Chem Sig Events
`
`April 26, 1999
`
`Executive Summary: Nothing to report
`
`Competitive Update: No new developments.
`
`The goal of the program is to discover smail molecule inhibitors of dipeptidyl peptidase IV (DP-4)
`for use in the treatment and prevention of diabetes.
`lnhtbition of DP—4 should prevent
`the
`degradation of GLP—1 and potentiate its actions in vivo. We have been working to identify novel
`and proprietary conformationally restricted dipeptide scaffolds which would mimic the binding
`interaction of the known DP4 inhibitor BlVlS-326430 (lle—Pyrrolidide). Since this inhibitor can adopt
`a variety of configurations (two of which are shown below), emphasis has been placed towards
`generating lactams A and E3 which differ in their placement of the key pharmacophores required
`for binding to the enzyme.
`
`
`
`
`
`Me
`
`Me
`
`0
`
`O =
`” M./akr
`
`"H2
`‘.
`
`Me 0
`
`:
`
`BMS~3264-30
`
`O :>
`
`N
`
`R
`
`H
`
`O
`
`A
`
`)1"! H
`
`~«~ *3
`hr“
`
`0
`
`3
`
`the assay has now been completed utilizing purified pig kidney DP4
`Full automation of
`(inhibitorlenzyme preincubation time of 5 minutes).
`in the “exo" amino bicyclic series (generic
`Structure A), four new compounds which attempted to incorporate a requisite hydrophobic group
`in the scaffold (geminal dimethyl
`for BMS-345588 and BMS~3464-7'6, benzyl
`for Bil/IS-
`345698/BMS—345699, and propyl for BMS-345623) were assayed. None of the compounds
`elicited significant
`inhibition at 10 uM. Based on recent modeling results performed by the
`Macromolecular Structure Group, future emphasis will be placed in generating the related bicyclic
`azocine (8_.5—fused ring structure) which should better adopt the low energy conformation of BMS—
`325430.
`
`Z‘
`
`M; S g
`N\/
`’- X’;->\
`
`Me
`
`"2"
`
`]/
`0
`
`H2“
`
`0
`
`H Kl
`Me, 5
`u\\\ 75
`ME -F
`
`\\
`
`H2N
`
`H
`
`N
`
`*
`
`0
`
`H
`
`N
`
`M
`
`e/\ at
`
`H2N
`
`0
`
`BMS-345588
`
`BNES-346476
`
`BMS—345698
`('3°m9l' A at 9')
`BMS-345599
`
`BMs-345523
`(single isomer at *)
`
`(isomer B at *)
`in our last report it was stated that the "endo” amino bicyclic compound BMS—309909 exhibited
`significant inhibition of human DP4 at 10 uM upon 30 min incubation with the enzyme. Recent
`testing of this compound versus the pig kidney enzyme showed no inhibition with this compound.
`A retest versus human DP4 will be performed once additional enzyme is avaiiable. The 6,5—fused
`compound Bil/|S~344554 and the 7,5-fused compounds BMS-346575 and BMS-346587, designed
`to incorporate a requisite hydrophobic interaction in the molecules, were inactive against pig
`kidney DP4. Again, based on modeling results, future emphasis will be placed on generating the
`related 8,5-fused systems with special emphasis on the effect of stereochernistry at
`the
`bridgehead center.
`
`Page 1 of 2
`
`Astraleneca Exhibit 2183
`Mylan V. Astraleneca
`IPR2015-0,13-l0,
`
`AstraZeneca Exhibit 2183
`Mylan v. AstraZeneca
`IPR2015-01340
`
`Page 1 of 2
`
`

`
`O
`
`BNIS-339909
`
`0'
`
`BMS-344554
`(‘10:1 mixture at *)
`
`/\“-.
`
`O
`
`EMS-346575
`
`BMS-346587
`(1 :1 mixture at *)
`
`Page 2 of 2
`
`Page 2 of 2