Current Topics in Medicinal Chemistry, 2007, 7, 569-578
`
`569
`
`Aromatic Heterocycle-Based DPP-IV Inhibitors: Xanthines and Related
`Structural Types
`
`Bruce G. Szczepankiewicz* and Ravi Kurukulasuriya
`
`Metabolic Disease Research and Target & Lead Discovery, Abbott Laboratories, Abbott Park, IL, 60064, USA
`
`Abstract: Xanthines and xanthine-like DPP-IV inhibitors were first disclosed in 2002. Since then, several dozen accounts
`of xanthine-based DPP-IV inhibitors have been published. Only a few presentations and journal articles have appeared,
`with the vast majority of information coming from the patent literature. DPP-IV inhibitors related to the xanthines include
`purine analogues with other arrangements of the nitrogen atoms in the core structure, imidazoles, uracils, pyrimidines,
`pyridines, and some fused pyridines. At least one compound derived from the xanthines has advanced into clinical trials,
`making it likely that these molecules will play a major role in the DPP-IV inhibition arena over the next several years.
`
`the Boehringer-Ingelheim
`the Novo-Nordisk and
`both
`patents. As xanthines lacking N-1 and N-3 substituents are
`also available, substitution at these positions is possible as
`well. The Boehringer-Ingelheim group disclosed some IC50
`data with their xanthines, indicating that the IC50 values vs.
`DPP-IV for compounds 3-5 were in the 1-5 nM range. (Fig.
`(1)) The Novo-Nordisk group disclosed no biological
`activity data in their patents, but a later presentation included
`more information [11] (Fig. (2)). Xanthine 6 was a very
`potent DPP-IV inhibitor with IC50 = 4 nM. It was highly
`selective against other dipeptidyl peptidases including DPP-
`II, DPP-8, and DPP-9. Selectivity against other dipeptidyl
`peptidases is a desirable property for DPP-IV inhibitors,
`
`NH2
`
`N
`
`NN
`
`O
`
`N
`
`N
`
`R
`
`O
`
`3 R =
`
`IC 50 = 5 nM
`
`IC50 = 3 nM
`
`IC 50 = 2 nM
`
`O N
`
`H2
`
`O
`
`N
`
`4 R =
`
`5 R =
`
`INTRODUCTION
`
`The history and significant milestones of dipeptidyl
`peptidase-IV (DPP-IV) and DPP-IV inhibition are subjects
`of the article by Hans Demuth in this special issue of
`Current Topics in Medicinal Chemistry [1]. Aromatic
`heterocycle-based DPP-IV inhibitors have become an impor-
`tant class in this arena over the past five years. This article
`will cover three classes of DPP-IV inhibitors: 1. xanthines
`and xanthine mimetics, 2. pyridines and pyrimidines, and 3.
`imidazoles and uracils. Each of these sub-classes bears some
`resemblance to the others, as the core serves to orient
`peripheral groups that maintain several points of contact
`necessary for potent DPP-IV inhibition. Heterocycles that
`were not derived from xanthine-based inhibitors, and hetero-
`cycles that do not exhibit overlapping structure-activity
`relationships with xanthines will not be covered in this
`review.
`
`1. XANTHINES AND XANTHINE-BASED HETERO-
`CYCLES
`
`The biological activity of xanthine-based alkaloids has
`been known for nearly two hundred years, dating back to the
`isolation of caffeine in 1820 by Runge. Due to the wide array
`of biological activities seen with purines, and the role that
`purine alkaloids including xanthines have played in the
`history of organic chemistry, natural xanthine alkaloids and
`synthetic xanthine analogues are present in the screening
`collections of most pharmaceutical companies [2]. These
`archival compounds were the original sources of the
`xanthine-based DPP-IV inhibitors.
`the DPP-IV-inhibitory
`The first patents describing
`activity of xanthines came from Novo-Nordisk [3-9] and
`Boehringer-Ingelheim
`[10]. The Novo-Nordisk group
`described the straightforward synthesis of inhibitors such as
`xanthine 1 starting from 8-chlorotheophylline (2). (Scheme
`1) This route allows for easy modification of the N-7 and C-
`8 positions, and many examples of such analogues appear in
`
`*Address correspondence to this author at Metabolic Disease Research,
`Abbott Laboratories, R4MC AP10/L12, 100 Abbott Park Road, Abbott
`Park, IL 60064-6098, USA; Tel: (847)935-1559; Fax: (847) 938-1674;
`Email: bruce.szczepankiewicz@abbott.com
`
`Fig. (1). Some selected DPP-IV inhibitors from Boehringer-
`Ingelheim.
