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Saidulu DaraJRF

. . .Med Chem Div

he - -Glucose Scaffold as a - urn Mimetic. , . . , . ,Ralph F Hirschmann K C Nicolaou Angie R Angeles. , .Jason S Chen and Amos B Smith

. , , .Vol 42 1511 2009

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IntroductionActivity and selectivity are typically the first considerations when designing

.a drug

, , ,Pharmaco kinetic properties such as absorption Distribution MetabolismExcretion and

.Toxicity are also equally important considerations

Peptides play an important role in biology

However their therepautic use is limited by their poor Pharmaco kinetic.properties They are

)1 Subjected to proteolysis results in short biological half lives even afterparenteral administration

)2 The amide backbone of peptide form Hydrogen bonding with water present in, extra cellular fluid there by they can n t cross the cell membrane easily

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-eptidomimeticsHistoryThe poor metabolic stability and tarensport properties associated with

thaback bone of potential peptidal therapautic agents led to investigate thepeptido mimetics

The design of peptido mmimeticsanticipated by Farmer raplacing a peptidewith a cycohexanering and attaching relavant amino acids

Belanger and Dufrense described non peptidicmimic of the enkephalinswich incorporated

, ,2 2 2 bicyclo octane scaffold

NH2

OH

H2N

HN

NH

HO

O

O

O

HN

O

NH

O

OH

S

H2N

HN

NH

HO

O

O

O

HN

O

NH

O

OH

1-et nkephlin

-eu enkephlin

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son and colleberators reported peptido mimetic wichwas designed to mimic( )ipeptide thyroid releasing harmone TRH

NHN

NH2

O

NBn

O

2 TRHThe enkephalins are endogenous ligandsfor

morphine receptorsthe activity of natural product morphine provides comelling evidencethat the amide

back bone is not always required for binding of peptide peptidalreceptor ligands

NH

HO

O

HO Morphine

http://upload.wikimedia.org/wikipedia/commons/f/f8/Thyrotropin-releasing_hormone.svghttp://upload.wikimedia.org/wikipedia/commons/f/f8/Thyrotropin-releasing_hormone.svghttp://upload.wikimedia.org/wikipedia/commons/f/f8/Thyrotropin-releasing_hormone.svghttp://upload.wikimedia.org/wikipedia/commons/f/f8/Thyrotropin-releasing_hormone.svghttp://upload.wikimedia.org/wikipedia/commons/f/f8/Thyrotropin-releasing_hormone.svghttp://upload.wikimedia.org/wikipedia/commons/f/f8/Thyrotropin-releasing_hormone.svghttp://upload.wikimedia.org/wikipedia/commons/f/f8/Thyrotropin-releasing_hormone.svg

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( ):omatostatin SRIF( ) .Somatostatin is a tetra deca peptide that binds to its somatostatin receptor

, , .It inhibits the release of Growth harmone Glucagon Insulin and gastric acid

It is produced released through out the CNS and acts as a neuro modulator wit, .Physiological effects on neuro endocrine motor

Somatostatin present in two forms) -1 SRIF 14 containing 14 amino acids) -2 SRIF 28 containing 28 aminoacids

.Both are formedmby selective cleavage of Prosomatostatin

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studies of this harmone confirmed that the -turn is responsible for binding a.al transduction

NH

HN

HNHN NH2

NH

HN

H

NO

NHNH O

O

O

O

O

ONH

O

HO

ph

H2N

O

NH

NH

HN

H2NO

OS

S

HN

OHO O

OH

O

O

hp

:TRUCTURE.Veberet al proposed a bioactive conformation of Somatostatin in whichPhe7-Trp8-Lys9-Thr 0 occupy , + , + , +i 1 i 2 i 3 positions of -turn

.respectively

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:ONSTRAINED SRIF ANALOGS. .Veber et al setout to develop a lower molecular weight peptide in hopes ofimproving bothStability toward proteases and oral bio availability

Veber and co workers designed and synthesised cyclic hexapeptides byincorporating critical

- .turn

They synthesised cyclic hexa peptides - ,363 301 and MK678NH

HN

HN

NH

NH

O

O

O

N

O

OH

HN

OO

NH2

H

-L,363 301

NH

HN

O

O

HN

O

H

N

O

NH2NH

O

NMeO

OH

NH

MK678

The he in both the analogs is important and thought to be mimic the.hydrophobic region

Clinical evalutionof -K 678c onfirmed the hoped for longer duration(> )action 4h when- -Administrated orall However the oral bioavailabilit of MK 678 is onl 1 3

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videnced that the amide back bone of cyclic hexapeptide and SRIF is not necess,ng and signal transductionuide leding to the development of peptido mimemtic

