.

70

chemicals, with some highs and lows, over the past 25 years (Figure 1). As such, this

71

analysis will focus on the metrics for active ingredients launched post-1990 since data is

72

more readily available and the aim is to better understand the newer areas of chemistry,

73

and hence more recent driving forces in the current marketplace. From this data an

Since 1991, there has been a continuous flow of new crop protection


Page 5 of 40


74

effort is made to identify attributes that allow for the continued success of some first to

75

market crop protection products, as well as the attributes that become opportunities for

76

follow-on crop protection compounds to build on and surpass their forerunner(s) in

77

terms of sales. In the second part of this perspective a number of case studies are

78

presented which illustrate the relative importance of the factors in governing how the

79

first to market may fare, and how important those attributes may be in determining new

80

modes of action (MoAs) offering success in future years.

81 82

DATA

83

In an attempt to identify the most important and relevant factors that make a compound

84

a sales leader within a class of chemistry, data from selected classes of the nearly 300

85

herbicidal, fungicidal and insecticidal active ingredients registered in the last 25 years

86

was used in the analysis.

87

defined by the Fungicide Resistance Action Committee (FRAC),13 Herbicide Resistance

88

Action Committee (HRAC), 14 and the Insecticide Resistance Action Committee (IRAC).

89

15

90

sales / volume data.16 Since many of the active ingredients launched in the last 25 years

91

are still new to the market and have not yet seen significant sales, active ingredients

92

included in the analysis had to have 2016 sales of at least $50 million, and have at least

93

one member of the class had to have sales of >$100 million for that class to be

94

included.

95

greater than $50 million in sales, only the top in sales are recorded in Table 1. Lastly,

96

compounds belonging to any of the unknown MoA classes, or those with a multisite

Crop protection chemical classes were based on those

The data for the analysis was derived, in part, from launch date and 2016 end-user

If more than five a.is within a class were launched since 1991 and had



97

designation were omitted. Some classes were included wherein the first member was

98

launched prior to 1991.

99

classes / subclasses, with nine of the ten first to market herbicides falling into this

100

category. In these cases, the data for the first to launch agrochemical was added back

101

to the analysis. Any pre-1991 launched product which was a sales or volume leader

102

was added back. Finally, an approximate product launch order is provided in Table 1.

103

Pre-1991 compounds within the class as well as those with sales less than $50 million

104

were considered when assigning a launch order to a product. No attempt was made to

105

distinguish the product launched within the same calendar year and they are treated as

106

being introduced into the marketplace concurrently. The resulting 27 crop protection

107

chemical classes used for the analysis (Table 1) represent a useful sampling of the

108

defined crop protection compound classes, accounting for just under half ($30.2 billion;

109

47.8%) of the $63.3 billion 2016 end-user value of the crop protection chemical market.

110

Table 1 also includes eight of the top ten products by sales. Most notably missing is the

111

number one crop protection product in terms of both sales and volume, glyphosate,

112

since it was launched in 1974 and has not had any follow-up analogs that have become

113

products. Finally, in addition to data from Agranova,16 for some specific analyses, an

114

internal proprietary database was used representing Manufacturer Level Sales

115

providing a fair representation of overall market value for the most widely used actives

116

and products.

117

ANALYSIS.

118

Each product area was evaluated, and in doing so it is important to note that there are

119

some distinct market differences between herbicides, fungicides and insecticides that

This situation was especially prevalent among herbicide


Page 6 of 40

Page 7 of 40


120

influence the value and success of an active ingredient. First, the global herbicide

121

market in 2016, at ~$27 billion was roughly 50% larger than either the global fungicide

122

(~$18 billion) or insecticide markets (~$16 billion) (Figure 3). Secondly, the herbicide

123

and fungicide markets, more so than the current insecticide market, are dependent on

124

mixtures of active ingredients, primarily to gain the necessary spectrum to address the

125

weed or pathogen complexes in many crop systems.

126

product is sold containing a single active ingredient it is often formulated so that the

127

grower can easily tank mix it with other pesticidal products. The commercial objective is

128

to give the grower a convenient single solution that provides the spectrum of control

129

they require. This means that the breadth of spectrum and efficacy of a single herbicide

130

or fungicide active ingredient is important, but also how its strengths and weaknesses

131

complement the strength and weaknesses of another herbicide and / or fungicide

132

selected for tank mixing or developed as a pre-mixture. It is increasingly important to

133

understand that the relative efficacy of an herbicide or a fungicide may shift with time

134

due to resistance development, which presents opportunities for development of new

135

active ingredients and / or mixing partners.

136

herbicide area where the cornerstone of a market segment may be the control of a

137

single or a few key weed species within a geography, that are no long effectively

138

controlled by existing active ingredients

139

Also impacting crop protection chemistry use patterns are the changing farm practices

140

that have evolved over the last 25 years that have affected the herbicide, fungicide and

141

insecticide markets unequally. Specifically, genetically modified (GM) crops been most

142

impactful in the herbicide market and least impactful on the fungicide business. Recent

If an herbicidal or fungicidal

This has been especially true in the



143

studies suggest GM insect resistant crops have reduced the amount of insecticides

144

used on cotton and maize,17,18 impacting the value of these markets for insecticides. In

145

contrast, GM crops with herbicide tolerance simply resulted in a significant shift in the

146

types of herbicides applied.

147

fungicides and insecticides in the seed treatment market.19 The attributes required for a

148

successful foliar and seed applied pesticide are not identical, but can at times be met by

149

a single active ingredient, as in the case of the insecticide imidacloprid.20 The flexibility

150

to use imidacloprid in both market segments contributes to its continued success

151

relative to other neonicotinoids.

152

One commonality among all three markets is that the agronomic and environmental

153

attributes (i.e. soil and water residual, non-target toxicity, bioaccumulation, etc.) of an

154

active ingredient do not solely determine its commercial success. The global reach of

155

the offering company; registration; marketing; and sales strategies and well as out

156

licensing agreements can all impact the trajectory of an active ingredient’s adoption by

157

growers. Although important, due to their complexity, and company specific nature,

158

these factors (sales, marketing, etc.) are beyond the scope of the present analysis.

159

However, regardless of business strategy and its execution, crop protection active

160

ingredients which best meet the grower’s and increasingly consumer / societal needs,

161

are most likely to have the largest impact in the market.

162

HERBICIDES.

163

Within the three acetolactate synthase (ALS) inhibitor subclasses (HRAC B1, B2 and

164

B3) (Table 1) and the seven other herbicidal MoAs examined, no first to market product

Somewhat tied to GM crops is the growing use of


Page 8 of 40

Page 9 of 40


165

currently leads in sales or volume. Three factors have played a role in this. First, the

166

nine MoAs in this analysis cover selective herbicides.

