DP4 Chem Sig Events
`
`August 11, 1999
`
`Executive Summary: The goal of the program is to discover small motecule inhibitors of ciipeptidyl
`peptidase IV (DP4) for use in the treatment and prevention of diabetes.
`lnhibiton of DP4 should
`prevent the degradation of GLP—'i and potentiate its action in vivo. Recently, BMS—35637Q was
`identified as the first BMS proprietary DP4 inhibitor with high potency against the enzyme (Ki = 28
`nM). Future analogs will be directed towards optimization of the N-terminal amino acid residue and
`the incorporation of other novei prolyl surrogates.
`
`Me
`
`NMK i
`
`0
`
`CN
`
`HZN
`
`BMS-356379
`DP4 Ki = 28 nM
`
`Competitive Update: At the recent ADA meeting in San_ Diego, Novartis presented data on their
`phase I DP4 inhibitor, NVF’-DPP-728 (I050 = 6 nM, covered in application W0 98f‘t9998). This
`compound is water—soluble and short-acting (t1f2 = 2 h) and is to be administered at mealtimes.
`NVP—DPF’—728 increases the half-life of endogenous GLP-‘l four to five—fold. Acute dosing (‘l0
`umol/kg)
`led
`to
`normalization of glucose
`tolerance and beta—cell
`responsiveness
`in
`dexamethasonetreated glucose-intolerant rats. Additionally, Prous reports that Probiodrug is in
`proof—of—princip|e phase ll diabetes studies with the DP4 inhibitor P32i98 (believe to be
`isoleucine-thiazolidide) and may be seeking licensing partners for development.
`
`H
`N\ N\/‘N/Wfn
`|/
`H
`0
`NVP-DPP-728
`
`CN
`
`NC
`
`‘/5
`NJ
`
`H2N
`
`o
`
`P32I98
`
`(tentative structure)
`
`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.
`lnhibiton of DP-4 should prevent
`the
`degradation of GLP—1 and potentiate its action in vivo. The main thrust of our efforts have been
`directed towards identifying novel and proprietary conformationally restricted dipeptide scaffolds,
`two of which are generically represented by structure A and B, which would mimic the binding
`interaction of the known DP4 inhibitor BMS-326430 (lle-pyrrolidide).
`
`Me
`
`N
`
`0
`
`e
`H N
`2
`
`_
`"H2
`: \\\»Kn/N
`Me/_\\
`0
`Me
`
`BMS-326430
`DP4 Ki = 440 nM
`
`l:> R
`H2”
`
`( in
`
`0
`
`A
`
`N
`
`N
`
`HN/—
`
`R
`
`B
`
`Q
`
`Page 1 of 3
`
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`IPR2015-013-I0
`
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`Page 1 of 3
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`

`
`Internal bicyclic amino—lactams BlVES—35D385, BMS-350403, ElMS—35'l431, BMS-349231, and
`BMS—355493 were generated to explore the sterochemical requirements for binding in a fully
`elaborated lle—pyrrolidide constrained mimetic. Unfortunately, all of these compounds were
`essentially inactive against DP-4. Attempts to generate the corresponding 8,5-fused amino-
`lactams, predicted by modeling studies to adopt an orientation more favorable to binding, to date
`have been elusive.
`In
`the external bicyclic amino—|actarns series, BMS-349054 and its
`diastereomer BMS—349058 were poorly active vs DP4. Chemical attempts to generate the related
`8,5-fused system were not successful but the synthesis of the corresponding 7,5—fused Eactam is
`in progress. A substantial number of compounds have been generated in this program in an effort
`to explore a variety of binding conformations and substituent orientations required for small
`molecule inhibition. The SAR suggest that the pyrroiide/thiazolide binding pocket in DP4 is very
`tight and likely cannot toterate the incorporation of carbon bridges (a conformational
`locking
`element present in all these systems). Thus. new compounds syntheses within the chemotypes
`related to structures A and B are being de-emphasized.
`
`H
`
`rm.
`
`HN/Ta
`N\/‘
`o
`
`BMS—350403
`
`'
`
`HN
`K‘
`N
`’“'-\‘\\[T
`) 0
`
`BMS-355493
`
`H
`
`was
`i'n..\‘~“\fi]/N
`) o
`
`EMS-350385
`
`H
`
`HN
`// h QR N
`’ ‘\
`Cir
`>
`
`BMS-349231
`
`H
`
`HN/13
`N
`o
`
`Bi‘-'13-351431
`
`*
`
`a
`NH O
`
`*5
`N
`BMS-349054 {isomer A)
`BMS—349058 (isomer B)
`
`In an attempt to identify proprietary DP4 inhibitors, structures more closely related to the literature
`compounds
`(eg. BMS-338358)
`are
`being
`explored. The
`cyclopropyl
`substituted
`2-
`cyanopyrrolidides BMS-356279 and BIVIS-357151 were recently found to be the first novel and
`potent
`leads in the program, Ki = 28 niV| and 1600 nM respectively. Based on this recent
`information, future efforts will be directed in generating additional cyclopropanated derivatives at
`both the N- and C—terminus of the molecule. Novel heteroatom substituted prolyl derivatives will
`also be examined.
`
`Me
`
`Me
`
`If’ 3
`
`N
`
`Me
`
`Me
`
`Me
`
`Me
`
`_55‘;«
`
`N
`
`0
`
`CN
`
`0
`
`cm
`
`0
`
`cu
`
`BMS-3_38358
`DP4 KI = 1 nM
`
`BMS-356379
`DP4 Ki = 28 nM
`
`BMS-357151
`DP4 Ki = 1600 HIV!
`
`BMS-355838 and l3MS—355839 were generated as novel amide surrogate replacements related
`to BMS—326430 (DP4 Ki = 440 nit/l). Although both compounds exhibited activity comparable to
`BMS~32643O in the screening protocol, Ki determination showed these compounds to be
`
`Page 2 of 3
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`Page 2 of 3
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`

`
`significantly less potent.
`position.
`
`indicating an absolute requirement for an amide functionality at this
`
`M5
`
`H2»:
`
`Me
`
`O
`N
`I
`N\‘o|-]
`
`M9
`
`H2N
`
`Me
`
`D
`
`‘”OMe
`
`1
`N
`
`BMS-355838
`DP4 Ki =47,000 nM
`
`BMS-355839
`DP4 Ki = 173,000 nlvl
`
`
`
`'
`
`Page 3 of 3
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`Page 3 of 3