Structure-Activity Relationships (SAR) & Drug Optimization
Structure-Activity Relationships (SAR) & Drug Optimization CH 405/505
Popular in Medicinal Chemistry
Popular in Chemistry
This 42 page Class Notes was uploaded by Evan Roberts on Friday February 27, 2015. The Class Notes belongs to CH 405/505 at University of Alabama - Tuscaloosa taught by Timothy Snowden in Spring2015. Since its upload, it has received 195 views. For similar materials see Medicinal Chemistry in Chemistry at University of Alabama - Tuscaloosa.
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Date Created: 02/27/15
Patrick An Introduction to Medicinal Chemistry 5e 11 Dx f rd university Pmssi E lga n 39 vlt AC KrP 39 quot vx mvquot v Oxford University Press 2009 ii Dx rd U Wi UE FSiW Fregg mag E Dxf rd Univergity Prensa 2099 Isselte5 GMquot tons of mtacules w HM Same Sf vr Vadean and S H JCVLU39E rEZUI mmon39FY 39 U526 15 repfmmnh She135 md hs or 61803 an Sicn39c I PolarClN39 hadrank 0413 HBDHBH epcMSenu an IF l f IESQSk l es 54 M 00 339 New dassseqk 3 E quot50 SKIES 5 0 3 S bcnay or Jfouvs I cml ck Sinai MiHes o dr Mn39QBVcouS am khaki Pro csua Simuu b n 6 03 C d QCJIVI39Hej some h SOSI ui k L a Mquot 1 K OH e 7 NH cwhngEm R 039 QC D LN 01 aka l I is 39 IMPORTANT GROUPS FOR ACTIVITY Oxford University Press 2009 WWI5 r E XNor0 H i Ii Binding site Binding site ilLiJa g E CH3I R H gt R Me Ether CH3COCI CH gt R n 3 Ester CH38020 LIAIH4 OH gt n quot 3 gt R H Alkane on Mehols Possible of anal on binding egg Ether analogue l Smrie shield latheransom V 7 CH3 7 I K 3i X N or O i 7 Binding site Binding site No interaction as HBD Possibly no interaction as HBA 1 w binding site binding site 7 I hydrophobic hydrophobic region f k t H2 lRaNi gt acts no awn is if 39 Emilion 5 M i39 Ch shr 3km la ruinmac 1 Chair 7DI39UQ g eyeiuiuo m H2 PdC gt 61ina athioc kg e roi HM no m be a M wsqS Jem zlzzl aws SA 93 mng 1 10 939 K OCH3 R0 S RHRF q Hog RJ C H 3 DO NI S 39HN above 25 up en 6 1 2quot P 315k SQquot Querw 39 1ch invot l39kld 0 know UOS Rae and Ne ctL q SN 3 mpoc Im k b odok 6 Hon 4 SHn3 nkw AR 9th mu 39 R a WWW a GS wok H EMIM quotNelly 5 a m S LI M U Mus SOS39RNLS w39 4 39 d bl inleq ME qr iggtrrv 39 b ndllvs Qrus c POSS binding site fit WdlmpiM piic Binding site 0 RJLR39 Ketone Planar 5p2 carbon centre 395 BMW Psii 39 I I binding site I ad Mkmes on and I g interactions i I r NaBH4 0quot LIAIH4 H Binding site x N or O 2 Alcohol Tetrahedral sp3 rbon centre E d of Jr J39 u w 3 3 3 K Elr sigmaK o 5080M 5 1 Shale 3 will 95quot i UOQ Q he H b ms Lwa quot A amer xK Wl 3 ka 05 sgbi l 9E on I z 3 u um c m is 39 l 39i in V pi i I I II I n i l a 39 bmdm Interactions If is mnmsed 539 CN39M ght I It g Binding site i if 6 Intranet 1 x N or o Binding site 39 IL 7 G39 Emil H I X N or O Binding site Binding site Home Free based 3 Amines are only able to act as HBA s no hydrogen available to act as HBD on 1 2 3 at nalogn of CHacOCI H on hind Amide analogue N CHI R in Binding site No interaction Notes 1 and 2 amines are converted to 2 and 3 amides respectively oAmides cannot ionize at physiological pHs so ionic bonding is not possible An amide N is a poor HBA and so this eliminates HBA interactions Steric effect of acyl group is likely to limit NII acting as a HBD 2 amide Possible binding interim lls g 0 o 39 e g TI Binding site Binding site Full synthesis of 3 amides or replace with CR3 CF3 4 3H an 77l H F m JFMBS I39 are hulaca n1 IPH 28 a ATOM ARC CAN ts Qr 1to e ism M a b khan 2M 39HLBS an UN quot23 fe lace I 1 ch HchOCYCl39C Ammt repiacc