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`3949
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`Cantributinn of Imnization and Lipophilicity to Drug Binding to Albumin:
`
`A Preliminary Step tnward Bindistribution Predictimz
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`Giusepgw Ermmull. Miriam Lurenti. and Giulia Czrimn’k
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`Understanding the malemlar mecllmllsms governing albumin binding is a maior challenge in
`absorption—illstrlbtlticm‘ mgtabollsm~excreti0n predictlen. T0 gain insight mm this mmplex
`field, an ultracentrlfugation mellmd m measure the drug fraction bound m bevine semtm
`albumin [%B(DAB}] is gresex‘lted. The semml part Qf the study shows: the dependence 0f
`the experimental binding pm‘ameier 0:1 lcrnlzatlan and lipflphllifliy degcg'ipmrs (pill; and log
`139““ for a Series of 14 structurally diverse drugs. Finally, a {lacklng strategy ls used ti}
`ratimnallza the findings; like results confirm the mastly [unspecific nature of the interaclilml {If
`albumin with natural ligands.
`
`Introduction
`
`Tim mm! 10 acrccu almmplimtwillsirilmllmlmtnetaln
`llsmwzxcreliml (AlJMln) maniclszi‘lsslllrs a! 21 war}; Early
`stage at drug; :lewlupmmn is rapidly gmwing‘ l‘rczlczin
`binding influgrenms many pharmamkinertia: (‘Ilamclgegrlx
`“(‘5‘ and umy lnwlw mm m‘ mavma] mm:t‘mmmlwulms
`The alnmlml simalimm ix llml in which rmly mm pi‘mlein
`is involved. ’llm must. frequent vase mmxaz‘m me <lmg~
`allmmin complex, 3mm albumin is: {he most. abundant
`53161311123 pmmin, at armmd 0.6 mM labuut ~40 gilOUD ml”.
`4%}? Bérazauscé 0f its abumlanmje.
`ll
`is [immutable w
`assume {hat the binding Strength {ll a given drug; to
`30mm albumin and thus free: drug (:xposuz'cé is I‘Lmdar‘
`mental w unilarsmnding llwrapcuiic respenwsil
`Human 39mm albumin (FHA). 21 585 l‘GSillllé} pmmm,
`mmmns {ham lmnmlogmm (lmnaim {lalmlml l-lll}. mm
`mmlming m" lwn Sillxlmnains {A and l3)
`that sham
`mmmml slx‘lmiuml E‘lfitllfilllfi. Rural)!" audios have also
`mpmtmi llm crystal filt‘lmlm'szas ml“ l’lSl‘l will} 3mm 01' its:
`ligands:
`fairy Etilt’l$,4‘5 warl‘arinfi pmgmlhl, and ham
`mama.“
`
`A llmmmm Wgwiém indicates three Inajm” limita-
`lltms ml“ plamm pmmln binding slllililésr
`{i} reams
`(alnalneil in different, lalmraim’les am not, alum comm
`rablefl-‘A” (ii) qual’irimtim strucmmw pllammmkinetia
`rmmimmlxlps {QSPRR} m llw ficzlcl am nfl’m) limitc’:{’l tn
`structurally mlamd clasges ofmmpaunclam”‘7 and {iii}
`despite lint: high numbvmf puwwful {llfllllfiula r modeling
`welt; availabls: today, limbs: is in prewlim only CHIC”. report
`as? plamna pmlrfiin binding,”
`This mud»)! aims in illl‘lfllll iufm'maliun UH drug albw
`mm binding mechanisms by using; a simtcigy lléififitl {m
`the mmhlualinn ul‘ erxmzt’lrnmllal data and ululemlaz"
`Izmclulmg mods, namely, mnfarmmimml analysis and
`(lacking filmlugiax The paper is: (lividml
`into llmm
`parts:
`first, an ul15mmnlwrifugatizm muttlwd (nlfrmrcezr
`rrifugmiml
`is a Vl’liltily uxezc'l
`teaclmique m memmz‘e
`lfindlnglfiiil was seat up ta cleami‘mimir drug binding m
`bovine 519mm albumin (BSA) alxpcwimmmlly, ”I‘m: melhwl
`was applied 1:0 :1 31:1 {ll structurally ill‘v’czrmz drugs; (”guru
`
`‘ T0 wlmi‘n cmi‘esgmxlamm should he addmsmdl T91: +13%} ”BREWER
`Fax; +333fi§ lfi?fi?i35? li- alzail/ gillllE—ukximlé’mr’limvil.
