DP4 chem sig events 010600.doc
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`Page 1 of 4
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`Astraleneca Exhibit 2172
`Mylan V. Astraleneca
`IPR2015-013-I0
`
`AstraZeneca Exhibit 2172
`Mylan v. AstraZeneca
`IPR2015-01340
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`Page 1 of 4
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`

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`DP4 Chemistry Significant Events
`
`January 5 ,1999
`
`two companies, Novartis and
`indicate that
`literature reports
`Competitive Update: Recent
`Probiodrug, are currently pursuing DP4 inhibitors in the clinics for the treatment of diabetes. DPP
`728 (Novartis) was reported to be well-tolerated in both animal toxicology and phase I studies.
`Clinical results indicate that DPP 728 increases GLP-1 levels in healthy and diabetic subjects and
`improves fasting and prandial glycemia in Type II patients. Phase II trials were initiated September
`1999 and NDA submission is proposed for 2003. P32/98 (Probiodrug) has also completed phase I
`trials where it was demonstrated to be well tolerated. Probiodrug is actively seeking a partner for
`development/licensing of P32/98. Both compounds are characterized as short-acting inhibitors in
`vivo (DPP 728 t1,2 in man is 2 h).
`Me
`
`Me
`
`rs
`NJ
`
`0
`
`P32/98
`
`(Probiodrug)
`DP4Ki=110 nM
`
`H
`
`N
`
`H
`
`0
`
`CN
`
`NC
`
`/N
`
`DDP 728
`
`(Novartis)
`DP4Ki=7nM
`
`Current FTE’s: 4.5
`
`Executive Summary: The DP4 program has developed potent and proprietary leads with desirable
`metabolic and pharmacokinetic properties and has demonstrated proof-of-principle in modulation of
`glucose homeostasis in vivo with orally active compounds. On this basis, the program will request
`conversion from early to full phase status at the January LDOC meeting. Limited SAR on one of our
`primary lead compounds, BMS-356379, has recently identified BMS-405295 as a single digit
`nanomolar inhibitor of DP4. In vivo and pharmacokinetic evaluation of this compound is in progress.
`BMS-356379 was tested orally in normal rats and found to elicit an increase in insulin secretion in
`response to an oral glucose tolerance test under conditions in which plasma DP4 activity was
`inhibited ~70%. The observation is consistent with the proposed mechanism of action for DP4
`inhibitors.
`
`Me
`
`N-terminal
`modification
`N L}
`
`Me
`
`H2N
`
`0
`
`CN
`
`B|v|s-35s379
`DP4 Ki = 27 my]
`
`Me
`
`Me
`
`Me
`
`H2N
`
`N
`
`0
`
`CN
`
`BMS-4_05295
`DP4 KI = 6nM
`
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`

`
`[APG]
`
`Monthly Summary 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 potentiate its action in vivo. BMS-356379 represents one of
`our earliest and most promising leads in the program. To explore the effect of modification at the N-
`terminal amino acid residue, a small solution phase library of analogs were prepared incorporating
`commercially available amino acids. The resulting SAR demonstrates a significant dependence of
`activity based on the nature of the substituent at this position. Incorporation of large residues such as
`tryptophan (BMS-405236), S-benzyl cysteine (BMS-405227), and cyclohexylalanine (BMS-394147)
`are not well tolerated by the enzyme. Optimal activity appears to be associated with highly branched
`aliphatic residues such as isoleucine (BMS-356379), norleucine (BMS-405290), valine (BMS-
`405292), and particulary t-butylalanine (BMS-405295), the latter of which is the first BMS proprieatry
`inhibitor to exhibit single digit nanomolar potency against DP4. Although based on limited SAR, N-
`alkylation of the terminal amine group (BMS-405283) appears to result in a dramatic loss in potency.
`Current plans are to incorporate other commercially available amino acids into this framework,
`especially proline and their dervatives, but initial data indicates that optimal activity will
`likely be
`found with highly branched aliphatic residues, few of which are readily accessible, thus precluding
`quick access to derivatives via combinatorial chemisty.
`
`R1
`
`CO2H
`
`1- B°°‘N
`[£2
`
`EDAC
`_
`_
`_
`_
`
`:|(:)£’l:,r:rg|(:le|1Dzloée, pyridine
`
`R‘
`
`(R)-sec-butyl
`CH2SBn
`
`CH2-3-indole
`
`CH2CH2Sme
`
`CH2CH(Me)2
`
`n-butyl
`
`i-propyl
`
`(S)-sec-butyl
`
`i-propyl
`
`t-butyl
`CH2-c-CGH11
`
`c-CGH11
`
`R2
`
`H
`H
`
`H
`
`H
`
`H
`
`H
`
`Me
`
`H
`
`H
`
`H
`H
`
`H
`
`TFA
`
`HN
`
`O
`
`NH2
`
`BMS #
`
`356379
`405227
`
`405236
`
`405240
`
`405244
`
`405274
`
`405283
`
`405290
`
`405292
`
`405295
`391147
`
`395067
`
`R1
`
`N
`
`H||\I)\I(
`R2
`0
`
`CN
`
`DP4 Ki (nM)
`
`27
`109
`
`230
`
`134
`
`109
`
`169
`
`1937
`
`20
`
`29
`
`6
`110
`
`13
`
`In vitro pharmacokinetic and metabolic profiling data has recently been obtained on two other leads
`in the program, BMS-383680 and BMS-382436. In contrast to BMS-356379 and BMS-382436 which
`show no in vitro metabolism in human liver microsomes (10 min @ 10 uM), BMS-383680 exhibited a
`modest metabolic rate (0.15 nmol/min/mg) in this system. Like BMS-356379, both BMS-383680 and
`BMS-382436 show low propensity for P450 inhibition (>10 uM for all P450’s tested) and are non-
`hepatotoxic in the human hepatocyte assay. Caco-2 permeability for BMS-382436 could not be
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`[APG]
`
`measured but permeability for BMS-383680 (48 nm/sec) was somewhat lower than BMS-356379
`(110 nm/sec). The data suggest that, although potentially weaker in vitro than BMS-383680, BMS-
`356379 may possess more optimal properties for in vivo inhibition.
`
`In vivo: The DP4 inhibitor BMS-356379 was orally administered (100 mg/kg) to normal rats 30
`minutes prior to an oral glucose challenge. DP4 enzyme activity measured in the plasma using a
`DP4-specific fluorescent peptide derivative substrate was inhibited by 65-72% over the next 40
`minutes (Figure below,
`left panel). This was associated with a faster mean insulin response to the
`oral glucose load (right panel). Although the trends observed for insulin response in normal rats were
`not statistically significant,
`they are consistent with the mechanism of action proposed for DP4
`inhibitors. These studies contribute to a proof-of-principle for the idea that DP4 inhibition in vivo can
`result in improvements in the insulinotropic hormonal axis, consistent with potentiation of GLP-1(7-
`36) as an underlying mechanism.
`
`Figure. Acute effects of BMS-356379 (100 mg/kg, p.o) on plasma DP4 enzyme activity and insulin
`secretion in response to an oral glucose tolerance test in normal rats.
`
`60
`
`40
`
`insufln
`
`BMS—356379
`
`BMS—356379
`
`minutes
`
`minutes
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