Soniaquot N 39 l on smut 13 C 5 Ole o Possible binig interac ons Binding site X N or 0 Binding site X N or 0 His 148 D oThe nitrogen of an amide cannot act as a HBA lone pair interacts with neighboring carbonyl group 39 Tertiary amides unable to act as HBD s H R i N OH H OH M RI a 5 quotZN RI o 0 CarbOXYIle acid Amine LilAlH4 c Nllz quot2 1 Amlne NaH Mel CH3 RN N I g n 0 3 Amide N i I Hydrolysis splits molecule and may lead to loss of activity due to loss of other functional groups only suitable for simple amides Hydrolysis leads to dramatic increase in polarity which may affect ability of analogue to reach target if in viva tests are done Reduction to amine removes carbonyl group and can establish importance of the carbonyl oxygen but reaction may be difficult to do if other labile groups are present 26 on Amidgg Analogues N Methylation prevents HBD interaction and may introduce a steric effect that prevents an HBA interaction Analogue i quot1 steric shield quotl binding site No binding as HBD Binding of 0 as HBA hindered eids acid rare 739 Rare except in regions with low pH ie stomach upper small intestine vagina and some cancer cells Binding site X N or 0 No5quot Common mz es m 2 ma pl 3 95 R O 3 R a o we vm at l H gm ro bquot uper 0quot Sam D Q 9 r 3 gr R o I I 1 s an so mspjc so HBA o 39 S is W39amw M c Squot 1 k1lfhmnmk K H 9013 3 n a a R K 3 G O mk andg 5 K l 7am H1 ou H33 acHVI39Kvon Solgur H Km 3quot mum 5e SUI nqm 66 quotj H Clr t Pyrrolt On Q39 km39 kg amk 5 10 PM 0 393 investScdbq Pro 685 N 39 1 p n 5 Igoskres ogcx 5min comPoonb U J r Va Y39t RmchalIHQJ be O k e h 8amp91n W G HAL aSUIUES mi 5 woul 39lq kca k wasr Ein gni 3VI IGWP5 323 on 39Carboxylic Acids Psible in ding interactions ca rhogylate ion comain w a 39 Iqaluit quot 39l i 3 quotNE 39 g MIR Binding site x N or 0 Binding site X N or 0 Charged oxygen atoms are strong HBA s Group can interact by ionic and hydrogen bonding at the same time w my C arboaylic Acids Rx OH H R39gH R c onl PMEIDIE anmgm ii quot o 0 Enter LiAlH4 RCOH quot H2 1quot Alcohol oReduction removes carbonyl oxygen as potential HBA and prevents ionization oEsterification prevents ionization HBD interactions and may hinder HBA by a steric effect 30g anatomic I 3quot sisalii shield 3 IE 395 7 ag In i Llli llill 35 binding site I HBonding hindered No ionic bonding possible 2 L DJ Cocbomihc 16 momecqu L 0 0 o I l e w u KCOH KQO EGANLL 1 cJ RAG 0 pm 0 o g 063 g H R quot e P ll o f M o K I 1 K NHZ 3E4 Sdgom e H V Pk 5Phon with QUH L bklis skrcs H K N a O A c 71 N RJKN kha o e 395ka C Mm gayeras o E1 RIL ORl w RA oR39 R l N X XNQSO 0k C 4174ch 4n VNQ M hY rG y39Ec 51 mamas Possible binding interactions Hbonding as HBA by either oxygendcarbonyl greatly preferred 1 H OH R 0 NaOH lcl CHa gt 39039 Ho CHa o 0 Ca rboxyllc acld Alcohol LiAIH H OH 4 2 I o Hydrolysis splits molecule and may lead to a loss of activity due to loss of other functional groups only suitable for simple esters Hydrolysis leads to a dramatic increase in polarity which may in uence ability of analogue to reach target if in viva tests are used oReduction to alcohol removes carbonyl group and can establish importance of the carbonyl oxygen but reaction can be difficult to do if other labile functional groups are present 39 on Esters are usually hydrolysed by esterases in the blood Esters are more likely to be important for pharmacokinetic reasons ie acting as prodrugs 39 Prodrug 1 VV lia l j i Af 39 D gt a II n Fmdrug Esterase quot V o 1 fen Ester masks polar groups Allows passage through