`
` 1568-0266/07 $50.00+.00
`
`© 2007 Bentham Science Publishers Ltd.
`
`Boehringer Ex. 2011
`Mylan v. Boehringer Ingelheim
`IPR2016-01563
`Page 1
`
`

`
`570 Current Topics in Medicinal Chemistry, 2007, Vol. 7, No. 6
`
`Szczepankiewicz and Kurukulasuriya
`
`The investigators at Boehringer-Ingelheim continued a
`vigorous effort to pursue xanthine-based DPP-IV inhibitors
`following their initial disclosure [13-25]. Another team at
`Eisai also published a series of patents on xanthine-based
`DPP-IV inhibitors [26-28]. Both of these groups included
`IC50 data in their patents, elucidating more of the SAR about
`the xanthine core. (Fig. (3), Fig. (4)) Many examples bear a
`2-butynyl substituent at N-7, which can effectively replace a
`butenyl or benzyl group while maintaining excellent
`inhibitory potency vs. DPP-IV. The data indicate that C-8
`piperazine or (3-amino)piperidine groups are approximately
`equipotent, (compounds 15-19) consistent with the results
`presented by the Novo-Nordisk team [11]. The Boehringer-
`Ingelheim investigators also showed that an open chain
`amine maintained inhibitory potency (compounds 20-22).
`There are hundreds of examples of N-1, C-2, and N-3
`substitution in these patents, and it is clear from the IC50 data
`in Fig. (1-3) that very different substituents at N-1, C-2, and
`N-3 can give potent DPP-IV inhibitors. Additionally, both
`the Boehringer-Ingelheim and Eisai groups prepared 1H-
`imidazo[4,5-d]pyridazine (23, 24) and 3H-imidazo[4,5-
`c]pyridine (25) cores for some active analogues [29-33] (Fig.
`(5)). The Boehringer-Ingelheim group [34] and another
`group at Fujisawa [35] also claimed compounds based on a
`hydrazide-type structure (26, 27). Thus, major changes in the
`region from N-1 to N-3 (xanthine numbering) are tolerated.
`A series of patents from Sumitomo claimed xanthines
`and xanthine analogues. The Sumitomo group also disclosed
`some pyrazolopyridine-based inhibitors. The arrangement of
`the heteroatoms in the core was important for DPP-IV
`activity, as exemplified by the difference in potency between
`pyrazolopyridines 28-30. (Fig (6)) Other analogues (eg. 31,
`32) resembled the xanthines and analogues shown in Fig. (1-
`5) [36-41].
`
`CN
`
`Cl
`
`NN
`
`O
`
`N
`
`O
`
`N
`
`8
`
`Cl
`
`a
`
`HN
`
`7
`
`N
`
`2
`
`N
`
`1
`
`O
`
`3
`N
`
`O
`
`NC
`
`N
`
`1
`
`NN
`
`O
`
`N
`
`O
`
`N
`
`b
`
`NH2
`Reagents and Conditions: a) (2-cyano)benzyl bromide, K2CO3, KI,
`DMF, 25 ºC (93%); b) 3-aminopiperidine dihydrochloride, Et3N, i-
`PrOH, 130 ºC (microwave), (43%).
`
`Scheme 1. Novo-Nordisk synthesis of xanthine-based DPP-IV
`inhibitors.
`
`since investigators at Merck have shown that activity against
`some of these can lead to toxicity [12]. In vivo inhibitory
`data were presented for a related analogue, fluorophenacyl
`xanthine 7, though an IC50 value was not disclosed. At a dose
`of 10 mg/kg in normal Wistar rats, plasma DPP-IV activity
`remained below 5% of vehicle dosed animals for over 10 h.