167

controls unwanted plants, but is safe to the traditionally bred crops. Most often this is

168

accomplished by taking advantage of differential metabolism of the active ingredient.21

169

Secondly, the coupling of non-selective herbicides, primarily glyphosate and glufosinate,

170

with GM row crops expressing resistance to these two herbicides, greatly altered

171

herbicide use patterns in the associated crops supplanting a number of selective

172

herbicides, and also affecting interest in the discovery and development of new

173

herbicides.21

174

impacted equally. Those selective herbicides developed for weed control within corn,

175

cotton or soybean, in regions accepting GM organisms, like the Americas, were

176

impacted to a larger extent than those targeting non-GM crops like rice or wheat.

177

However, the recent appearance of weed resistance to a number of herbicides,

178

especially glyphosate, has re-kindled interest in new herbicide discovery. Although no

179

new herbicidal MoA has been brought to the market in over 25 years,22,23 researchers

180

have looked for and found innovative solutions through new active ingredients that act

181

within established MoA classes, providing improved attributes over existing options to

182

meet growers continually evolving needs. These products were not just targeted for

183

non-GM market segments. A newer best-in-class product may exhibit improved efficacy

184

or broader spectrum of weed control which could include controlling undesired

185

broadleaves or grasses that have developed resistance to other herbicides,24,25

186

including the previously mentioned non-selective herbicides. Technology which offers

187

the grower increased flexibility is also rewarded in this space.

That is, the active ingredient

Furthermore, not all selective herbicides within a MoA class were


That could include


Page 10 of 40

188

improved selectivity to a single crop, expanding selectivity to cover multiple crops, or a

189

shorter soil half-life in the environment that may positively affect crop rotation flexibility

190

allowing growers greater leeway to adjust planting decisions based on factors such as

191

commodity crop prices.

192

FUNGICIDES.

193

Unlike herbicides, there has been substantial innovation within the fungicide space in

194

bringing new MoAs to the marketplace, and GM fungicide resistant crops have not yet

195

been a disruptive technology. Of the eight FRAC target site groups shown in Table 1,

196

all active ingredients within five of the MoA classes were launched within the last 25

197

years. Within the three groups in which the first to market active ingredient was

198

launched pre-1990, none remain as sales leaders, including metalaxyl.

199

the factors making sales leaders of particular follow-on herbicides, superior efficacy and

200

environmental fate attributes26,27 of the follower, mefenoxam, drove its success. It is a

201

somewhat unique example though, in that mefenoxam [R methyl-N-2-(methoxyacetyl)-

202

N-(2.6-xylyl)-alanate)] is simply the bioactive (R)-isomer of metalaxyl. In addition to the

203

active ingredient within mefenoxam, half of the material within metalaxyl is its

204

stereochemical isomer with the S-configuration, which is ~1000 times less potent.27

205

Interestingly, the innovation in this instance is really the heterogeneous chemical

206

catalysis process that allowed for the multi-ton preparation of the key chiral

207

intermediate, methyl R N-(2,6-dimethylphenylalanate), on route to mefonaxam.28

208

The evolution of succinate dehydrogenase inhibitors (SDHI) is also illustrative of factors

209

influencing the success of a.is within a class over time. Carboxin the first commercial


Analogous to

Page 11 of 40


210

SDHI was launched primarily as a seed treatment in 1966. The utility of the SDHI MoA

211

against additional fungal market segments was demonstrated with thifluzamide (Rohm

212

& Haas, 1997), which could be applied foliarly as well as via seed treatment, and then

213

followed by boscalid (BASF, 2003) which offered additional spectrum. Changing pest

214

pressure has also impacted this chemical class. Since 2000, Asian soybean rust, which

215

many SDHI fungicides perform well against, has become a major problem with >US$ 2

216

billion being spent annually in Brazil alone on chemical control of this pathogen.29

217

Almost 50 years after the launch of a product in this FRAC group, agrochemical

218

discovery groups continue to mine this well-established MoA area as shown by the

219

recent registration submissions for impyrfluxam.30

220

Within the MoA classes where the first to market active ingredient was launched within

221

the last 25 years, three of the five offerings remain market sales and volume leaders.

222

Two offerings, ametoctradin and fludioxonil, FRAC categories C8 and E2 respectively,

223

represent molecules used in products leading to significant market value, but without

224

apparent competitive fast-follow molecules.

225

competitors were not using these early entries as templates for follow-on innovation, but

226

the lack of new innovation around these particular fungicide classes may be due to a

227

number of factors that coalesced to limit a.is that act via these MoAs and possess

228

properties that would allow them to be commercially competitive in more economically

229

valuable fungicide market segments. This has not been the case within the chemistries

230

that act at the mitochondrial electron transport complex III Q0 site as shown by the

231

research / patent activity in the late 1980s and 1990s.31,32 A number of major

232

agrochemical companies of the time (Zeneca Agrochemicals,33 BASF,34 Novartis35 and

This should not be interpreted that



Page 12 of 40

233

DuPont36) saw the value proposition around the mitochondrial electron transport

234

complex III Q0 site inhibitors and their research resulted in four products being launched

235

in quick succession in 1998 and 1999. Azoxystrobin (Zeneca), launched in 1998 clearly

236

differentiated from kresoxim-methyl in terms of pathogen spectrum and global crop

237

utility, which is reflected in its current (2016) higher standing in sales (Table 1).

238 239

INSECTICIDES.

240

In this arena the crop protection industry has been the most prolific in bringing new

241

MoAs to the market place. Of the two subgroups and seven other major insecticidal

242

MoA groupings in this analysis (Table 1), products in all but two were launched after

243

1991. Also striking is the number of first to market active ingredients which remain a

244

market leader. Abamectin launched before 1991, as well as six of the seven first to

245

market MoA products launched post-1990, have held on to their number one sales and

246

volume leadership, four of these are doing so even 20 years after launch. Like the

247

fungicide azoxystrobin, excellent spectrum and global crop utility is key to keeping them

248

best-in-class. In addition two of the insecticides, spinosad and abamectin, are unique

249

among all market leaders in that these two are complex natural products produced via

250

fermentation rather than chemical synthesis. Many of the technologies, capabilities and

251

infrastructure to discover and bring to market fermentation derived products differ from

252

those required for traditional synthetic crop protection products.

253

AgroSciences further capitalized on those competitive advantages by developing semi-

254

synthetic derivatives, emamectin benzoate37 and spinetoram,38 respectively, which

255

provided an altered or enhanced spectrum coupled with improved efficacy.


Merck and Dow

Both of

Page 13 of 40


256

these active ingredients became successful insecticides, but in 2016 had not yet

257

eclipsed their natural product predecessors (Table 1).