`
`ll with welldlspcrfiizd lipflphilicity and whimlion Char
`adxu‘isllcs. Sewmi. the mlalimmllips lmtwcrm albumin
`binding and log I?” {llm luggarillml uf “ll! (llslrilmllcm
`cmszicmnl I) Ell. pH 7.4 in ()Ciiinill/Valflf. traditionally
`asguumgl l0 ilmlllléalfit binding in albumin“) Wen: ana»
`ljgzucl following a rmnm appmarh m llpnplllll€rllyZ33 m
`mlclltiml, a careful check, 01” lilies literature: was made. and
`Hm dsepvmlmm», of I‘vliahlv Hurling rlvm‘rigwlm's and
`lipmplailicity is discussed far tlm 5mm» ml; 0f mmpuumls
`Finally, a link ixrrwaen axpm‘luwntal I'Ersull‘fi and mo
`liitulm‘ interaction mmfllanlsnm was Sought” fl. search
`in the 'l’mmin Data Bank” furnifilml a wmlmr ("if
`resulls for the [ISA {iltlifljw In parlimlma in Blmlla
`clmrya E3Lé-11n4 tlw l1 igh mauluiian (£th crystallagmpl‘ll?
`(lttlzcrmmafiml {2.2 EX} enabled [1m pmition 0f twp
`pmymfnl nmlerulm m be: {lsz£(%z‘r11ilmtl mmmhlguausly
`Knowing Hm caystal strutttme ml“ the (:mnpltzx :«md {wing
`he Milli". (1"imlm::11§m' upmaiing mn’imnmmn’l [Ez‘clgram
`pack age? a fililliéi‘lllfil“ llmkmg simlesgy was sell up that
`was able to mnfii’m Hm QSPRR x’czsultfi DwmlL the
`Study (:m'milmica in am um’llrmmmlmg of l he mall‘mllar
`arms itwalvml in drug~allmmm Humanism and llms,
`a tlm predict lam 0f biocllslribmiml pmpmrtles.
`Results and Disfiusslmx
`
`Data Set 0? Cflmpounds. The gmal of nut study is,
`a 11mm pmliminayy lmlfiwalllblmxlml insights mm tlw
`‘alo {11’ imimimn and llpog‘lhillclty 'm albmnm blaming.
`by walking an a small hut significant. dam 3m {Pigurv
`l} fur which high ptmisicm uxpmz'imcnial (larcrmiItalians
`22m: bum: wrfm‘mml. A careful uxzunim‘zlicm uf mrum
`pmtflin binding data reported in the llmmtm‘tz shows;
`:hat msults olmiiueil in clll‘fisremt: lalmmmrlsgss am mi
`01113:} mmparablfi. glue: m failure m (last film the expert
`nwnml a‘uficlillmls in pl‘npw' (Mail. l[13:111wa 1y ctlslnblmzll
`with ilmll‘ficiml muilmcmlngiml atmravy, and lamp
`{lt‘apriam clmice ui" xlusm‘iptw‘sl
`Primg'ipal mmgimlwll analysis (PCA) wars used m
`iiwafitlgmez the llemmgemily {If the marking data sealgzl’
`Figures 2 giWS U312: scams uf Hm first:
`two principal
`campmmrtm {ll am} 12], which clzzficribe 7l% (31"
`film?
`diwwsaily in {he descriplm‘s spam. Th?» data all was:
`album!
`it) CGVQI‘ all film“ qumlmnm of the REA plat,
`sl'um‘ing [u be liaim‘ugmmuus am} llms Signiflwnl.
`
`
`
`1‘9 2604 American ljhemlral Social;
`30.102 lefjlrllMlIETfilla CC‘ZLT $21513
`Published (m Wily €l7lll2/2lll‘lt’l
`
`EKR Therapeutics, LLC
`
`Exhibit 2017
`
`Page 1
`
`CRTXCAR0008083
`
`EKR Therapeutics, LLC Exhibit 2017 Page 1
`
`

`

`3950 Jauma!()fMecifrinai Chmfisw 15004 I}?! J? N0 16
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`fraciiuzn A13;
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`titansstam exprmmsd in mM”, m. {mg} its [he number of
`binding sites :39? {Jr-11min :mimtula assmtiamd m KM
`(3?ng P} is: 3119 mm: pnmain cm’smntmt’imL and (A:
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`Figure 3A. (:1;
`1
`it» [‘cpr" " "Mimi fur “mafimhvxiim hanged
`cm the exparirmnml data mpmtatd in mm”? m 3H5
`For 1m: sakeof clarity. the immild Liam“: Mm] i. which
`I“£thtf[“t3 m a Immaturabm 2:15:35 bf Sims Qf law affinity and
`is assmtiemszd with iizxptarimtéuml muditimm far mei
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`Equatiun I
`is mug simplified m 153:1 2 {fixtangular
`hypfzx‘hfila}
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`N0
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`Figure 2. Hmemgmwixy {2mm selected data set inwatigatm
`by PCA
`
`Determination of Albumin Binding. Tn {)hfain
`biniiing data Lllédtft‘ Figuring; canditmns, the weatherman
`ml W11 Iat‘ims ammtiarésd wixh rim hiulngimi mannmmmn
`must be erown. liiquaiion 1 {abiainfjci frum the Iaw at”
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`has been kept Gunman: at l.
