DP4—Chem—SE—103000.doC
`
`Page 1 of 6
`
`Astraleneca Exhibit 2178
`Mylan V. Astraleneca
`IPR2015-013-I0
`
`AstraZeneca Exhibit 2178
`Mylan v. AstraZeneca
`IPR2015-01340
`
`Page 1 of 6
`
`

`
`Monthly Summary:
`
`DP4 Inhibitors
`
`The goal of the program is to discover small molecule inhibitors of dipeptidyl peptidase IV (DP4) for
`use in the treatment and prevention of diabetes.
`Inhibition of DP4 should prevent the degradation of
`GLP-1 and GIP, potentiating their actions in vivo.
`Solution stability studies on a series of 14
`compounds has shown that at pH 7.2, 4,5-methanoproline containing DP4 inhibitors are significantly
`more stable than either 3,4-methanopro|ine- or non-cyclopropane-containing compounds, providing
`further support for this structural moiety beyond it’s critical role in securing proprietary coverage for
`the chemotype. Hydroxyadamantyl analogue BMS-477118, synthesized as a result of PK and
`metabolism study results with the non-hydroxylated precursor,
`is the most potent reversible DP4
`inhibitor known to date, with 6 hour ED50 of 0.5 umol/kg p.o. in the rat ex vivo plasma DP4 inhibition
`assay. This compares extremely favorably with the Phase II Novartis compound BMS-428245,
`which has > 100 umol/kg ED50 at this same 6 hour timepoint. Both BMS465980 and BMs-477118,
`the two most promising preclinical
`leads are currently undergoing extensive PD and PK
`characterization and toxicity profiling to enable ECN selection. As the more recent Novartis
`disclosure (BMS-471211) exhibits apparent slow-binding kinetics and subsequent improved ex vivo
`efficacy not observed with the Phase II compound BMS-428245,
`this compound will factor into
`benchmarking strategies as well.
`
`HO
`
`HO
`
`CN
`
`\
`/N
`
`I
`
`HN
`2
`
`N
`
`CN
`0
`BMS-465980
`
`N
`
`HN
`
`HN
`2
`
`CN
`0
`BMS-477118
`
`N
`
`“NW
`H
`0
`Novartis DPP-728
`BMS-428245
`
`CN
`
`HO
`
`N
`
`NW
`H
`0
`Novartis
`BMS-471211
`
`CN
`
`Competitive Update: A patent application from Molteni L. E C. Dei Fratelli Alitta Societa’ di
`Esercizio S.P.A. (WO 00/53171, Sept. 14, 2000) published, claiming the use of metformin in the
`preparation of pharmaceutical compositions capable of inhibiting DP4.
`In house in vitro assessment
`of metformin under our standard assay protocol showed no DP4 inhibition. Additional studies will be
`done to confirm this result.
`
`Detailed Report:
`
`DP4 Inhibitors
`
`The goal of the program is to discover small molecule inhibitors of dipeptidyl peptidase IV (DP4) for
`use in the treatment and prevention of diabetes.
`Inhibition of DP4 should prevent the degradation of
`GLP-1 and GIP, potentiating their actions in vivo. The ECN target profile for a DP4 inhibitor
`emphasizes sufficient therapeutic window and/or duration of action to allow QD dosing in order to
`provide a competitive advantage versus the Novartis Phase II compound NVP-DPP-728, which will
`likely require multiple daily doses due to a reported 50 minute half-life in humans.
`
`Solution stability studies conducted on a range of compounds from both proprietary an competitor
`chemotypes show encouraging SAR trends with this parameter (see Table 1). Relating the proline
`surrogate moiety structural
`features to pH 7.2 solution stability yields the following trend of
`decreasing stability: 4,5-methanoprolyl > prolyl > 3,4-methanoprolyl. Additionally, beta-branching on
`the amino acid moiety confers added stability, with beta-quaternary center-containing compounds
`best overall.
`Interestingly,
`though one might predict that substitution on the amine-N as in the
`
`Page 2 of 6
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`Page 2 of 6
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`

`
`Page 2
`
`Novartis compound BMS-428245 (DPP-728) would provide a steric impediment to cyclization onto
`the nitrile (the most likely mechanism contributing to solution instability at neutral pH based on the
`literature),
`this compound behaves similarly to other non-cyclopropanated compounds. These
`preliminary data support additional benefit to the presence of the 4,5-methanoprolyl residue beyond
`the critical role played in securing proprietary coverage.
`
`Page 3 of 6
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`Page 3 of 6
`
`

`
`Table 1. Solution stability of selected DP4 inhibitor compounds
`% remaining
`after 4 h
`pH1.1
`pH7.2
`
`proline moiety
`
`amino acid moiety
`
`BMS #
`
`Page 3
`
`% remaining
`after 24 h
`pH1.1
`pH7.2
`
`94.36
`
`96.34
`
`99.72
`
`99.75
`
`0
`
`4.94
`
`7.21
`
`20.27
`
`440617
`
`430516
`
`420597
`
`439421
`
`428245
`
`440823
`
`CN
`
`“
`
`‘ ‘N?
`
`CN
`
`“
`
`“
`
`KIN
`
`CN
`
`Q 97.93
`
`N.’““
`
`\t/
`MN“
`
`\|)
`
`Mr”
`
`98.62
`
`100
`
`Q 100
`
`N.’““
`
`25.43
`
`48.28
`
`54.42
`
`66.53
`
`Novartls
`DPP-728
`
`6?
`M1”
`
`Q
`
`100
`
`75.97
`
`98.33
`
`24.43
`
`99.85
`
`100
`
`77.59
`
`84.80
`
`99.63
`
`100
`
`27.16
`
`37.50
`
`395067
`
`442371
`
`356379
`
`405295
`
`431285
`
`431289
`
`429636
`
`430452
`
`“
`
`“
`
`“
`
`“
`
`“
`
`“
`
`“
`
`“
`
`N1"
`
`Q
`
`N1“
`
`\l)
`
`Mr”
`
`\t/
`MN“
`
`100
`
`100
`
`99.94
`
`Q 99.4
`
`N.’““
`
`9 97.6
`
`N1”
`
`Q
`
`M?”
`
`Q
`
`N5“
`
`100
`
`100
`
`81.88
`
`86.95
`
`94.01
`
`88.1
`
`92.9
`
`95.10
`
`95.94
`
`100
`
`100
`
`100
`
`nd
`
`nd
`
`98.69
`
`100
`
`46.28
`
`47.66
`
`74.19
`
`nd
`
`73.33
`
`79.01
`
`Page 4 of 6
`
`Page 4 of 6
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`