258

insecticides fewer followers within a class is observed, relative to what is observed

259

among herbicides and to a lesser extent fungicides.

260

competition within the molecules of a MoA class, which contributes to some extent to

261

the number of first to market active ingredients that remain leaders within their grouping.

262

There may be a number of reasons for fewer follow-on chemistries among insecticides.

263

First, of the seven MoA groupings comprised of synthetically manufactured active

264

ingredients, all members within six of the groupings were launched less than 25 year

265

ago, thus the time window for research organizations to discover and develop follow-on

266

chemistry within many of the insecticidal MoA classes has been shorter when compared

267

to the more mature herbicide and fungicide MoA classes. Second, the fact that there are

268

fewer discovery organizations to follow-on due to industry consolidation over this same

269

time period has likely played a role as well.4,5 Also, in the case of the two insecticidal

270

voltage dependent sodium channel blockers indoxacarb (IRAC Group 22A)38 and

271

metaflumizone (IRAC Group 22B),40 there are no class followers despite being an active

272

area of research by a number of companies.41,42 In this space, environmental fate

273

issues as well as identifying blockers with high insect efficacy and an acceptable

274

therapeutic index vs. homologous target site of non-target animal species was a

275

challenge.41

276 277

SELECTED CASE STUDIES


Even among synthetic

Fewer followers mean less


Page 14 of 40

278

The following case studies were selected to highlight the factors which enabled the first

279

to market within a chemical class / MoA group to remain the economic winner

280

(glyphosate and spinosad) or makes it vulnerable to being supplanted by a follow-on

281

offering (demethylase Inhibitor (DMI) class of fungicides and cyclic ketoenols).

282 283

Glyphosate (HRAC G). Glyphosate, launched as the first commercial herbicidal 5-

284

enolpyruvyl-3-shikimate phosphate synthase (EPSPS) inhibitor remains the market

285

leader within its MoA class after 45 years. Based solely on this active ingredient

286

effectiveness at controlling a broad spectrum of perennial weeds and favorable

287

environmental profile vs. many other hericides,43 one might expect some difficulty in

288

dethroning it as the market leader within the EPSPS class.

289

EPSPS class, discounting the trimesium salt of glyphosate, is no other HRAC-

290

recognized EPSPS herbicide has been launched within this time span. That after all

291

these years no other commercially efficacious active ingredient in this space has been

292

launched speaks to the very narrow structure activity requirements about the EPSPS

293

target site.

294

Glyphosate, in the context of coupling an herbicidal MoA with a transgenic herbicide

295

resistant crop was actually a fast follower behind bromoxynil resistant cotton and

296

glufosinate resistant canola.44

297

introduced in 1996. By 2015 half the acreage of genetically modified crops contained a

298

glyphosate resistance trait, and over half the volume of glyphosate used that year was

299

applied to those crops.23 The previously mentioned spectrum of glyphosate, favorable

300

environmental properties, plus technological advancements that allowed for improved

What is unique about the

Glyphosate resistant canola and soybean were


Page 15 of 40


301

crop tolerance traits to be incorporated in elite row crop lines without yield drag23,44

302

propelled and kept glyphosate as the leader in this segment. In the upcoming years

303

glyphosate, in relation to its use against genetically modified crops, may come under

304

pressure from other non-selective herbicides as weed resistance to glyphosate grows

305

and new herbicidal resistant traits (2,4-D, etc.) come on line.

306

C-14 Demethylase Inhibitor Fungicides (FRAC G1). The clearest example of a first to

307

launch fungicide being surpassed by later entrants in the same MoA is shown by the

308

Demethylase Inhibitor (DMI) class of fungicides.

309

with an initial focus on cucurbits, fruits and ornamentals in 1969.

310

pyrimidine-carbinol DMI fungicide followed in 197545 with registrations in tree fruits and

311

vines.

312

innovations by a number research companies. The result, a succession of 25 triazole

313

DMI fungicides having been launched since 1976,46 producing over this period of time a

314

series of new fungicidal DMI market leaders, starting with triadimefon and progressing

315

from propiconazole, to tebuconazole and prothioconazole.46

316

chemistry were explored, newer molecules brought forward properties that not only

317

broadened the spectrum of pathogens controlled, but also increased the overall crop

318

utility and thus sales. No database captures the total breadth of crops in which DMI’s

319

are used, however, one would just need to look at a label for triforine compared to

320

tebuconazole to see the incredible expansion in utility that has occurred with continued

321

innovation. Clearly, the earliest DMI patents opened the door for decades of innovation

322

that continues today with recent announcements from BASF for mefentrifluconazole

323

(trade name Revysol™)47 which is reported to be more intrinsically active at the target

Triforine was the first registered DMI Fenarimol, a

Initial triazole discoveries by Janssen Pharmaceuticals led to a series of


As new avenues of


Page 16 of 40

324

site than other azoles and effective against many resistant pathogen strains48 that have

325

eroded the overall effectiveness of the DMI fungicides through the years. Over the last

326

decade the environmental impact versus economic importance of many members of this

327

class have been a contentious issue, especially in Europe.49

328

opportunity may exist for yet a new DMI market leader with attributes that are more

329

closely aligned with the economic and environmental goals of the stakeholders in this

330

debate.

331

Spinosyns (IRAC Group 5). The spinosyns are fermentation derived natural products

332

(NP) discovered through a NP screening program in the mid-1980s.50,51 Launched in

333

1997, spinosad is a naturally occurring mixture of two of the most insecticidal spinosyns,

334

spinosyns, A and D.51 Spinosad acts at an allosteric site on the α6 subunit of the insect

335

nicotinic acetylcholine receptor,52 the first class of insecticidal chemistry to exhibit this

336

MoA.

337

because of its effectiveness in controlling a range of chewing insect pests, novel MoA

338

and very favorable environmental and toxicological profile.51

339

spinosyn-based product was launched, spinetoram, a semi-synthetic derivative with an

340

improved spectrum and efficacy.52 Spinetoram is the result of an extensive structure

341

activity exploration, ultimately successfully driven by an artificial intelligence-based

342

quantitative structure activity approach.38 Thus far, spinosad has retained its market

343

leadership in this small class of insecticides, primarily due to the complexities

344

associated with a challenging fermentation process and associated strain improvement.

345

However, it is anticipated that in the near future spinetoram could become the market

346

leader in this novel class of insecticides. While other spinosyn derivatives have been

Going forward, the

Spinosad is widely used in organic as well as conventional farming in part


In 2007 a second

Page 17 of 40


347

investigated,53 to date only spinosad and spinetoram have been commercialized.