`Bimiing itaescz‘iplzurs can be: divided mm mm (”alegtlriw
`awarding m their capacity 3:0 dascribiz that THE binding
`
`EKR Therapeutics, LLC
`
`Exhibit 2017
`
`Page 2
`
`CRTXCAR0008084
`
`EKR Therapeutics, LLC Exhibit 2017 Page 2
`
`

`

`Contributions :0 [hug Birgding In: fillbumin
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`Jaumal of Median??? Chemistry, «300%. VOL .1 7, Na. IS 39$!
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`
`
`EKR Therapeutics, LLC
`
`Exhibit 2017
`
`Page 3
`
`CRTXCAR0008085
`
`,
`Cab: ImMJ
`Figure- 3, Simulalima 9;“ binding curves. (A) Equation 1 m
`the case an“ mafimlwximi. IEprerimentai data {rammed in ref
`15): my 9:. 1.01. Km ~‘—’ 11.2 mM’ ‘. mm: w 0.83 mm“ 3. 1’ w
`0'5 mm (B) qu‘aum‘ 2 ““5 Emulate”: m“ m“ 33‘1”“:
`cmnpcunds whnse Ks. {X3 means Kg. 1} represents. nespectiwiy.
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`
`EKR Therapeutics, LLC Exhibit 2017 Page 3
`
`

`

`3952 Jauma! ostcifnnai Clmnfstry, 3004: ml. 4?, Mm 16‘
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`leg D“ dam range {mm
`~2i52 {rmflmmaxaie} m 64.25 {nicartiipn‘mi
`Relationg between Binding and Lipnphiliciiy
`(QSPRRJ. Tc: dam QSPkR studies an pmwin binding
`have Simwn innimiimi“ and iipaphilicityi EJL‘T‘EW’EM‘
`it) play fumiamemml governing {‘ulfifs, altimugh 5mm:
`1301mm has. 1mm [hmwn {in this traditimlai assuxiipljmn."
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`ficriptflrs. A discwia {lime itiVfiIS Wiriabité I {i = “I fin"
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`firm): at pH 37.4} was used as; an Independent variable
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`vafiama (m 3),
`
`%B(DAB} = 7.67ii235) « 10g 1:2“ w
`simian) * 1+ 52.24%431} (3)
`
`when: 133—“ 13, s x 11357? I3 x (L801. 23nd [3“: 253.
`In this and mi: fflilmwing ecguatiuns. 35% mnfideme
`limits are giwn in round brackizizs. 11 its file number 0?
`rimmmmds, :9 is “1%“. Standard Lizeviaiiun, :3 i3 iim minaret]
`{turn-21mm! {tmfficiflxm and Fisr fix: Fischer um. Th? [310%
`{if {he I‘mifiuais {not :shmmi indicates that axiiiudipim
`Emma is pnnriy [3t‘i¥flii‘i(éfl by this aquatic“).
`Qiispiie its limited statistical significanctt, m] 3 {mi
`(iiitis @583 1M3} [1133191th We” far [iregzmrmlmm (85%,
`lug i)” m ’LQE} and Litifluslcmui: {76%. 10;; if)“ m 3.13}
`faking values (”CPOY‘IL‘K} by “richer at Hi“? (iii) and Bii‘fiéa‘
`['{ifsptiCliViily}: (In: 331110 may 31150 he: said fur lfliiénjy’min
`(imp, I?” z 2A7; 8 ‘53 is [he izexpizirimtmtal value: i‘epcn'led
`in ”$43: 71% is this Cfllitiilai‘ml raw”). ititweiiiuu 3 aim
`predicm a vaiuti {if album 37% I'm“ imipi‘aimiuu {lug I)“
`W 3.03, in axccllcni agrccnmm witl‘i {he 33% rcpwrtrsd
`
`in [My Iitzéramriv“ Pregmmlunfi. ft‘fiiflfiffir‘iii‘m, gammy
`min, and imip ”amine WQFC ‘C‘im‘lfld m verify 11m predic-
`tive pciWeiI‘ Gf eq 3 immuse She original refermmas
`imambigimusly T‘L‘jD-m‘i experimental ilemiis and nunwv
`i133] results.