, - ,ose as Scaffold by Hirschmann et al taking cyclic hexapeptide L 363 301 as a g

lting glucoside 6 - , ,appeare to overlay well with L 363 301 with the side chains 6 mimicingthe Phe7 , -try8 , and Lys residues of - ,363 301at the , +i 1 and of - urn .respectively

O

O O

NH

O ONH2

O

NH

H

N

HN

NH

NH

O

O

O

N

O

HO

HN

OO

NH2

H - ,63 301 6

he choice of sugar scaffold offered several advantages over hydrocarbons like) Well defined conformation)Stereochemicalpurity of diverse starting materials) -Relatively well precedented etherification reactions compared with C C bond fo

.eactions

i l i l l i f l id i h

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Biological evolution of glucoside against the SRIF receptors onmembranes from both the

, ,Cerebral cortex and the pitutary as well as receptors on the surface of- ,AtT 20 cells

Demonstrated that 6 indeed binds the SRIF receptors and revealed thatacts as an SRIF

.partial agonistthe -Deoxyanalog .also possesed comparable affinity

O

O

NH

O ONH2

7

Comparison of -RIF 14 and lucoside 6

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ected -turn mimicry is validated by correlating the effects of side chain modpotency of glucoside 7 with the changes to binding affinities induced by the

- , .onding changes to L 363 301

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NH

HN

HN

NH

NH

O

O

O

N

O

HN

OO

NH2

H

NH

HN

HN

NH

NH

O

O

ON

O

HNOO

NH2

H

NHN

O

O

NH

O ONH2

O

O

NH

O ONH2

HN

N

- ,63 301 Phe7 His7 10

7 8

Ph imidazole

.6 fold activity increase

.5 fold activity increase

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( )ernative reorientation mode binding of Glucose Scaffold is called pseudosymis rationalized experimentally

- - ( )ring C3 O methyl imidazole congener of 11 having increased affinity for SRIF

O

O

O ONH2

OMe

O

H

N

N

- ( )e 4 des benzyl analog of 11 has no affinity activity against SRIF

O

O

HO ONH2

OMe

O

U t dl th l bi d t

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Unexpectedly the nlog 6 also binds to ( )uman neurokine 1 hNK 1 receptorof ubstance P an

(Antagonist and with a higher affinity IC5o ),150nM and to 2 adrenergicreceptors than for

.the SRIF receptor

This is surprising since the peptides RIF and P are chemically unrelatedand do not .bind each other s receptors

Although hNK1and -SST1 5are both GPCRs they share little sequence homologyin in the ligand

.binding domain

/ ,Nevertheless there are likely to be similarities b w GPCRs as evidenced by thep r i v i l e g e d.Structures and the proposed common small molecule binding domain of GPCRs

The evolutionary conserved ligand binding sites provide regions that accomidatethe projections

of side chains from the exposed surface of and - turn and their componentsor mimics and

.Helices may be similarly available for binding interactions

, ,The ability of 6 to bind the SRIF SP and 2 adrenergic receptors reflectsnot only a similarity

,Among the three corresponding GPCRs but also high degree of pseudo symmetryin the

.Sugar scaffold

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- ,he authors converted the cyclic hexapeptide L 363 301 which binds only SRIF rec.selective ligand for hNK1 receptor

- - .s readily accomplished by replacing Lys9 with Phe9 or p F Phe9

NH

HN

HN

NH

NH

O

O

O

N

O

HO

HN

OO

H

NHN

NH

HN

HN

NH

NH

O

O

O

N

O

HO

HN

OO

H

NHN

F(12 IC50 )95nM (13 IC50 )28nM

erence between the peptide and glucosideis that the sugar scaffold shows mul( . . ).modes i e high pseudosymmetry

- , ,cyclic hexapeptides L 363 301 12 and 13 bind their respective receptors thrinteractions namely those of the + +i 1 a n d i 2 residues of - .turn

glucoside6 binds to SRIF receptors via the C1 and C6 side chains but binds th.s via the C2 and C1 side chains

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( . . )The existance of multiple binding modes i e pseudosymmetry with in theglucoside scaffold

.Araises from the nearest diols

This property of glucoside6 explains its ability to bind the SRIF and NK 1

.receptors

hus the pseudosymmetry of a monosaccharide scaffold allows aingle functionalized sugaro present a multitude of - urn mimicingthe side chain ofeceptor enhancing the probability .f finding a favourable interaction.Taking this principle they generarted a compound library

Among them anolog 14 lacking C4 benzyl substituant binds the hNK 1 recepto(IC50 )nM but

.Does n t binds to SRIF receptorConversely the C3 benzyl substituent isimportant for hNK1 receptor binding but not

.SRIF receptor binding

Incorporation of methyl imidazole at C2enhances SRIF effinity while eliminating

.hNK 1 Receptor binding

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/UMMARY CONCLUSION

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THANKS