348

Although there have been a number of published synthetic approaches to the spinosyn

349

core,54 the excessive number of chemical and / or enzymatic steps (29–44) involved

350

makes synthetic production of the spinosyn macrolide an unattractive route to support

351

even a limited SAR program, let alone serving as a basis for a production route.

352

Hence, thus far, production of the spinosyns has remained through fermentation.

353

However, two decades after the launch of spinosad, the successful de novo design of

354

synthetic spinosyn mimics has been reported wherein the spinosyn macrolide core has

355

been replaced by a simple triaryl ring system; the first time that a synthetic mimic of a

356

macrolide NP has been successfully simplified in either crop protection of

357

pharmaceuticals.55

358

class of insecticides.

359

Cyclic Ketoenols. The cyclic ketoenols are a novel group of tetronic and tetramic acid

360

derivatives effective on a range of mite and sap-feeding insects currently composed of

361

spirodiclofen,

362

development). The first compound in this class, spirodiclofen, appeared in the ISO

363

common names listing in 200056 and was registered in 2002. Spirodiclofen came out of

364

a research program on herbicidal protoporphyrinogen-IX-oxidase inhibitors that

365

morphed into a series of herbicidal acetyl CoA carboxylase inhibitors, which in turn

366

further morphed into the tetronic acids which were then found to exhibit miticidal

367

activity.57 Further exploration of this area of chemistry then lead to spiromesifen, a new

368

analog with good activity on whiteflies (i.e. Bemisa tabaci), as well as mites,58 launched

369

a year after spirodiclofen in 2003.

Thus the possibility exists for new future additions to the spinosyn

spiromesifen,

spirotetramat

and

most

recently

spiropidion

(in

A third molecule in this series (spirotetramat) that



370

has become the class market leader, resulted from a parallel discovery effort around

371

tetramic acids,58 exhibiting a broad spectrum of activity against sap-feeding insects and

372

both phloem and xylem mobility.57,58 Launched in 2008, spirotetramat has had a far

373

larger impact on the market (based on sales) than the other members of this class

374

(Table 1) with sales (2016 end user, USD) of $326 million versus $181 million and $81

375

million for spiromesifen and spirodiclofen, respectively. In this case the broad spectrum

376

sap-feeding insect activity has been an important factor in the greater use of

377

spirotetramat, especially as a control option for sap-feeding insects resistant to

378

mainstream insecticides such as the neonicotinoids. Other new potential products in

379

this class of insecticides are being investigated by other companies (i.e. spiropidion56 by

380

Syngenta).

381

382

FUTURE PROSPECTS FOR FIRST TO MARKET PESTICIDES

383

As outlined above, there are a number of parameters that can and have impacted

384

whether the first active ingredient in a new class remains the market leader or is

385

supplanted by a later follow-on compound. The relative importance of these parameters

386

will vary based on the nature of the active ingredient, its target therapeutic area,

387

intended crop(s) and company goals / emphasis. These factors can include;

388

1 – Resistance or shifting pest spectrum in the market place.

389

2 – Regulatory or other significant advantage: i.e. new MoA, improved environmental or

390 391

toxicological profile. 3 – Improved efficacy


Page 18 of 40

Page 19 of 40

392 393 394 395


4 – New technology to allow exploitation: i.e. coupling with transgenic plants, new delivery options or other tools. 5 - Speed of follow-up: i.e. fast follow (within a year or two) vs. slow follow (5 to 10 years after initial product).

396

6 – Barriers to entry: such as complex chemistry or fermentation

397

7 – Improvements in synthetic routes or synthetic building blocks allowing new options.

398

8 – Marketing effectiveness of a company.

399 400

These parameters, and likely others, can have an effect singly, or in many instances it is

401

a combination of several of these factors that leads to market significance.

402 403

The consolidation that has occurred in the agrochemical side of the crop protection

404

industry has resulted in fewer, but far larger companies,5 that are capable of funding the

405

increasing costs of discovery, development and registration of new crop protection

406

chemicals.5,7 One potential consequence is that the number of competing active

407

ingredients in a new class of chemistry is likely to be smaller than in the past11 due to

408

fewer different companies exploring a particular area. As such, the first compound in a

409

new class may have an advantage if it provides a suitable combination of efficacy,

410

spectrum, affordability and favorable regulatory / environmental profile. Since any new

411

product is by necessity an attempt to balance these parameters, the relative success at

412

addressing all of these components will influence the relative ease or difficultly for

413

competing active ingredients to make inroads.

414



Page 20 of 40

415

In reviewing the data in Table 1, it is notable that the majority of the companies listed

416

are US and European, and few from Asia (e.g. Japan). In part this is an artifact of

417

selection criteria used, coupled with listing only the top five molecules in a class. As

418

noted earlier, many crop protection classes are rather large, especially those that have

419

been around for some time including a number of herbicides: sulfonylureas (39),

420

triazines (34), auxins (25+);59 fungicides: strobilurins (20), SDHIs (21), triazoles (31);59

421

and insecticides: carbamates (42), pyrethroids (80), organophosphates (165).11

422

many instances Japanese companies have also developed products for these and other

423

classes; however, due to the their smaller corporate size and the rising cost of

424

development, especially for global registrations, some of these companies need to co-

425

develop or license out their discoveries,5 thus losing some of the benefits of being first

426

to market.

In

427 428

As noted above, only one class of herbicides that fit our analysis parameters, was

429

developed since 1991 (triazolopyrimidines, ALS inhibitors) and the first product in that

430

class has been eclipsed by a number of more recently developed analogs (Table 1). All

431

other herbicides belong to classes which had their origins prior to 1991, and in all cases

432

the first compound in that class is now far exceeded in terms of sales by more recent

433

class members. The situation is similar for fungicides, with the exception of the largest

434

class of fungicides, the strobilurins, wherein the first member of the class, azoxystrobin,

435

has remained the market leader (Table 1).

436

resistance was slower to emerge as a problem, especially when compared to the

437

insecticides.3,5

For both herbicides and fungicides,

However, the increasing rise of both herbicide and fungicide


Page 21 of 40


438

resistance,3,60 will likely alter the current landscape making any new fungicide with a

439

new MoA, or especially a new herbicide with a new MoA, a difficult molecule to easily

440

displace.

441

Also as noted above, it is only in the insecticide arena that most first to market

442

molecules developed since 1991 have retained their market leading positions (Table 1).

443

It is also among the insecticides where several new classes with new MoAs have been

444

developed since 1991.11 In part this state of affairs is in response to a combination of

445

expanding insecticide resistance,3,5 desire for more environmentally favorable

446

compounds5,11 coupled with the need to find suitable replacements for many members

447

of older classes of chemistry.

448

that the size of new and future classes of chemistry are likely to remain small, with only

449

a few members. Thus, for insecticides there appears to be a greater likelihood for the

450

first molecule in a class to remain the prevailing product for some period of time.