`
`
`
`Figure 4. Pk}: afalbumin binding data 1(%B{DAB} with SDI
`and lipophiiicitjy {lug D”): l’mtiemgenenus series nfdmgaz: bases
`(4L neutral mmmunds and arripi‘mlitegz (C). and acids (I)
`1 meat relationships: (ibrainnd Fm nmmai and haw: mmpnumh
`are 3,517! [EQUFYCfiI 5(3) :0fo [hr COX'IUTWITES‘
`
`This: mimivmhip timwmm pmi‘ein hunting and lipa
`pi‘lilicity was graphically itwwsiigamd far the data 543$
`depictmi in Figum 1. Figum ’1 plats WJMUAB) v3 lug [)3
`Awarding 11:3 m; 3, Hm mmpaumfls an: {filfiafly’ Sizgmmtm
`Iii}? lit’mir (values: acids em: in mi: upper part (if the: mat:
`harms an: in lhs: Inwm‘ part, and immral drugs em: in
`rm 5111:1019 parL
`Imz‘mgizig iipuphilicit}z appears it: haw aimam in:
`impact rm Hm himiing nf am 13 with BSA as also deduced
`{mm mi; 3.13‘Limsm'iide 4 is; a hydmphilic mn’ipuund (10;;
`U :2 wiiiii) but is as strmiglfi; bound is) 855% as in
`dunmthacin 6 {Rig 1) x 1'61}? Hm Value fur impruxeii
`Cnuid mil
`{3&- tifltwminwi precisely but
`is in line wilh
`(iihm‘ acidic drugs.
`Niniirai (mnpisundss iwhaw {iifi‘tzwntiy fruit! fliiidfi; an
`iticrciase in limphilicity (roi'rtzspmuis [:0 an increase: in
`binding pmmnlagfl as shuwxa by wt] 4.
`
`%&B{DAB) = 7.3482256) - lug I)” -;r- 53.79(:t5.96)
`
`(4)
`
`whcrv mm 5, 9‘ m 133, r3 w 0352. and Fm 3.
`Ailmmin hintiing of imam {minim far amludipince; fiftt’:
`belem} is 911512 gawerned by iimphiiicii’y (at; 5)‘
`
`%B{DAB} — 8.71%???) ~ mg :3“ a» 3136:331)
`
`(5)
`
`whom {I m 4, s E 53.39. (9 z LL83. and FE Ni.
`:‘x 1?th hag recently imam puhlisimd by Kramchwit e1
`$11.9 «summing Flii'ltjflliil binding dam fat“ aimui {(301111ng
`{tugciiwr with imlixaiiun and iipnpiliiiciiy dcacx’ipimfil
`h mighi hi: imaraxsnng 1:: L153 94:} 3 (amimr m5 ti and 5}
`m predict (hem: data iml szm‘ii:nniztl}g ihn mhln has
`r1 [luliihfifl’ iifiii'awhaukts:
`(i) it is; mm {Euri'eéa‘i‘ m aaauamé
`a priori that plasma pmtcin binding acmrs iéxcrlusiwiy
`to aibumin {egg}. tin: pizrcesrlmgiz 0f haunt! iliiipraminc
`i3 {3: ‘2‘?) in Kmim‘hwii {El aLE’ wimmas 35% is Um Erma
`
`value fur albumin binding as civscriinxi in WCd‘CI‘ at,
`2:11.“), and COHVCI‘SKWI {if [Jithitiitaglf data :0 equivalent
`binding affinities: Shauiti he awidtzd (SW album}: (ii) ref
`79 rt:;:iin'tt:d in Kramdiwil (3i a1,” {fmm which mast data
`
`in Krai‘mrhwil's {aide were EXUHCLEKD i3 imam ssibiei in
`many witéntifitb betausu {if iii-a iimiluil availmiility; and
`(iii) it is my: CK‘EIT when eicctrical Spfiiifit‘iii dominaim at
`physiuiagiml [in anti smnmmws. rim inni'xai mt“: tiaiut‘fi
`0f the mmpnumi is in m‘mr (21L. phi?nyltmiaxmw at pH
`7.62 is an acid, rmi a neutral itcémpoumi}. fie-23‘ 1% u!“ these
`iimimt kins, We ieSLmI m 3 2m smmsa Svim‘iml mmpcmmifi;
`for which albumin binding; is unambigimmly imparted
`
`EKR Therapeutics, LLC
`
`Exhibit 2017
`
`Page 4
`
`CRTXCAR0008086
`
`EKR Therapeutics, LLC Exhibit 2017 Page 4
`
`

`

`Contributions :0 Dn'tg (firming In: (albumin
`
`Figure. 5. Must Mama (ins‘lfm‘mttr a? antlm’ligiinc ulnaimtd fi‘mn
`QMU Simiiziesl Inu‘imwlmulaz ”Ba aw Shawn
`
`
`
`
`in W: angina! fifffifltilk’féé. Clearly. mu validity“ (1113:} 3
`mm: he :3thle with additional (lame
`
`Case DfAmlodipine. Antimiiplim Mam; a prmmmmd
`amizm grrmp m phygiologiml pl‘L but
`in the p m;
`mpnrtm m Figure IL it
`ling in the: i‘egiun uf neutral
`mmpoumls. {filmnpoumll 2 its a clil\yclrcmwidlne (Di If?)