hydrophobic cell membranes 29 of 39 Pssihle interactions I Gmup W van derWaals interactions binding site hydrophobic s39Jvi ill I yellaneuus Functional Grops in oAcid halides too reactive to be of use Acid anhydrides too reactive to be of use Aldehydes rarely present too reactive to be of much use Alkyl halides not F present in anticancer drugs react with nucleophiles in DNA and proteins oAryl halides commonly present Not usually involved in binding directly Nitro groups rarely present because often toxic oAlkynes sometimes present poor stability not usually important in binding interactions oEpoxides rarely present react with nucleophiles in DNA and proteins oThiols present in some drugs as important binding group to transition metals eg Zn in zinc metalloproteinases oNitriles present in some drugs but rarely involved in binding Hum Functional groups may be important for electronic reasons eg nitro cyano sulfonates and sulfones CF3 aryl halides Functional groups may be important just for steric reasons eg alkynes azides tert butyl isopropyl N x s KUpr Caruops 1OSllt c5 R w I K C I R H K F chnt kh c loUK u 6 K b P quot Y quot W quothte M 9 16 Chases in emu Cha39m lenclxks mirthL have Ox bu impacrl 06 V1 ratck tooth IR ML am 1 Haifa23 chpohc MGQHMS f 013 H30 nucleoPh g 11pm row Ksu u KOH 665 Ad SHEan Cmr imk n or Ft like 393 a 3 OCS 0 R R39 W 390 139 D Q or RUIZ RAE u RAK 12mg Hetemycles Hydrogen Bonding Impact Methotrexate in Dihydrofolate Reductase DHFR Active Site Cfquot H H EiH x0 I I H gt j pb a peptide backbone 3quot pk Pb Pb pb pb hydrogen bonds Leu1 14 Leu4 Ala97 39 Unlvalent lsosteres CH3 NHz 0H F Cl SH Br lPr I tBu Blvalent Isosteres CH2 NH 0 S O ais a Trivalent Isosteres F N i w Ring equivalents A HcicLcoqdes Fauna m 03 6 03 a3cc1c 0r aroma c I Can U39Nohlt GM m Conen39i39 s qu Jemr lnc an SHucbre quot limif39 CM39Formg bnd 39I omerCSm quot CT t39HLc in inHCQCHQ Squot 5 Chemica shalom almwh ncn Mensach mekbokicc 8 mm Comm a an Harem cles In Dru Citd d quot i by 1 3r c SfQUPJ Ed u5l ik a c cHuH R 1 1 Piperi ine 393 i O 2 Pyh39a fne 4 3Pymleane C N L d SubJHHea Mir11d N R S S imida o e bHazo c N x I lt3 piPem b ne C N H 71 k m lt30 SA R7 o ij iVe Pugrmancz f fabl liha or CMMI QC PWPUHCS 9 cg lea 1390 WM 14 nch39onalz e MP0 quot p m 5 00 o esfablt r e Vhwchapufe experimtafl7 quot 5 Patrick An Introduction to Medicinal Chemistry 5e Chapter Pharmaeodynamics Pa l UWIMIZING BINDING ItNTEMCTIoNS To optimize binding interactions with target PD Only Reasons To increase activity and reduce dose levels 0 To increase selectivity and reduce side effects Common Stratg Vary alkylaryl substituents Extension Chain extensions contractions Ring expansions contractions Ring variation Isosteres classical and nonclassical Simplification Rigidification L1 1 ll thstitnents Rationale Alkyl group in lead compound may interact with hydrophobic region in binding site 1 Vary length and bulk of group to maximize interaction ll Q Hyd rophobic pocket interactions Receptor 1 Target Receptor 2 Off Target Binding region for N 5 van der Waals Vary substitution pattern eak llihmi HBondf r increased Binding Region activity IiBond Binding Region Binding forY site para substitution metaisubstitution Vary Aryl Suhstitments Vary substitution pattern Benzopyranones Antiarrhythmic activity best when substituent is at 7p0siti0n Vary Am Vary substitution pattern 73m 4 33 0 9 gapquot 39 09 7 r J Meta substltution Inductive electron wlthdrawlng effect Para substitutlon Electron withdrawing effect due to resonance Inductlve effects