`The calculated ED50 was 2mg/kg. Elaborating further on the
`SAR of the xanthines, the same group noted that the nitrogen
`atom proximal to the xanthine is crucial for potent DPP-IV
`inhibition (compounds 8 and 9). The most potent compounds
`were all N-3 phenacyl substituted xanthines, with several
`examples (10-14) giving IC50 values below that of 6.
`
`N
`
`NH
`
`NN
`
`R
`
`O
`
`O
`
`N
`
`O
`
`N
`
`R
`
`NN
`
`O
`
`N
`
`O
`
`N
`
`8 R = N
`9 R = CH
`
`NH2
`IC5 0 = 57 nM
`IC5 0 >500 nM
`
`10 R = H
`11 R = F
`
`IC50 = 3 nM
`IC50 = 3 nM
`
`N
`
`NH
`
`NN
`
`O
`
`O
`
`N
`
`O
`
`N
`
`6 R = H
`7 R = F
`
`IC 50 = 4 nM
`ED5 0 = 2mg/kg
`
`R
`
`NH2
`
`N
`
`NN
`
`O
`
`O
`
`N
`
`NH2
`
`O
`
`N
`
`14 IC5 0 = 2 nM
`
`N
`
`NN
`
`O
`
`O
`
`N
`
`O
`
`N
`
`N
`
`NH
`
`NN
`
`O
`
`O
`
`N
`
`O
`
`N
`
`13 IC50 = 2 nM
`Fig. (2). Novo-Nordisk xanthine-based DPP-IV inhibitors with biological data.
`
`12 IC50 = 1 nM
`
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`IPR2016-01563
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`
`

`
`Aromatic Heterocycle-Based DPP-IV Inhibitors
`
`Current Topics in Medicinal Chemistry, 2007, Vol. 7, No. 6 571
`
`N
`
`N
`
`NH2
`
`NH2
`
`N
`
`NH
`
`NN
`
`NN
`
`NN
`
`N
`
`O
`
`N
`
`N
`
`O
`
`N
`
`20
`IC 50 = 2 nM
`
`N
`
`N
`
`21
`
`IC5 0 = 1 nM
`
`N
`
`O
`
`N
`
`O
`
`N
`
`O
`
`N
`
`N
`
`O
`
`N
`
`22
`IC5 0 = 3 nM
`
`Fig. (4). Different C-8 amino groups and N-3 substituents maintain
`potency.
`
`compounds indicates that the point of attachment to the
`xanthine C-8 need not be an amine. A tertiary center
`imparted greater activity than a methylene group adjacent to
`the sulfur atom.
`A 2003 disclosure from Eisai showed a different
`arrangement of the amine and butynyl groups about the
`xanthine core [48] (Fig. (10)). These compounds were potent
`inhibitors, with purine-8-one 43 giving an IC50 value = 2.9
`nM. Because they lack a C-2 carbonyl group, these are not
`true xanthines, but the purine nucleus remains intact.
`Takeda/Syrrx also claimed some xanthine-like comp-
`ounds as DPP-IV inhibitors [49,50] (Fig (11)). Most
`xanthine-based DPP-IV inhibitors bear an amino group and a
`benzyl, alkenyl, or alkynyl group both attached to the
`imidazole ring. However, the Takeda/Syrrx inhibitors are
`substituted on the pyrimidine ring (44). Since the groups that
`seem to be most critical for DPP-IV inhibition are no longer
`attached to the imidazole ring, these investigators modified
`the
`imidazole ring and claimed a variety of fused-
`heterocycles not seen in other DPP-IV inhibitor patents. (Fig.
`(11)) These heterocycles include benzopyrimidine (45),
`pyridopyrimidine (46), and triazolopyrimidine (47). No IC50
`data were included in the patents disclosing these novel
`cores.