`calcium aniagonisi‘fi (:mnparablee in mimicry w nifez
`dipine but {tridnwacl with 100% aml availability am a
`long {dimination half life, Confm’mzitimml analysis
`{qumwlmd molacular clynamiml QMD} was; amid to
`unravci [he reassunze. far ms uncxpvgrucdly 51w mg bindi
`5.:
`if) BSA. The QMD [mulls indicate lhéfit in all retaimtd
`Ufa} (:(mf‘urmcra {1512312 l;:x;mrlnmnlal SifCliDfl) ”It“. pissiliw
`Isl lama uf Um pt‘lfl’unéit’flil amino gmup i3 always parfia l}!
`memkml and that in many of them an inelrmmicmlar
`
`hyilnragm mm (HE) is formed {Figure 5}. {Immatr
`2 y‘
`QMD at" 11123 neutral species revealed mat in the. absmee
`nf msiliw Charge rm mm rilmtimx elf mam mnformvrs
`mnlr‘l he smglzrsm’mi. This" finding wmslcl ammar t‘felfWé’mf
`m {‘xplélimng the pemlim plmrmexmmgiml lmhzwksr at“
`2: haunts. wurk it; in pmgmss m inwgiigale Um physi»
`cmmhmiml behavior {21' amlmliglinm in greamr (lamb.
`Logarithm cf the Highwperformance Affinity
`Claramatography Binding Canstani: {10g Kym‘} 1%
`log 1}”.
`llighlperfm‘manm affinity gllromamgmphy
`equipptfid with an Elsiim‘Jlirilizml I‘ISA mlmma has; mwrlfly
`been pwpcascd to clcmrmilm allu‘uniz’l bindingg Planing
`(3f chrmfiawgraphifi data takerl fmm Celmwarqia «:32 all
`(fable! 2) and log, If”? {Figure ~53 fur cairnpmmds 1mm
`Shn‘wml m: {lirfezmmta lwtiwvml rméuffal, basic. 2nd acidic
`drugs? lug K1532 hfiingg lirmm‘ly rammed tn lipxmhllicity
`by m} 6‘
`
`firm
`mg K ' a 0.22%0205) - lag 3:)“ w cauwfivj
`
`(6)
`
`where: “1—“: IQ,5~':=().22.13 ‘~=—' Oil. and [m 19,
`This finding mighi be causal b}; Cllwumwgmphic
`zirlifzms: humid albumin l3 (Junfcrmatiunaily n'ladificd
`am]
`is
`thus unamv m :“mpetétl:
`its; natural
`threw»
`climmsional stmciunzr. in aclcliiiism as; liwnuonccl almve,
`the prou‘éiufdmg (”Oilfifiltt‘fllliu!) ram) is the funclanwntal
`aspwi Lu hv 13km: inn) 2166mm} when dolwmining 95d}
`{0&8}. Thiis ram) mun»! be cictm‘nxincxcl
`in ctlxmmam
`
`Jaumal of Median??? Chemistry, «300% Va!» 47, Na IS 39%
`Table a. finding; {322142 ”l’zakm Frczsm the Liwmlum
`
`(1mg
`[03 film”
`Vulgffiplfil"
`amlmiulul I1}
`{32}
`26C!
`5311310211pr (2::
`3113‘
`filtloi‘uquine {3)
`GE ‘0
`fumm‘rmdv {Ii}
`$9328
`
`hydrm im‘mhiaztdv {5)
`84.0
`indmmlzélaain {fi}
`mm
`nmtlleu'exam l?)
`13221.0
`mpmxm {8}
`main; ipirw {9}
`pramsm (111}
`mm
`quinidim {11}
`{1.44
`rmliticlim $123
`8.1
`icmmxlmm {13}
`
`Wtrafiyclirw (14} 42138
`‘3 Dam when é‘mm ref 82 Lug Raw"
`103W -,
`iglfltgl En HIP
`mnditimzs (immibzsxd in Elm mm: '5 lgwcmmtag? {3? drug bmrmi
`it",
`{lésisrréa l‘?§2l§{l§‘l’l5)l, 31mm Iiikm? film:
`(14'
`211'? unluss‘
`inclit‘auicl
`mzl'mm‘iax? " (“mm ml‘ 732 5’ ll’mm rm” N. *“l‘i'mn m? 733.