leadlng to a weaker base Notes 39 Binding strength of NH2 as HBD affected by relative position of NO2 Stronger when N02 is39at para position Also impacts dipole moment 4wmc 48ml were direction 0 lt5 x we Neale Extension Functional Groups Rationale To explore target binding site for further binding regions to achieve additional binding interactions It In 39 I42 I quot I Hi H Iii 39 Iquot I iquot ll If Binding regions 6 Binding group Often used to deve10p seet s t but also to Wadi r r 39 l Extension Extra Functional Groups Examplle ACE Inhibitors Hydmpllo bic pocket 7 Hydrophobic pocket STI HN Binding site Binding Site tamiSh j A53 a 03 Extension Extra Function Groups 3quot quot imf m FOR391 i Example Nerve gases and medicines K P IFiCH3 O Sarin Ecothiopate 3 ewe gas by glaucoma treatment irreversible cholinesterase inhibition NOEE 0Extension addition of quaternary nitrogen s aquot I EH3 oExtra lomc bondlng interaction H 333 Y Increased selectivity for cholinergic receptor 3 ll Mimics quaternary nitrogen of acetylcholine EH3 o Acetylcholine jtension Extra Functional Groups Example Antagonists from agonists tilE U I CH3 HMquot Adrenaline garal olgl oc er g H3C g NH2 7 quotNM MEN N Hismmine Cimetidine Tagamet Antiulcerheartburn Chain Extension f Contraction Ratinale Useful if a chain is present connecting two binding groups Varyv enKW 7 of chain to optimize interactions J Weak Strong interaction interaction Chain quot 39 extension RECEPTOR RECEPTOR Binding regions A amp B Binding groups It Chain Extension Contraction Example N Phenethylmorphine lower IC50 than parent EHO V g a Binding Binding group group Optimum chain length 2 LS a g Expansion 1 Contraction Rationale To improve overlap of binding groups with their binding regions Ring expansi in Better overlap with i hydrophobic interactions Hydrophobic regions 4lt Remembd Had i m 3Hth so lowm MWMCH arc defy depewdw 6391 c9an 15 Expansion 1 39ction Vary n to vary ring size quotilll lllgmil39 I F f wm w 39 tllgilir 3 I 6 6Binding regions beHU39 31quot quot SF0 fvr binaln3 kitLS TWO interactions but Three interactions carboxylate out of range Increased binding Ring Variations Rationale Replace aromaticheterocyclic rings with other ring systems Often done to Pateni39 90634 quot i f quot l OZCHg n In DuP697 SC58125 Core r 39 scaffold General structure for N SAIDS SC 57666 l Variations Rationale Sometimes results in improved properties V Example Ring variation Structure I UK3946245 Antifungal agent Improved selectivity for fungal vs human enzyme Example Nevirapine antiviral agent Added Eugen C 39g39i n I HBA group Lead compound Nevirapine HIV reverse transcriptase inhibitor L lsoste 1 an Bioisostems Useful for Propranolol ISblocker oReplacing OCH2 with CHCH SCHZ CHZCHZ eliminates activity Replacing OCH2 with NHCH2 retains activity Implies 0 involved in binding as h i Al good vatample cg S AR sHakubut 51 1mm 109350 7 sosteres and ioisosteres Ra ouale for biuisuste quot 0Replace a functional group with another group which retains the biological actquotNIH typically to improve PK or to patent dodge Not necessarily the same valency Ex mple Anti s chotics p y Pyrrole ring bioisostere for gt amide group Etozmm r Etoz w Sultopride DU 122290 1anumywl on WE aim if girls u l 939 u I 2 ya n 3 l g l 1 15 ShudWe f5 mJe Prom lu On j39rnq coumJ 261 We ve I bur hue3 no pawled ck pins 13 Simpli cation Rationale Simplifyjng the molecule makes the synthesis of analogues quicker and cheaper Simpler structures may t the binding site easier and increase activity