`More distantly related to the xanthines are isoquinoline,
`quinoline, benzimidazole, and benzotriazole-based DPP-IV
`inhibitors from Takeda/Syrrx. (Fig. (12)) The isoquinolines
`were the first to appear in 2002 [51], followed by the
`quinolines [52,53], then the benzimidazoles and benzotria-
`zoles. [54] Limited biological data were disclosed with these
`compounds, but isoquinoline 48 gave an IC50 = 280 nM,
`while quinoline 49 gave an IC50 = 710 nM. An aromatic
`core, an alkyl amine, and a substituted phenyl group are
`
`NC
`
`O
`
`N
`
`NH
`
`15
`IC50 = 1.7 nM
`
`NN
`
`N
`CONH2
`
`N
`
`O
`
`NC
`
`O
`
`NH2
`
`N
`
`NN
`
`16
`IC50 = 2.2 nM
`
`N
`
`O
`
`N
`
`NH2
`
`N
`
`N
`
`NH
`
`O
`
`NN
`
`N
`CONH2
`
`N
`
`O
`
`18
`
`IC50 = 6.4 nM
`
`NN
`
`O
`
`N
`
`O
`
`N
`
`17
`IC5 0 = 4.1 nM
`
`N
`
`NH
`
`NN
`
`19
`IC5 0 = 47 nM
`
`N
`
`O
`
`N
`
`O
`
`HN
`
`O
`Fig. (3). Some Eisai xanthine-based DPP-IV inhibitors with IC50
`data.
`
`Some further SAR information about the C-8 position
`was disclosed by Ansorge and co-workers at the Institut für
`Medizintechnologie Magdeburg [42,43] (Fig (7)). Their data
`demonstrated that a tertiary amine distal to the C-8 attach-
`ment point (33, 34) was much less active than a secondary
`amine (35, 36). More information about this position was
`provided by investigators at Sanofi-Aventis who disclosed
`some IC50 data on diazabicyclic amines at xanthine C-8 (37,
`38) [44,45] (Fig (8)). The Sanofi-Aventis group also incor-
`porated an 8-(aminoalkyl)ether (39)or an 8-(aminoalkyl)
`thioether (40-42) into the inhibitor scaffold. [46,47] (Fig.
`(9)). The potent DPP-IV inhibition demonstrated with these
`
`Boehringer Ex. 2011
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`

`
`572 Current Topics in Medicinal Chemistry, 2007, Vol. 7, No. 6
`
`Szczepankiewicz and Kurukulasuriya
`
`NH2
`
`NH2
`
`N
`
`Cl
`
`NN
`
`27 (Fujisawa)
`
`No IC 50 data
`
`N
`
`NN
`
`O
`
`N N
`
`NH
`
`24
`
`(Boehringer-
`Ingelheim)
`
`IC50 = 3 nM
`
`N
`
`O
`
`O
`
`O
`
`N N
`
`NH2
`
`N
`
`NN
`
`26
`
`(Boehringer-
`Ingelheim)
`IC 50 = 1 nM
`
`CN
`
`N
`
`N
`
`O
`
`O
`
`NC
`
`O
`
`N
`
`NH
`
`N
`
`N
`
`N N
`
`23
`
`(Eisai)
`
`IC50 = 7.2 nM
`
`O
`
`O
`
`N
`
`N
`
`N
`
`25
`(Eisai)
`IC 50 = 7.3 nM
`
`N
`
`NH
`
`NC
`
`Fig. (5). Xanthine core modifications from Boehringer-Ingelheim Eisai, and Fujisawa.
`
`Cl
`
`O
`
`N
`
`N
`
`N
`
`N
`
`Cl
`
`Cl
`
`O
`
`N
`
`N
`
`N
`
`F
`
`O
`
`F
`
`HN
`
`N
`
`N
`
`N
`
`N
`
`N
`
`29
`
`IC5 0 = 5 nM
`
`NH2
`
`30
`
`IC5 0 = 15 nM
`
`NH2
`
`F
`
`NH2
`
`N
`
`NN
`
`O
`
`N
`
`HO2C
`
`32
`
`IC50 = 0.5 nM
`
`N
`
`F
`
`NH2
`
`NC
`
`Cl
`
`NN
`
`NC
`
`N
`
`28
`
`IC50 = 893 nM
`
`NH2
`
`N
`
`O
`
`N
`
`O
`
`O
`
`31
`
`IC50 = 7 nM
`
`N
`
`NH
`
`NN
`
`O
`
`HN
`
`O
`
`N
`
`36
`IC50 = 800 nM
`
`N
`
`NH
`
`NN
`
`O
`
`N
`
`O
`
`N
`
`35
`IC5 0 = 400 nM
`
`NH
`
`N
`
`Fig. (6). Xanthine analogues from Sumitomo.