`
`
`
`
`
`
`
`
`Figure 6. Linear relationships between log Kbm‘ (literature:
`data) and lag 0% [321305 (‘32 mantra] compuunds and ampho
`lites i”). and acids {I}.
`
`22 well
`ram:
`log Km’ 2:;
`I‘lwmfm‘e,
`graphic zmihods;
`defined pammetm‘.
`In miller wnn’ls, the tlwa ways; uf
`obtaining l;;‘»S,-"\ binding (llnlt’r‘emmnrlInga:icm and 2:1ffinil;y
`chmmamgmphy) are Hm, “in!erullangaabla mammal: the};
`are: gmzrnml by 22 (iifiiarmn halmxm 22f infiarnmlcttular
`imm‘mttimlzs. Ixn’erestingly, asimilm llahavim‘ has hem
`523,911
`in studies mmparmg Iipaphillgiiy in lipasmum’
`”water asyslxzms with {AM minim"; dam.“
`Percentagr:
`(If Total Sarum Protgin Binding
`WraiflPEM w; lag 197'“. Fur mm reg-111m l4 Ixm‘tpmxm’ls,
`clam (Humming mml [Magma pf’iflffilll binding [9235(13138}?
`"llama 2} wem 315:: (filllmn‘ml and mugged fmm if} m 99‘}?i
`To: a BM? sippnimimmirm, we can assunw 31ml,
`
`%B(DPB) = 923mm) - awmcp} 2» %B{m.hers)
`
`(2')
`
`where filiaBKIJPB} and ‘léBlDABl are dafinnd abovu 9613/
`{PROP} is (ht: pmtenmgv of drug hmmd m {11 lgiyz‘nprrw
`mm, and Eléfilmlius) is the percmltfigg of drug, bound.
`to that (”cumming plasma prcsamints (mainly Iipoprulwius}
`The miatimxship hetwmu ‘J‘fiBUDPBE and lipuphilicily
`is illusti'ai‘mi in Figure 7A. l'liam again, acids are: {mum}
`mum Sl‘é‘mlgly {Iran twutml wulpuumks. [Jaws limiting {1w
`weal-«:32 (utilimlipme again binds mun: than uxpwfiml
`considering its; anionic nature}. 17m“ acizlfi, them was. m}
`apprmflahlw varimimx heelwmn ‘§?2l3(l3§\l3§ and 92313“ 3143}
`{1‘23le 2}, which mnfirms that albumin binding is the
`majm‘ {mint (“leiifii‘mining mid binding {0 serum IEI‘UEMI‘IS
`Fm“ acids,
`[kw Hmh‘ibutiuns fmm ‘fiie‘ollBiACW and {368/
`{uthvrs} in mg 7 can bu magimtml,
`
`EKR Therapeutics, LLC
`
`Exhibit 2017
`
`Page 5
`
`CRTXCAR0008087
`
`EKR Therapeutics, LLC Exhibit 2017 Page 5
`
`

`

`3954
`
`Jmmza! oeredfrinai Clmnfstry, 3004: ml. 4?, Na 16‘
`
`
`il‘rmrmdi (“I 517‘
`
`
`
`
`
`Figure 7. Relationships between ElélllUPEl} and %}3(UAB} and
`lipopllilicily.
`(A) ‘E’c‘lBEDPBl vs 10g 19”“ {E‘s} "QBQJPBJ {heavy
`lines;:
`- - '. carlcms; -, neutral cmmmunds} and ‘k’ulfifljfislfil {thin
`lines:
`. , v, «misfits; “x [mural mmwmmixj and lag 1}“.
`
`Fur nmltml drugs: and hawx, ihcs: z‘leg'wm'lmme «sf‘ “all
`(DPBl
`(an lipcaphilisiiy is; 315:)
`linear (€ch
`8 and 3'),
`mspectiwly, and Figure 713),
`
`
`
`9613mm): 6A54{::2,03)~10g I)“ - 74A9(::4.71)
`
`(3)
`
`1.1611911: I; 2 5, 5:: H15. 1‘3 : aim. and I”: if).
`
`%B(DPB) a 23.21::;~.2m;u~ lag a“ + BEBE-.284)
`
`(9)
`
`wlmm n m 4, 3 m 4.82, 1“" a (L384, and FE 138‘
`{Elmer inspecilma of 2 he: 5103395" obtained plotting, $12313
`{DAB} am”! “’nBlDPfll rmpactiwzlyk as t'lelmn'lnm vari
`ables (anal log {)7 “3 as an imlemmdtmi variable} indicates
`that in slap presmce ul‘ Hub W‘huléf serum gu‘mxaina‘ an
`inhuman in 31mm OCFUI‘S for (in! inns hm rm! l'nr mtmml
`Ltmmwumls {Figum 7%} This mulcl he: in Elma will! an
`additional maltributimm Iran“: MEI“ binding {01‘ bases:
`AG? indeed prefercmiall}; bifidfi bask: cmnpuunds?