451

Thus as outlined above, perhaps now more than in the past, the prospects for the first

452

molecule in any one of the therapeutic areas is likely to have a significant advantage.

453

Although the first into a new area of chemistry has to work out all of the issues for that

454

chemistry, potentially forging a path for others to follow, that company also captures an

455

initial patent estate for that chemistry. Patents from each company have gotten larger,

456

more numerous, and more complex, making it that much more challenging to break into

457

an area of chemistry, although it is obviously occurring. That is why, in many instances,

458

the time investment in discovering a new area of chemistry is no greater than trying to

459

break into an existing area of chemistry.4

460

market space and gets to set the stage for grower use, perception and consumer

As noted previously,11 it is also within the insecticides

Additionally, first to market captures the



461

acceptance. Conversely, next generation molecules can potentially be positioned to

462

address gaps in spectrum, show efficacy increases and provide additional convenience

463

for the grower, all assuming that the first molecule leaves such gaps open.

464

ACKNOWLEDGEMENTS

465

The authors thank Drs. Jeffrey Nelson and Michael Loso for useful discussions and

466

comments during the preparation of this article.

467

reviewers and especially the Editor for their very useful suggestions.

We also thank the anonymous

468

469

The authors declare no competing financial interest.

470

Author Contributions: BAL & TCS defined the project, JEH & TCS with assistance from

471

RJB, GH, GK & REG conducted the data analysis; all authors contributed to organizing,

472

writing and editing the manuscript.

473

474

REFERENCES

475

1. Godfray, H. C. J.; Beddington, J. R.; Crute, I. R.; Haddad, L.; Lawrence, D.; Muir, J.

476

F.; Pretty J.; Robinson S.; Thomas, S. M.; Toulmin, C., Food security: The

477

challenge of feeding 9 billion people. Science 2010, 327, 812-818.

478 479

2 Tilman, D; Balzer, C.; Hill, J.; Befort, B. L., Global food demand and the sustainable intensification of agriculture. PNAS 2011, 108, 20260-20264.


Page 22 of 40

Page 23 of 40

480 481 482 483 484 485 486 487 488 489


3. Sparks, T. C.; Nauen R., IRAC: Mode of action classification and insecticide resistance management. Pestic. Biochem. Physiol. 2015, 121, 122-128. 4. Sparks, T. C., Insecticide discovery: An evaluation and analysis. Pestic. Biochem. Physiol. 2013, 107, 8-17. 5. Sparks, T. C.; Lorsbach, B. A. Perspectives on the agrochemical industry and agrochemical discovery, Pest Manag. Sci. 2017, 73, 672-677. 6. Jeschke, P. Progress of modern agricultural chemistry and future prospects. Pest Manag. Sci. 2016, 72, 433-455. 7. Lamberth, C.; Jeanmart, S.; Luksch, T.; Plant, A., Current challenges and trends in the discovery of agrochemicals. Science, 2013, 341, 742-746.

490

8. Shelton, K. A.; Lahm, G. P. Building a successful crop protection pipeline: molecular

491

starting points for discovery. In Discovery and Synthesis of Crop Protection

492

Products; Maienfisch, P.; Stevenson, T. M., Eds; American Chemical Society:

493

Washington D.C., 2015; pp 15-23.

494 495 496 497 498

9. Menn, J. J. Contemporary frontiers in chemical pesticide resistance. J. Agric. Food Chem. 1980, 28, 2-8. 10. Eto, M. Organophosphorus Pesticides: Organic and Biological Chemistry, CRC Press, Cleveland, OH, 1974, p. 387. 11. Sparks, T. C.; Lorsbach, B. A. Insecticide discovery – Building the next generation

499

of insect control agents.

In Advances in Agrochemicals: G-Protein-Coupled

500

Receptors and Ion Channels as Targets for Pest Control, Gross A, Coats J. R.;

501

Ozoe, Y., Eds; American Chemical Society, Washington D.C. pp. 1-17.



502 503

12. Perry, A. A.; Yamamoto, I.; Ishaaya, I.; Perry, R. Y. Insecticides in Agriculture and Environment, Springer-Verlag, Berlin, 1998, 261 p.

504

13. FRAC: Fungicide Resistance Action Committee. http://www.frac.info/docs/default-

505

source/publications/frac-code-list/frac_code_list_2018-final.pdf?sfvrsn=6144b9a_2

506

(Accessed: 3 April, 2018)

507 508 509 510 511 512

14. HRAC: Herbicide Resistance Action Committee. http://hracglobal.com/tools/worldof-herbicides-map (Accessed: 3 April, 2018). 15. IRAC: Insecticide Resistance Action Committee. http://www.irac-online.org/modesof-action/ (Accessed: 3 April, 2018). 16. Agranova Alliance, Crop Protection Actives. http://www.agranova.co.uk/ (Accessed: 18 June 2018).

513

17. Perry, E. D.; Ciliberto, F.; Hennessy, D. A.; Moschini, G. Genetically engineered

514

crops and pesticide use in U.S. maize and soybeans. Sci. Adv. 2016 2 (8),

515

e1600850. DOI: 10.1126/sciadv.1600850.

516

18. Brookes, G.; Barfoot, P. Environmental impacts of genetically modified (GM) crop

517

use 1996-2015: Impacts on pesticide use and carbon emissions. GM Crops & Food

518

2017, 8, 117-147.

519

19. Grassi, M. J. Global seed treatment Market to Hite $4.45 Billion by 2018 Croplife

520

2013.

521

hit-4-45-billion (Accessed: 13 June 2018).

522 523

http://www.croplife.com/crop-inputs/report-global-seed-treatment-market-to-

20. Jeschke, P.; Nauen, R. Neonicotinoids-from zero to hero in insecticide chemistry. Pestic. Manag. Sci. 2008, 64, 1084-1098.


Page 24 of 40

Page 25 of 40


524

21. de Carvalho, S. J. P.; Nicolai, M.; Ferreira, P. R.; Figueira, A. V. O.; Christoffeleti, P.

525

J. Herbicide selectivity by differential metabolism: Considerations for reducing crop

526

damages. Sci. Agric. 2009, 66, 136-142.

527

22. Duke, S. O. Why have no new herbicide modes of action appeared in recent years? Pest Manag. Sci. 2012, 68, 505-512.

528 529

23. Green, J. M. The rise and future of glyphosate and glyphosate –resistant crops Pestic. Manag. Sci. 2018, 74, 1035-1039. DOI: 10.1002/ps.2014.4662.

530 531

24. Duy, L.; Chon, N. M.; Mann, R. K.; Kumar, B. V. N.; Morell, M. A. Efficacy of

532

Rinskor™ (florpyrauxifen-benzyl ester) on herbicide resistant barnyard grass

533

(Echinochloa crus-galli) in rice fields of Mekong Delta, Vietnam. J. Crop Sci.