`
`Cl
`
`NN
`
`F
`
`N
`
`O
`
`N
`
`O
`
`N
`
`34
`IC50 = 7,500 nM
`
`N
`
`NN
`
`33
`
`O
`
`N
`
`O
`
`N
`
`IC 50 = 41,000 nM
`
`Fig. (7). C-8 tertiary amines are inferior DPP-IV inhibitors.
`
`Boehringer Ex. 2011
`Mylan v. Boehringer Ingelheim
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`
`

`
`Aromatic Heterocycle-Based DPP-IV Inhibitors
`
`Current Topics in Medicinal Chemistry, 2007, Vol. 7, No. 6 573
`
`N
`
`NN
`
`O
`
`N
`
`O
`
`O
`
`N
`
`N
`
`NN
`
`O
`
`N
`
`O
`
`O
`
`N
`
`NH
`
`38
`
`IC50 = 7.2 nM
`
`NH
`
`37
`
`IC50 = 1.6 nM
`
`Fig. (8). Recent examples of bicyclic amines.
`
`NH2
`
`S
`
`NN
`
`O
`
`N
`
`O
`
`O
`
`N
`
`41
`
`IC50 = 1.7 nM
`
`NH2
`
`S
`
`NN
`
`O
`
`N
`
`O
`
`O
`
`N
`
`O
`
`NH2
`
`NN
`
`O
`
`O
`
`N
`
`O
`
`N
`
`39
`
`IC5 0 = 4.5 nM
`
`40
`
`IC50 = 7 nM
`
`O
`
`NH2
`
`S
`
`NN
`
`N
`
`O
`
`O
`
`N
`
`42
`
`IC50 = 72 nM
`
`O
`
`NN
`
`NC
`
`HN
`
`N
`
`N
`
`Cl
`
`N
`43
`IC50 = 2.9 nM
`
`Fig. (9). Ether and thioether linkages at C-8.
`
`Fig. (10). An example of Eisai purine-8-one based DPP-IV inhibitors.
`
`O
`
`CN
`
`O
`
`CN
`
`O
`
`CN
`
`N
`
`N
`
`N
`
`45
`
`Cl
`
`NH2
`
`N
`
`N
`
`N
`
`N
`
`46
`
`N
`
`N
`
`N
`
`NH2
`
`N
`
`N
`
`N
`
`47
`
`NH2
`
`CN
`
`O
`
`NH2
`
`O
`
`N
`
`44
`
`N
`
`N
`
`N N
`
`Fig. (11). Takeda/Syrrx compounds substituted on the pyrimidine ring.
`
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`

`
`574 Current Topics in Medicinal Chemistry, 2007, Vol. 7, No. 6
`
`Szczepankiewicz and Kurukulasuriya
`
`NH2
`
`Ki (DPP-IV) = 2nM
`Ki (DPP-8) = >3,000nM
`Ki (DPP-9) = >3,000nM
`
`NH2
`
`Ki (DPP-IV) = 12nM
`
`CN
`
`N
`
`55
`
`CN
`
`N
`
`56
`
`NN
`
`NN
`
`O
`
`N
`
`O
`
`O
`
`O
`
`NN
`
`Fig. (14). Abbott xanthine-mimetics.
`
`Fig. (15). X-ray structure of 55 bound to rat DPP-IV. Green =
`protein carbon, orange = inhibitor carbon, blue = nitrogen, red =
`oxygen.
`
`inhibitors, the binding mode of many xanthines is likely very
`similar to that shown in Fig. 15.
`
`2. PYRIDINE- AND PYRIMIDINE-BASED DPP-IV
`INHIBITORS
`
`A 2005 patent by Takeda (Japan) disclosed a series of
`pyridine-based DPP-IV inhibitors (57-59) including IC50
`data [60] (Fig. (16)). Like the Takeda/Syrrx benzimidazoles,
`these pyridines bear an aminomethyl group ortho to a
`
`O
`
`H2N
`
`O
`
`48
`
`O
`
`O
`
`NH2
`
`N
`
`IC 50 = 280 nM
`
`NH2
`
`NN
`
`NH2
`
`N
`
`N
`
`N
`
`F
`
`50
`
`Cl
`
`52
`
`Cl
`
`F
`
`NH2
`
`49
`IC50 = 710 nM
`
`N
`
`NH2
`
`O
`
`N
`
`NH
`
`Cl
`
`51
`
`Fig. (12). Quinoline, isoquinoline, benzimidazole, and benzotria-
`zole scaffolds from Takeda/Syrrx.
