DP4 Chemistry Significant Events
`
`Janua.-y5,/.
`
`'1-6~
`
`Competitive Update: Recent literature reports indicate- that two companiBS, Novartis and Problodrug,
`are currently pursuing DP4 inhibitors in the clinics for ti1e treabnent of diabetes. DPP 728 (Novartis)
`was reported to be well--tolerated In both animal toxicology and phase I studies. Clinical results
`Indicate that OPP 728 increases GLP-1 levels in healthy arK:! diababc subjacts and improves fasting
`and prandial glycemia in Type II patients. Phase II trials were 1n11iated Septemb-er 1999 and NDA
`submission is proposed tor- 2003. P32/98 (Probiodrug} has also completed phase I tnals where it was
`demonstrated to be well tolerated. Probiodrug is actively sookmg a partner for development/licensing
`of P32198. Both compounds are characterized as short-acting inhibitors in vivo (DPP 728 t112 in man iS
`2 h).
`
`Mey ...
`HzN~O
`
`s
`
`0
`
`P.32/9B
`(F'robiodrug)
`DP4 Ki= 110 nM
`
`DDP728
`(Novartis)
`DP4Kl=7nM
`
`Current FTE's: 4.5
`
`Executive Summary: The DP4 program has developed potent and propnetary leads with desirable
`metabolic and pharmacoklnetic properties and has demonstrated proof-of-pnnc1ple in modulation of
`glucose homeostasis in vlvo with orally active compounds. On this basis, lhe program will request
`conversiOn from early to full phase status at the January LDOC meeting. Umited SAR on one of our
`primary lead compounds, BMS-356379; has recently identified BMS-405295 as a s1ng1Et 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 1olerance test under conditions in which plasma DP4 actMty was inhibited
`-70%. The observation is consistent With the proposed mechanism of action for DP41nhlbttors.
`
`N-terminal
`moclffication
`
`::t::N~
`
`CN
`
`0
`
`BMS-356379
`DP4KI=27nM
`
`BMS-4-D5295
`DP4 Ki =6nM
`
`AstraZeneca Exhibit 2182
`Mylan v. AstraZeneca
`IPR2015-01340
`
`Page 1 of 3
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`

`
`Page2
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`Ucnthly Summaty The goal af the program is to discover small molecule inhibitors of dipeptldyl
`peptidase IV (DP4) foc use in the treatment and prevention of diabetes. lnhibi1ion of DP4 shedd
`preverrt the degradation of GLP-1 and potentiate Its action in vivo. SMS-356379 represents one of our
`earlest and most promising l~s in the program. To eKplore lhe effect of modification at the N(cid:173)
`terminal amino acid residue, a small solution phase library of analogs were prepared incorporating
`commercially available amino acids. Tne resulting SAR demonstrates a significant dependence of
`ac1Mty based on 1tle nature of lh& substituent at this position. lnc:crporation of large residues such as
`byptophan (BMS-4052.36), S-benzyl cysteine (BMS-405227). and cydohexylalanine (BMS-394147)
`are not wall tolernted by the enzyme. Dplimal activity appears to be associated with hi'Jhly branched
`aliphatic residues such as isoleuctne {BMs-356379), norieudne (BMS-405290}, valine (BMS-4D5292),
`and particulary t-butylalanine (Bhi!S-405295}, the latter of which ls 1he first BMS propneatry inhbitar to
`exhibit single digit nanomolar p:Jtency against OP4. Atthough based on limited SAR, N-alkylation of
`the terminal amine group (Bt..tS405283) appears ta resuH in a dramatic loss in potency. Current plans
`are 10 incorporate otr\er commercially available ami1o acids into this framework., especially proline and
`their dervatlves, but inrtial data indicates that optimal activity wil likely be found with highly branched
`aliphatic residues, few of whiCh. are readily accessible, thus preclud1ng qui::k: access to derivatives ""ia
`combinatorial chemisty.
`
`:j
`
`HN
`TFA.
`
`0
`
`NH2
`
`R1
`
`.
`
`1· Boc..,N,X.COzH
`I
`
`...
`
`EDAC
`
`2. POCl3, imidazole, pyridine
`3. TFA, prep HPLC
`
`BMS#
`356379
`405277
`405236
`405240
`405244
`405274
`405283
`405290
`405292
`4!]5295
`391147
`395067
`
`R'
`(R}-sec-001)<
`CH,SBn
`CHr3-indole
`CH~H~me
`CH,CH(I.te),
`n-butyt
`1-pmpyl
`(S)-sec-b""'
`~pyl
`t-butyt
`CHre-Cst-111
`c-e,H,,
`
`R'
`H
`H
`H
`H
`H
`H
`Me
`H
`H
`H
`H
`H
`
`·~Jy·~
`
`R,
`
`0
`
`CN
`
`DP4 Ki (nM}
`27
`109
`230
`134
`109
`169
`19:l7
`20
`29
`6
`110
`13
`
`In Vitro pharmacokinetlc 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 BM$-382436 which
`shOVf no In vitro metabolism in human liver m1crosomes (tO min@ 10 uM), BMS-383680 exhi::Jited a
`modest metaboliC rate (0.15 nmoVmlnfmg) In this system. Uke BMS-356379, both BMS-383680 and
`BMS-382436 shcNI low propensity for P450 i'lhibition (>10 uM for all P450's tested) and are non(cid:173)
`hepatotoxiC in lhe human hepatocyte assay. Caco-2 permeability for BMS-382436 could nol be
`measured but permeabUity for Bt..t$.383680 (48 nmfsec) was somewhat lower than BMS-356379 (110
`nmlsec). The data suggest that. although potentially weaker In vitro than BMs-383680, BMS-356379
`may possess more opiimal properties fa' In vivo inhibition
`
`Page 2 of 3
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`-- __ ,.- - "·~ ----
`
`Paga3
`
`In vrvo: The OP4 inhibitor BMs-356379 was orally admi11Sierocl (100 mgJkg) to normal rats 30 minutes
`prior to an oral glucose challenge. DP4 enzyme actNrty measured 1n the plasmtf ustng a DP4-specific
`fluorescent peptide derivative .substrate was inhibited by 65-72% over 1he.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
`signrficant, they are consistent with the mechanism of action proposed for DP4 inhbttors. These
`stlldies contribute to a proof-of-prinCiple for the- idea that DP4 inhihltiDn 11'1 vivo can result in
`Improvements 1n the 1nsuJmotropic hormonal axis, consistent with potentiation of GLP-1(7-36) as an
`underlying mechanism.
`
`Fig~re. Acute effects of BMS-356379 (1CO mglkg, p.o) on plasma DP4 enzyme activity and insulin
`secrefion in .-esponse to an oral glucose tolern.nce test in normal ra1s.
`OP4 actNity U/ml
`
`insulin nglm/
`
`60 /::::-- 4
`
`40
`
`3
`
`2
`
`20-
`
`0
`
`~
`BMS-356379
`
`0
`
`0
`
`20 30
`10
`minutes.
`
`40
`
`0
`
`30
`20
`10
`minutes
`
`40
`
`Page 3 of 3