534

Biotechnol. 2018 21: 75.

535

25. Rice Herbicide: Dow’s Loyant with Rinskor Approved by EPA, agfax (2017)

536

https://agfax.com/2017/09/25/rice-herbicide-dows-loyant-with-rinskor-approved-by-

537

epa/ (Accessed: 22, June 2018).

538

26.

Metalaxyl and Mefenoxam Active Ingredient Data Package May 19, 2015

539

https://www.dec.ny.gov/docs/materials_minerals_pdf/mefenoxamdata.pdf.

540

(Accessed: 11 June 2018)

541

27. Perez-Fernandez, V.; Garcia, M. A.; Marina, M. L. Chiral separation of metalaxyl

542

and benalaxyl fungicides by electrokinetic chromatography and determination of

543

enantiomeric impurities. J. Chromatogr. A 2011, 1218, 4877-4885.

544

28. Park, O. J.; Lee, S. H.; Park, T. Y.; Chung, W. G.; Lee, S. W. Development of a

545

scalable process for a key intermediate of (R)-metalaxyl by enzymatic kinetic

546

resolution. Org. Process Res. Dev. 2006, 10, 588-591.



Page 26 of 40

547

29. Langenbach, C.; Campe, R.; Beyer, S. F.; Mueller, A. N.; Conrath, U. Fighting

548

Asian soybean rust. Front Plant Sci. 2016; 7: 797. DOI: 10.3389/fpls.2016.00797

549

30. Sumitomo Chemical submits registration application for new INDIFLIN fungicide

550

[Online].

551

http://news.agropages.com/News/NewsDetail---25341-e.htm [1 June 2018].

552 553

AgroNews

(2018).

Available:

31. Balba, H. Review of strobilurin fungicide chemicals J Environ Sci Health B. 2007, 42, 441-451.

554

32. Jordan, D. B.; Livingston, R. S.; Bisaha, J. J.; Duncan, K. E. ; Pember, S. O.;

555

Picollelli, M. A.; Schwartz, R. S.; Sternberg, J. A.; Tang, X. S. Mode of action of

556

famoxadone. Pest Sci. 1999, 55, 105-118.

557

33. Clough, J. M.; Godfrey, C. R. A.; Streeting, I. T.; Cheetham, R. Preparation of 2-

558

[[(phenoxy)pyrimidinyloxy]phenyl]-3-methoxypropenoates

559

fungicides, Eur. Pat. Appl. (1990), EP 382375

560 561 562 563 564 565

as

agrochemical

34. Wenderoth, B.; Rentzea, C.; Ammermann, E.; Pommer, E. H.; Steglich, Wolfgang; Anke, T. Preparation of oxime ether fungicides, Ger. Offen. (1988), DE 3623921 35. Isenring, H. P.; Weiss, B. Preparation of [(iminooxy)tolyl]acrylates and analogs as fungicides, Eur. Pat. Appl. (1991), 460575. 36. Geffken, D.; Rayner, D. R. Preparation of fungicidal oxazolidinones, U. S. Patent (1990) 4957933.

566

37. Pitterna,T. Chloride channel activators/new natural products: Avermectins and

567

milbemycins, In Modern Crop Protection Compounds, Vol. 3, 2nd ed. (W. Krämer,

568

U.Schrimer, P. Jeschke, M. Witschel, eds.), Wiley-VCH, Weinheim, 2012, pp.

569

1305-1326.


Page 27 of 40

570


38. Sparks, T. C.; Crouse, G. D.; Dripps, J. E.; Anzeveno, P.; Martynow, J.; Gifford, J.

571

Artificial neural network-based QSAR and the discovery of spinetoram.

572

Computer-Aided Molec. Des. 2008, 22, 393-401.

J.

573

39. McCann, S. F.; Cordova, D.; Andaloro, J. T.; Lahm, G. P. Sodium channel blocking

574

insecticides: Indoxacarb. In Modern Crop Protection Compounds, Vol. 3, 2nd ed.

575

(W. Kramer, U.Schrimer, P. Jeschke, M. Witschel, eds.), Wiley-VCH, Weinheim,

576

2012, pp. 1257-1273.

577

40. Kuhn, D.; Takagi, K.; Hino, T.; Armes, N. Semicarbazone insecticides:

578

Metaflumizone, In Modern Crop Protection Compounds, Vol. 3, 2nd ed. (W.

579

Kramer, U.Schrimer, P. Jeschke, M. Witschel, eds.), Wiley-VCH, Weinheim,

580

2012, pp. 1273-1282.

581

41. McLaren, K. L.; Hertlein, M. B.; Pechacek, J. T.; Ricks, M. J.; Tong, Y. C.; Karr, L. L.

582

Preparation

of

3,4,N-triaryl-4,5-dihydro-1H-pyrazole-1-carboxamides

583

insecticides Eur. Pat. Appl. (1992), EP 508469.

as

584

42. von Stein, R. T.; Silver, K. S.; Soderlund, D. M. Indoxacarb, metaflumizone, and

585

other sodium channel inhibitor insecticides: Mechanism and site of action on

586

mammalian voltage-gated sodium channels. Pestic. Biochem. Physiol. 2013,

587

106, 101-112.

588 589 590 591

43. Duke, S. O. The history and current status of glyphosate Pestic. Manag. Sci. 2018, 74, 1027-1034. 44. Reddy, K.N.; Nandula, V. K. Herbicide resistant crops: History, development and current technologies. Ind. J. Agronomy 2012, 57, 1-7.



592 593

45. Hewitt, H. G. Fungicides in Crop Protection, CAB International, Wallingford, Oxon, UK, 1998, 232 p.

594

46. Stezel, K. Chemical Control of Septoria Leaf Blotch: history, biological performance,

595

and molecular mode of action of DMI fungicides [Online]. EPPO Workshop ‘Azole

596

fungicides and Septoria leaf blotch control’, Rothamsted, UK, 2010-12-07 / 09

597

Available:

598

https://archives.eppo.int/MEETINGS/2010_conferences/septoria/04_Stenzel.pdf

599

[15, May 2018].

600

47. BASF reaches major milestone in the global development of its new fungicide [Online].

Available: https://www.basf.com/en/company/news-and-

601

Revysol®.

602

media/news-releases/2016/03/p-16-151.html [1 June 2018].

603

48. Azole fungicides – Going back to the future? [Online] Crop Protection Magazine

604

(2017) Available: http://www.cpm-magazine.co.uk/2017/01/08/azole-fungicides-

605

going-back-future/ [13, June 2018].