`Intaractifin 0f Nautral Cmflpnunds with HSA
`Investigated by Mfliecular Mattieliug. The results
`uhminml with cc; 3 3312mm bi: Ccmfirmntcl by a (fucking;
`isluily, In particular. drugs with 3 high value 0? gal}
`{GAB} should Shaw batter clmzking than illfifififi with law
`binding {31‘0pt3f‘llifi3.
`The crystal mull; mm 131' ”SA cmupiexcd with a
`(mmlmr Elf 13 adage Rama“ 5 and {:xugmwus Iigmlds‘g-f has
`rmmnly been mpomxl, ll‘ur this maxim, in 0m" {13mm
`[alumni study. WI: used l‘ISA instead 0f 35%;, fur which
`an X my exists.
`In this paper, {Making results aw (liscunsmzl win; than
`{iiiil ml prefermnte maps; (scam the Experimvntal Sectiun
`
`for {2013115}: briefly, this {ml puu‘lucm mm grjdx. a gram}
`{my Elm! imticams the pmferrm lxydrzlplmbir mntact
`Iiwgicms and a real ORE} thal indicatm the {)i‘iifiw‘l‘fid pular
`mulwarl s‘cegimm. If film hydrnphohiz: mniuiius; (If the ligand
`match the hydmpimhic nagitzm; ilu' inlla‘z‘aclmw is aptiv
`mal (and likewise fer the: palm mniatias and regions):
`Ccmwzrsuly,
`if thaw hydrophobic groups (31’ Elm ligamlfi
`match the [301m [53320115. 01‘ vice: wrsa. thfi: lamractfzcm
`i3 pm“:
`Valiflatifln 0f {ha Backing Px‘flcedure. With the?
`aim M taming HZP flanking pmmfinm. pmmfm was;
`gubiocml m the decking calculating. In the crysstal
`Sirmtmm»? pmpnfm mm bind in lwn Slims: Elm first {FRI}
`is locatm’l in mtbdumain “IA and is. [he gm». ml" highest
`affinity“? the semml (1)122} ’15; 1043mm! in sulxlmmzzzin HHS
`The: ducking pf‘mfflillll‘fi was sucmssful in rmn'xlucing
`the binding made: {if pmpnfal mum} Bxper‘imezutmly in
`bulk slim, but. (July PRI is {Sallfiiikfl‘lfij 339m.
`Both the X ray {mnpliax and the calculated wmpim
`(it’ll mwal that this. prumlbl mvlmule binds ix: 21:? ape-la?
`pawkc‘éi' wil h the pl :mnlic: hydmxyl group. making a weak
`HP) {3le A} with Hm main {‘l’min cm‘l’mnyl uxyggm 0f
`Latvia!) final “with Llw. amnmsic ring of the lamlmcule
`aamlwlul‘md l.)t‘:§Wm:il Hm {side :zhmu ml Max:453- and
`AsnBQL 0m (1f the. Wm isnpwmpyl gmups makm: mmmn
`um» awlm Ujl'tlfiilltia m mm (mil of the make: (mainly will}
`A5213”;
`”317211433. and AlaMEl), wllm‘ms the (ulnar lb;
`czxymsml a! the aqueous; eemranw. alzhngh it mamas
`(til-filflflfi With several fiilltt Ithaizm {Arg‘llll 'l‘yr’lll. and
`IEWlBfl}. The ism H‘npjy‘l gmup Immed at (Ma mnulfh (if
`
`tilw {Nimkli‘l
`is ml
`32% by abet,“ E30“ as finnpamd m {111:
`Kray solutizm m atrium (TIDIIEFZCT wnh vicinal FifSiEjllOS<
`Tim s3rim1i:ati0n £331 Eli‘s {he przéfemmiz maps: €135}:st
`39-;
`Shawn in Figure 8‘ Mom the ducking flalmlallmls. a
`possible: {Sigmund binding muck: {Cl} was found at lewmr
`
`mm {iii-mu mmrgizas (about I kcallmal
`«A what. {kl} hut
`mm memmfmn (lacs not fit the pmfmxmw maps well
`{dam nor slmwn} and thus was; discarded.