`
`Page 4
`
`Table 2.
`
`In vitro, in vivo, and PK data for selected DP4 inhibitor compounds.
`rat ex vivo
`
`isolated
`porcine
`
`plasma DP4
`inhibitory E050
`
`CYP450
`
`compound
`
`DP4 Kis (nM)
`
`(iimol/kg, p.o.)
`
`PK (rat)
`
`inhibition (NM)
`
`HO
`
`H2N
`
`é
`
`N
`
`CN
`0
`BMS-465980
`
`6 7
`
`'
`
`slow-binding
`
`%F 59
`
`“/2
`
`1-25
`
`*
`
`1A2
`
`209
`
`2019
`2D6
`3A4BFc
`3A4BzRES
`
`>100
`
`>100
`
`99
`>100
`96
`77
`
`Ho
`H2N
`
`N
`
`slow-binding
`
`TBD
`
`0
`CN
`BMS-477121
`
`H2N
`
`N
`
`CN
`0
`BMS-469767
`
`HO
`H2N
`
`CN
`
`N
`
`0
`
`cN
`1 8
`
`14.7
`slow-binding
`
`18.9
`slow-binding
`
`%F 2.2
`11,2
`1.35
`
`%F TBD
`11,2 TBD
`
`:23
`gas
`$33
`28;9
`3A4BFc TBD
`3A4BZRES TBD
`
`gég
`2019
`2D6
`3A4BFc
`3A4BzRES
`
`:88
`>100
`>100
`23
`22
`
`aaggg
`gég
`>188
`28;9
`>
`3A4BFc >100
`3A4-BzREsaCt|V n
`
`1 \
`/N
`N
`
`E
`
`N
`
`Hfior
`
`7.6
`
`%F 96
`
`[\/Q
`CN
`
`1A2
`>100
`209
`>100
`:3?
`:33
`3A4-Biro >1
`BZRESHC IV n
`
`t'
`
`’
`
`3A4
`
`BMS-428245 (Novartis)
`
`@ Q
`fiw
`0
`
`N
`
`CN
`
`HO
`
`BMS-471211 (Novartis)
`
`50-6
`slow-binding
`
`%F 96
`’[1/2
`1.73
`
`>100
`>100
`>100
`>100
`
`1A2
`209
`2019
`ZD6
`3A4-Biro
`3A4-BZRES >1
`
`* approximation only, evidence of enterohepatic recirculation
`
`Page 5 of 6
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`Page 5 of 6
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`

`
`Page 5
`
`The strong correlation of potent ex vivo plasma DP4 inhibition in rats with compounds that exhibit
`apparent slow-binding kinetics has been strengthened with additional enzyme kinetic and animal
`studies. This phenomenon is not observed with the Novartis Phase II compound BMS-428245,
`though the more recently disclosed Novartis compound BMS-471211 shows a characteristic potency
`shift in the ex vivo rat assay. Following up on the highly potent proprietary adamantane containing
`inhibitor, BMS-469767 with pharmacokinetic and metabolism studies revealed a profile similar to that
`exhibited previously with vinyl-containing analogues such as BMS-431285 and BMS-440925 (see
`Table 2). Extremely poor bioavailability, together with rapid metabolism with rat and human liver
`microsomes and mild CYP3A4 inhibition strongly suggested that
`this compound’s activity was
`mediated through a rapidly produced metabolite. Guided by LC/MS data, synthesis of a likely
`metabolism candidate, the product of hydroxylation at a ring juncture resulted in the discovery of
`BMS-477118, the most potent DP4 inhibitor to date in the rat model. This new analogue is devoid of
`P450 inhibitory activity, and is much more stable to microsomal incubation. This compound also
`represents a significant improvement in synthetic accessibility, and has been rapidly scaled up. Both
`BMS-465980 and BMS-477118, the current preclinical leads are undergoing extensive profiling in
`order to allow ECN selection. Assays unden/vay or scheduled include: acute OGTT in Zucker fatty
`rats, chronic in vivo efficacy studies in ZDF rats measuring glucose, insulin, GLP-1, and GIP levels,
`and PK studies in cynos.
`In addition to these PD and PK studies, both of these compounds have
`tested clean in HERG assays, and are scheduled to undergo additional tox profiling,
`including 2-
`week rat tox, Ames assays, Cerep profiling, and HHA’s.
`
`Competitive Update: A patent application from Molteni L. E C. Dei Fratelli Alitta Societa’ di
`Esercizio S.P.A. (WO 00/53171, Sept. 14, 2000) published, claiming the use of metformin in the
`preparation of pharmaceutical compositions capable of inhibiting DP4.
`In house in vitro assessment
`of metformin under our standard assay protocol showed no DP4 inhibition. Additional studies will be
`done to confirm this result.
`
`Page 6 of 6
`
`Page 6 of 6