`
`features of inhibitors 50-52 that are conserved among most
`of the known xanthine-based DPP-IV inhibitors.
`A series of patents from Takeda/Syrrx disclosed some
`fused pyridines bearing more resemblance to the xanthines,
`the first of these appearing in 2002 [55-57] (Fig (13)). The
`aminomethyl group ortho to a substituted phenyl group was
`again preserved, but other positions varied (e.g. 53 and 54).
`Abbott disclosed a series of compounds that were
`xanthine mimetics as DPP-IV inhibitors [58,59] (Fig. (14)).
`Maleimide 55, was potent (Ki for DPP-IV = 2 nM) and
`selective with no inhibitory activity towards DPP-8 and
`DPP-9. Hydrazide 56 was also a potent inhibitor. The crystal
`structure of 55 bound to rat DPP-IV revealed that the critical
`binding features were the 3-amino piperidine interacting
`with Glu 203 and Glu 204 and the maleimide showing a p-
`stacking interaction with Tyr 548. (Fig. (15)) There was no
`direct interaction with the hydroxyl group of Ser 631 (the
`catalytically active serine in DPP-IV). Given the significant
`homology between maleimide 55 and the xanthine-based
`
`F
`
`O
`
`Cl
`
`F
`
`O
`
`N
`
`O
`
`N
`
`N
`
`NH2
`
`N
`53
`
`O
`
`N
`
`NH2
`
`N
`54
`
`Br
`
`N
`
`NH2
`
`O
`
`Fig. (13). Pyridopyrimidine inhibitors from Takeda/Syrrx.
`
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`
`Aromatic Heterocycle-Based DPP-IV Inhibitors
`
`Current Topics in Medicinal Chemistry, 2007, Vol. 7, No. 6 575
`
`O
`
`O
`
`O
`
`N
`
`N
`
`imidazole and [1,3,4]triazole-based DPP-IV inhibitors (63,
`64) with biological activity in the tens of nanomolar range
`[66]. (Fig (18)) These are clearly derived from the xanthine
`skeleton by excision of the C-2 and N-3 atoms.
`
`NH2
`
`N
`
`X N
`
`N
`
`O
`
`N
`
`NH
`
`63 X = CH
`64 X = N
`
`IC5 0 = 99 nM
`IC5 0 = 24 nM
`
`Fig. (18). Imidazole- and Triazole-Based DPP-IV Inhibitors.
`
`Takeda/Syrrx has published a series of patents on uracil-
`based DPP-IV inhibitors. The uracil-based inhibitors keep
`the structural features that appear in nearly all other series of
`xanthine-based DPP-IV inhibitors, i.e. an aminopiperidine
`substituent, and a benzyl group ortho to the position occu-
`pied by the piperidine ring [67-72]. These uracil derivatives
`were derived from xanthine-based inhibitors during the lead
`optimization process. This effort culminated in the discovery
`of SYR-322 (65) with an IC50 = 4 nM, and in monkeys, an in
`vivo half-life of 5.7 h with 100% oral bioavailability [73,74].
`SYR-322 was last reported to be in Phase III clinical trials
`for type 2 diabetes mellitus. A three step synthesis of SYR-
`322 from 6-chlorouracil (66) is shown in Scheme 2 [73].
`
`CONCLUSIONS
`
`A significant effort by a number of research groups has
`been invested in the aromatic heterocycle-based DPP-IV
`inhibitors. Although very limited information has appeared
`in the journal literature, the number of patents claiming DPP-
`IV inhibitors of this structural class makes it clear that
`intense and highly competitive research efforts have focused
`on these compounds, and more accounts of this work are
`likely to appear within the next few years. Some information
`has been disclosed at scientific meetings, giving indications
`of the binding mode, selectivity over other dipeptidyl
`peptidases, and pharmacokinetic behavior of these DPP-IV
`
`OH
`
`O
`
`N
`
`57
`
`IC50 = 5.1 nM
`
`NH2
`
`N
`
`58
`
`H2N
`IC 50 = 3.5 nM
`
`F
`
`O
`
`NH
`
`N
`
`H2N
`
`59
`
`IC50 = 7.4 nM
`
`Fig. (16). Aminomethylpyridine-based DPP-IV inhibitors.