Simpler structures may be more sdgc rW f and less 0149 if excess functional groups are removed however oversimplification can have opposite effect Will am PK f f Simpli eatio Methmils Retain groups that fit 7 i Co EFth EL Remove unnecessary functional groups 39 Simpli eatinn Remove unnecessary rings 1 Example Morphine Levorphanol Excess functional groups Unnecessary ring J 18 Mtatian Metha s Remove chiral centers eg make an isostere or take advantage of V 39m igr quoti V ank I Z w Chiral V Achiral drug Elmira Center drug a Achiral drug 09 3 Y CH3 or 7 0 Indie Comm Jita q H RAJ 1 10 Mug Leave 9 Important simplify in 5 7 to avoid oversimpli cation 39Tds k egg Shockore cor biD Ojfch ac ui 6 dealermine 6K1ch 09 each cmse Made I Pharmacophore Nurtw Simplification does not mean pruning groups off the lead compound In most cases will affect REEimam 7 m5 Simpli catiun Example a hurt Simputemem works buck 6 Roma PT Y39 seel 541916 Lama est0L5quotSNA blohsml new 39Flig ihl e Mead Int EEFHEI EI ailments in E Aspe iein Ilfmymt xim EEK39 39 t g iEt I Benzodiazepine H71 ring rammed L3 Disadvantages Oversimplification may result in decreased af nity activity or selectivity Simpler molecules often have more Con ormaliw L4 high bimb39mc MM due in NVI Enmnrc c 39 en Likely to interact with more than one target binding site Us 73 MJECLQ Will affect ICE and other important PK parameters 1 The Active Conformation Active Conformation conformation adopted by a drug when it binds to its target identification of the active conformation is required to identify the 5 thmcmmrL virtual or through SAR of C IL mamas393 t identifies possible conformations and 7 39 Ill their relative stabilities Easier and more accurate to compare activities of rigid analogues Rotatable bonds Dopamine Locked bonds on 3 aky ha 73 ticked clout 46 Hi active WMHM 3 Wt 939 anok More paw 19 Note End0genous lead compounds are often simpleland exible Fit several targets due to different active conformations This typically produces 7 si g peace in drugs slngle bond rotatlon gt Flexlble chaln leferent conformatlons Rigi ify molecule to limit conformations conformational F CWM TI39 Increas es activity greater chance of desired active conformation being present Increases selectivity reduced chance of undesired active conformations in at his quot biwif Disadvantage Molecule is more complex and may be more difficult to synthesise 1 a H H ME BOND ROTATION RECEPTOR RECEPTOR2 1 Rigidi eation quotemails a lutroduee Ff 7 Bonds within ring systems are locked and cannot rotate freely rotatable bonds xed bonds RIGID MES SENGER Rigidi eatioh Methods Introduce im Test rigid structures to see which ones have retained active conformation Introducan rlngs L9 Ridi ta un Rigidi mtinn a lutmducae HEW quot i quot rnncE d39 hands FlexlbIlIe chaln 19 Rigid Emmpleg Inhibits platelet I Important binding groups aggregation guanldlne exlble chaln dlnzeplne rlng ystem Hg Rigid Show you My ehmplei M SAR 4 aw gammae u CmHvdins Tieatinn Examples Cmmhretisttin antiemeer I Rotatable bond CH3 Com bretastatin A4 Combretastaun More active N Clues dado show 6 bibbiquot 35 Introduce Iii w quotf steric block Y 1 E 32 Ster39c bloc Untavourable conformatlon Flexnble Slde cham Introduce 7 of steric block 39 39 1 ca Coplanarity allowed Orthogonal rings preferred Rigldl catlon Methods r SRHC blocker Serotonin antagonist Introduce methyl group Steric r clash H orthogonal j 39 I I I ME rings Increase in activity Active conformation enforced
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