`Interaction Made 9f Unionized Cmnpounds with
`HSA as I‘leducefl fmm Malerzular Mndelingl The;
`tumbling 3:11:13! was; extmxilml in three Lmimizml mm-
`]:ummds kwluz’lging m the: data 39:: (I’ligut‘a l}. hydrcxtldo
`mlfimidm nicardipérm, and pr‘amxin, agsuming that, their
`binding site is tlm saw: as that M progmfal (PRU. This
`asfitmxpiion ‘15 {amenable} because it has bum Shown
`hat mgr pmpofvl himling site can also acmmmoclam
`argt: multzcules Sllifh as fal ty atri<l3.7 In ailcliilon, lottaténg
`be: binding Sim. 0f the nemtral mulmules in site: [HA is
`hit must masmml‘rlm thing it} do. butt-mm“ tjyp‘awlly
`ligands in am: HA are bulky lut‘wt‘myclia: animm will;
`he {Marga slimmed in a fairly natural msiticm (if the
`mulemlex *lhis differezmtiatm [139m {mm the:
`ligands;
`ypwal a? sin! INA, which arr giannrally’ firrm’latir and
`manual; 21 chargm, if pwsuns. is anionic and [mated mo re
`pm‘ipherically on [kw nmlmtuifi. ”3 Nmiceriheéless, Work is
`in prugwfis EU explm‘ifi nlltw‘ fillies; in {Dax‘timlar Fm acidic
`
`nuiemzlfls.
`
`A wieliwiu'cicy inwsllgaimu mettle: using Absulv“
`(luscripwrs {according to Abraham‘s; ilel‘miliun,” if} is:
`he sl'miar Mcimwmfs walmne and :1 and if am {he
`solutes ll--b{mcl donor acidity and l-lbmkcl RCCGDEDI‘
`lmsicity. mspecl’iwzalfl Hawaii; that hydrmrhEm‘thiamdc
`is. muglaly Elm same size as pmpol‘zat (If;
`is. 3.652 far
`pmpuful and 1.?3 [hr 5) but pxazscms; mum hydmphllic
`
`
`
`EKR Therapeutics, LLC
`
`Exhibit 2017
`
`Page 6
`
`CRTXCAR0008088
`
`EKR Therapeutics, LLC Exhibit 2017 Page 6
`
`

`

`(anztriburions 3'0 [Aug 19inng m A lbw/2m;
`
`jnurxmi 0f :Lfi'mu‘igrina? Chef‘nvisfly. Effie??? V01» 4?. Mi ’53 3955
`
`Figures. 131890301aviantalinntfi it; the PR} siw. T119? Etydr‘ikphilic p ‘9 arena»? map {96% grahabiliiy? is in refl. and 13163 hydmphcshic
`IEI‘E’WTEW‘E map (‘Efllfifa pmbabilit‘y} is in gram. Hydmgms wera rwmvad for x‘laz‘ity.
`
`
`p.
`
`gmups; man propoffil {a 5—” 0‘3? andfi? m (1.3? fat" gat'apaiul
`ami a 2 1x26 and g? 2 1.72 far hydmcl’llnfihimide}:
`nimrriipim is; hugger than pmpnf‘nl (1:; is; M32}. hm. a
`stmng “133 armpmr pmpmty {(11 m 031 and g? m 220).
`ami presents a mrmélml liyc‘h‘upkmhic: group {phunyi}:
`prams‘m has; rmxghiy Hm same: Siyivatmhmmic pmffla
`as nimrxiipine {1};
`is 374, a 2 (L24. and ,5? r 2.22};
`meamziy, BSA bim’iing gmmcm’icrs (fable 1} are air‘ni
`Iarly madman: fm 5 and 10 and high fin" 9. Appliamiun
`{sf the ducking promiimv 10 hydrmthlmrtEliazidt: givmz mm
`m‘ientazimm (CS3 and {:21} with a differencta in im’emc:
`mm mic-.rgy that is. below (H kmxnmz.
`In QI’iC-Ilt‘dtimz C9 (Figure: 9A). 1m:hydmdtiurtl’xietzidc
`sulf‘nnamidr muimy is lmawd at, (me (rm! {)f 1111* PM
`puckui . in pmximity m VaHi‘W and AIWMQ, whereas ! hi":
`1,21! thimiiazint‘ suifimidfi: (unitary fm‘ms a 3&1: bridge?
`wiz‘h Argsliz (90% sirezngm and 22% A: and 2‘: H13 mm
`the hydmxyt grasp 317371"!!! 1 (45% Sl‘fiifigth and 3.2 A}.
`The phvnyt mo‘ml}; is shifted with mapum in prayerful,
`and me sandwiirh tmwem the Slidi; {thaws DI" Le2u453
`
`is; ham (:vidmil. Tht: pmfunmm: mam shuw
`and AsnSEZI
`a Inmkzat m. and in particular, the mflfmian‘lide gram}
`dues nm Fit
`the. mapss.
`In uriematéuu (121 (Figure: QB), hydrflfi}llfil'fhifiiidt? h;
`flippuil uwr with wwum‘ Lu {19;
`in {hits 13056.
`the
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