`
`substituted phenyl group. A 6-isobutyl substituent is also
`present in many of the pyridines, while the 2- and 3-pyridyl
`positions seem to be tolerant of more variation.
`In 2004 Roche disclosed a novel series of aminomethyl
`pyrimidines discovered from a high-throughput screen. [61-
`65] Starting from HTS hit 60, optimization of DPP-IV
`inhibitory activity gave diphenylpyrimidine 61. (Fig. (17))
`Compound 61 is a potent DPP-IV inhibitor exhibiting
`excellent ADME properties but was found to inhibit CYP3-
`A4 and induce phospholipidosis in cultured fibroblasts. SAR
`at the 2-phenyl group led to the discovery of 62 with an IC50
`of 9 nM showing no induction of phospholipidosis and
`reduced CYP3A4 inhibition. No in vivo data were disclosed
`with these compounds.
`
`3. IMIDAZOLE AND URACIL-BASED DPP-IV INHI-
`BITORS
`
`Imidazole also serves as a scaffold for DPP-IV inhibition.
`A group at Boehringer-Ingelheim claimed a series of
`
`NH2 NH2
`
`NH2 NH2
`
`NH2 NH2
`
`N
`
`N
`
`O
`
`N
`
`N
`
`N
`
`Cl
`
`Cl
`
`61
`
`IC50 (DPPIV) = 10nM
`IC50 (CYP 3A4) = 5.4m M
`phospholipidosis induction
`
`Cl
`
`Cl
`
`62
`
`IC 50 (DPPIV) = 9nM
`IC50 (CYP 3A4) = 30m M
`no phospholipidosis
`
`OO
`
`N
`
`N
`
`60
`
`HTS hit, IC50 = 10m M
`
`Fig. (17). Aminomethylpyrimidine-based DPP-IV inhibitors.
`
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`

`
`576 Current Topics in Medicinal Chemistry, 2007, Vol. 7, No. 6
`
`Szczepankiewicz and Kurukulasuriya
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`
`[9]
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`[10]
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`
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`[15]
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`[16]
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`[17]
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`[19]
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`[20]
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`[21]
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`[22]
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`[23]
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`[24]
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`L.
`8-[3-Amino-piperidin-1-yl]-xanthines,
`Their
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`
`NH
`
`a, b
`
`O
`
`O
`
`N
`
`Cl
`
`N
`
`O
`
`O
`
`CN
`
`N
`
`H2N
`
`TFA
`
`N
`
`N
`
`O
`
`SYR-322 (65)
`
`NC
`
`O
`
`NH
`
`66
`
`c
`
`Cl
`
`Reagents and Conditions: a) i. NaH, LiBr, (2-cyano)benzyl
`bromide, DMF/DMSO, 0fi25 ºC, (54%); b) NaH, CH 3I, THF/
`DMF, 0fi35 ºC, (72%); c) i. NaHCO 3, R-(3-amino)piperidine
`dihydrochloride, CH3OH, 100 ºC, ii. TFA (60%).
`
`Scheme 2. Synthesis of SYR-322.
`
`inhibitors. All of these data appear favorable for drug
`development. With the disclosure of the structure of SYR-
`322, the advancement of aromatic-heterocyclic DPP-IV
`inhibitors into human clinical trials is a certainty. As more
`data are released, we will be able to draw a more complete
`picture of the in vitro behavior of these DPP-IV inhibitors,
`their efficacy in animal models and in humans, and their
`relative merits
`in
`the
`treatment of human diseases,
`particularly type 2 diabetes mellitus.
`
`ABBREVIATIONS
`
`DPP-IV
`DPP-II
`DPP-8
`DPP-9
`ADME
`
`CYP3A4
`
`= Dipeptidyl peptidase IV
`= Dipeptidyl peptidase II
`= Dipeptidyl peptidase 8
`= Dipeptidyl peptidase 9
`= Acronym for absorption, distribution,
`metabolism, and elimination
`= Cytochrome P450, 3A4 isoform
`
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