606

49. Sterns, J. Pesticide Makers Warn of EU Grain Cuts From Tougher Health Rules.

607

https://www.bloomberg.com/news/articles/2016-06-14/pesticide-makers-warn-of-

608

eu-grain-cuts-from-tougher-health-rules. (Accessed: 15 June 2018).

609

50. Thompson, G. D.; Dutton, R.; Sparks, T.C. Spinosad - A case study: An example

610

from a natural products discovery programme. Pest Management Sci. 2000, 56,

611

696-702.

612 613

51. Kirst, H. A. The spinosyn family of insecticides: realizing the potential of natural product research. J. Antibiot. 2010, 63, 101-111.


Page 28 of 40

Page 29 of 40


614

52. Crouse, G. D.; Dripps, J. E.; Sparks, T. C.; Watson, G. B.; Waldron, C. Spinosad

615

and spinetoram, a new semisynthetic spinosyn. In. Modern Crop Protection

616

Compounds. Vol. 3, 2nd ed. (W. Kramer, U. Schirmer, P. Jeschke, M. Witschel,

617

eds.), Wiley-VCH, Weinheim, 2012, pp. 1238-1257.

618

53. Sparks, T. C.; Watson, G. B.; Dripps, J. E.; Crouse, G. D.; Raman, B.; Daeuble, J.;

619

Oliver, M. P. Nicotinic acetylcholine receptor allosteric modulators: Spinosyns. In

620

Modern Crop Protection Compounds. Vol. 3, 3nd ed. (P. Jeschke, M. Witschel, W.

621

Krämer, U. Schirmer, eds.), Wiley-VCH, Weinheim 2018, In press.

622 623

54. Bai, Y.; Shen, X.; Li, Y.; Dai, M. Total synthesis of (-)-spinosyn A via cabonylative macrolactonization. J. Am. Chem. Soc. 2016, 138, 10838-10841.

624

55. Crouse, G. D.; Demeter, D. A.; Samaritoni, G.; McLeod, C. L.; Sparks, T. C. De

625

Novo Design of potent insecticidal synthetic mimic of the spinosyn macrolide

626

natural products. Sci. Rep. 2018, 84861. DOI: 10.1038/s.41598-018-22894-6.

627

56. Alan Wood Database, Compendium of Pesticide Common Names: Index of New

628

ISO

Common

Names,

629

(Acceseed:18 June, 2018)

http:

//www.alanwood.net/pesticides/index.html

630

57. Bretschneider, T.; Fischer, R.; Nauen, R. Inhibitors of lipid synthesis: Acetyl-CoA-

631

carboxylase inhibitors. In. Modern Crop Protection Compounds. Vol. 3, 2nd ed.

632

(W. Kramer, U. Schirmer, P. Jeschke, M. Witschel, eds.), Wiley-VCH, Weinheim,

633

2012, pp. 1108-1126.



634

58. Bretschneider, T.; Fischer, R.; Nauen, R. Tetronic acid insecticides and acaricides

635

inhibiting acetyl-CoA-carboxylase. In Bioactive Heterocyclic Compound Classes;

636

Lamberth, C.; Dinges, J., Wiley-VCH, Weinheim, Germany, 2012, pp. 265-278.

637

59. Sparks, T. C.; Hahn, D.; Garizi, N. Natural products and agrochemical discovery. Pest Manag. Sci, 2017, 73, 700-715.

638

639

60. Fisher, M. C.; Hawkins, N. J.; Sanglard, D.; Gurr, S. J. Worldwide emergence of

640

resistance to antifungal drugs challenges human health and food safety. Science,

641

2018, 360, 739-742.

642

61. Turner, J. Ed. The Pesticide Manual, 17th ed., British Crop Protection Council, Alton, UK, 2018.

643

644 645

62.

Troyer, J. R. In the beginning: the multiple discovery of the first hormone herbicides. Weed Sci. 2001, 49, 290-297.

646

647


Page 30 of 40

Page 31 of 40


648

649

Figure Legends

650

Figure 1. Product areas of new active ingredients launched since 1991. Data derived

651

from launch dates.16

652 653

Figure 2. Global value of new active ingredients launched before and after 1991, and

654

among fungicide, herbicides and insecticides launched since 1991. Data derived from

655

2016 end user sales.16

656 657

Figure 3. Distribution of the global crop protection chemicals market – 2016 end user

658

sales.16

659 660

Figure 4. Total modes of action as defined by FRAC13, HRAC14 and IRAC.15 Excludes

661

unknown, multisite inhibitors or target site subgroups.

662



Figure 1.


Page 32 of 40

Page 33 of 40


Figure 2.



Figure 3.


Page 34 of 40

Page 35 of 40


Figure 4.



Page 36 of 40

Table 1. Year of Launch and End User Sales for Selected HRAC, FRAC and IRAC Mode of Action Groups

Herbicides HRAC

B1

B2

B3

C1

E

F2

Class / Compound

Company

Launch Year & 1 (Discovery Company)

2

Launch 3 Order

Acetyl CoA carboxylase inhibitors diclofop-methyl 4 fenoxaprop-P-ethyl* clodinafop-propargyl haloxyfop-P-methyl cyhalofop-butyl 5 pinoxaden

Bayer CropScience Bayer CropScience Syngenta Dow AgroSciences Dow AgroSciences Syngenta

1975 (Hoeschst) 1990 (Hoeschst) 1995 (Ciba-Geigy) 1995 (Dow) 1996 (Dow) 2006 (Syngenta)

54 326 345 103 114 369

1 9 12 12 14 17

Sulfonylureas chlorsulfuron primisulfuron-methyl nicosulfuron* iodosulfuron-methyl sodium mesosulfuron-methyl trifloxysulfuron-sodium

Du Pont Syngenta Ishihara Sangyo Kaisha Bayer CropScience Bayer CropScience Syngenta

1982 (DuPont) 1991 (Ciba-Geigy) 6 1992 (ISK) 1999 (AgrEvo) 2001 (AgrEvo) 2001 (Ciba-Geigy)

28 116 373 214 419 151

1 9 12 26 27 27

Imidazolinones imazapyr imazethapyr* imazapic imazamox

BASF BASF BASF BASF

1985 (AmCy) 1989 (AmCy) 1996 (AmCy) 1997 (AmCy)

90 250 56 163

1 4 5 6

Triazolopyrimides flumetsulam diclosulam florasulam penoxsulam pyroxsulam thiencarbazone-methyl

Dow AgroSciences Dow AgroSciences Dow AgroSciences Dow AgroSciences Dow AgroSciences Bayer CropScience

1994 (Dow) 1998 (Dow) 1999 (Dow) 8 2004 (DAS) 2008 (DAS) 2008 (DAS)

55 167 236 276 220 209

1 7 9 13 14 14

Triazines simazine atrazine* amicarbazone

Syngenta Syngenta Arysta LifeScience

1955 (Geigy) 1957 (Geigy) 2004 (Bayer)

47 210 64

1 2 17

PPO inhibitors oxadiazon flumioxazin sulfentrazone carfentrazone-ethyl* saflufenacil pyraclonil

Bayer CropScience Sumitomo Chemical FMC FMC BASF Bayer CropScience

1969 (AgrEvo) 1992 (Sumitomo) 1996 (FMC) 1997 (FMC) 2009 (BASF) 2009 (AgrEvo)

87 239 325 291 271 96

1 8 11 13 20 20

Triketones pyrazoxyfen isoxaflutole mesotrione* topramezone tembotrione pyrasulfotole

Ishihara Sangyo Kaisha Bayer CropScience Syngenta BASF Bayer CropScience Bayer CropScience

1986 (ISK) 1998 (Rhône-Poulenc) 2001 (Syngenta) 2006 (BASF) 2007 (Bayer) 2008 (Bayer)

7 239 865 166 246 180

1 5 6 8 9 10

7


Sales

Page 37 of 40


K3

L

O

Benzamides propachlor acetochlor* metazachlor S-metolachlor flufenacet dimethenamid-P

Monsanto Monsanto BASF Syngenta Bayer CropScience BASF

1965 (Monsanto) 1991 (Monsanto) 1993 (BASF) 1997 (Ciba-Geigy) 1998 (Bayer) 2000 (Sandoz)

7 494 146 530 144 271

1 11 12 16 17 18

CBI inhibitors dichlobenil quinclorac* indaziflam

Generic BASF Bayer CropScience

1960 (Philips-Duphar) 1991 (BASF) 2010 (Bayer)

4 55 133

1 3 4

Auxins MCPA 2,4-D* aminopyralid

Generic Generic Dow AgroSciences

1940s (multiple) 9 1940s (multiple) 2006 (DowElanco)

91 569 192

1 4 23

9

Fungicides FRAC

C2

C3

C8

D1

E2

G1

Class / Compound

Company

Launch Year (Discovery company)

Sales

Launch order

Phenylamides metalaxyl* mefenoxam

Syngenta Syngenta

1983 (Ciba-Geigy) 1996 (Ciba-Geigy)

162 240

1 5

SDHIs carboxin boscalid* penthiopyrad isopyrazam bixafen fluxapyroxad

Chemtura (Crompton) BASF Mitsui Chemicals Agro Syngenta Bayer CropScience BASF

1966 (Uniroyal) 2003 (BASF) 2008 (Mitsui) 2010 (Syngenta) 2011 (Bayer) 2011 (BASF)

70 433 134 280 280 154

1 7 8 9 10 10

Strobilurins azoxystrobin* kresoxim-methyl trifloxystrobin pyraclostrobin picoxystrobin fluoxastrobin

Syngenta BASF Bayer CropScience BASF Syngenta Bayer CropScience

1998 (Zeneca) 1998 (BASF) 1999 (Novartis) 2001 (BASF) 2001 (Zeneca) 2005 (Bayer)

1,758 276 1,110 1,402 169 405

1 1 4 7 7 11

Triazolopyrimidyl amines ametoctradin*

BASF

2010 (BASF)

101

1

Anilinopyrimidines pyrimethanil* cyprodinil

BASF Syngenta

1994 (Schering) 1995 (Ciba-Geigy)

60 173

1 2

Phenylpyrroles fludioxonil*

Syngenta

1995 (Ciba-Geigy)

190

1

C14-Demethylase inhibitors triforine prochloraz* difenoconazole

BASF BASF Syngenta

1969 (Celamerck) 1983 (Boots) 1991 (Ciba-Geigy)

2 95 395

1 5 18



H5

Page 38 of 40

tetraconazole epoxiconazole prothioconazole

Isagro-Ricerca BASF Bayer CropScience

1993 (Agrimont) 1995 (BASF) 2004 (Bayer)

104 443 729

20 27 33

Carboxylic acid amides dimethomorph* iprovalicarb mandipropamid

BASF Bayer CropScience Syngenta

1994 (Celamerck) 1998 (Bayer) 2008 (Syngenta)

142 53 238

1 2 5

Company

Launch Year (Discovery company)

Insecticides IRAC

Class / Compound

2B

Phenylpyrazoles

fipronil* ethiprole 4A

05

06

22A 22B 23

28

1

Sales

Launch order

BASF

1994 (Rhône-Poulenc)

616

1

Bayer CropScience

2005 (Rhône Poulenc)

66

2

Neonicotinoids imidacloprid* acetamiprid thiamethoxam thiacloprid clothianidin dinotefuran

Bayer CropScience Nippon Soda Syngenta Bayer CropScience Sumitomo Chemical Mitsui Chemicals Agro

1994 (Nihon Bayer) 1996 (Nippon Soda) 1997 (Syngenta) 2000 (Nihon Bayer) 2002 (Takada) 2002 (Mitsui)

1,322 377 1,302 165 565 105

1 2 4 5 6 6

Spinosyns spinosad* spinetoram

Dow AgroSciences Dow AgroSciences

1997 (Elanco) 2008 (DAS)

293 125

1 2

AvermectinsMilbemycins abamectin* milbemectin emamectin benzoate

Syngenta Mitsui Chemicals Agro Syngenta

1988 (Merck) 1992 (Sankyo Agro) 1998 (Merck)

1,040 74 185

1 2 3

Oxadiazines Indoxacarb*

DuPont

1998 (DuPont)

212

1

Semicarbazones metaflumizone*

BASF

2007 (Nihon Nohyaku)

111

1

Ketoenols spirodiclofen spiromesifen spirotetramat*

Bayer CropScience Bayer CropScience Bayer CropScience

2002 (Bayer) 2003 (Bayer) 2008 (Bayer)

81 181 326

1 2 3

Diamides flubendiamide chlorantraniliprole* cyantranilaprole

Nihon Nohyaku / Bayer Du Pont Du Pont

2007 (Nihon Nohyaku) 2007 (DuPont) 2012 (DuPont)

392 1,235 62

1 1 3

16

61

Data adapted in part from Agranova and The Pesticide Manual 16 Millions USD, data from Agranova 3 The estimated order in which a compound was launched relative to the first compound listed 4 * = volume leader 5 Bold = sales leader 6 Ishihara Sangyo Kaisha 2


Page 39 of 40


7

American Cyanamid Dow AgroSciences 9 62 Discovered simultaneously and independently by several different groups / companies 8



Graphical Abstract


Page 40 of 40

Crop Protection Discovery: Is Being the First Best? - Journal of

Recommend Documents