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Medch563_Final_2009 - Medicinal Chemistry 502-563P 1 WM(26...

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Unformatted text preview: Medicinal Chemistry 502-563P 1. WM (26) Final Examination 11. Wk) (20) March 18, 2009 111. [K (26) IV. HQ (21) v. KC (26) VI. C. (21) Eval. ’0 (10) Write neatly. Confine your answers to the space provided. TOTAL 150 (150) I. (26 points) A. (12 points) Briefly compare and contrast the expected pharmacological properties and, where possible the expected therapeutic uses for members of each pair of compounds. Provide a rationale for why these differences are expected and indicate what biological target is important to each. 1- H\ ,N02 OCH3 C H C CH H3C‘Ncnzi}cuzs--CH2-CH2-NHd—NHCH3 3 / l 3 H3C’ and ‘N H2 H l f’nfi. A69”: «A1. MBA Til/LL WW2 QEZDJ Wayl— Ah O/S\<\N WW. 3%; #3 MMé/WW 25‘- ) M N - OCH3 2/ 2: E W) M deWXfWMjiZ/MM)§%M flfltfiwflgwy W “/[email protected](W)Wz%fi W12 W 2 _ 9H H__ OH CH3OCH2CH2 —<\ / OCH2CHCH2 -NH-CH(CH3)2 and CHZNHC(CH3)3 T434 74 A/g’WfLV M17 / 2 ”/W HO 111:0: g, ,4, M, Lu'éZZ Naq’f’Yfi‘W' CHZOH MJmW’jfi %% WM ‘ 2 B. (6 points) Aromatic hydroxylation of propranolol in vivo produces several hydroxylated metabolites, the most prominent being 4'—hydroxypropranolol. Write a rational chemical mechanism for its formation, accounting for retention of about 60% of deuterium from 4'—deuterium labeled propranolol. OR 0 (?H in vivo \ R = CH2CHCH2NHCH(CH3)2 —a> / D (H) r, f— D : 0. 0 AW H’ t on we. ’0 D i 10:” C. (8 points) Explain chemically why the following agents are hydrolyzed at different rates. Partial structures and a mechanism are expected. R H o} o 0 II + - n + _ u + _ O H C—C—OCH CH NMe B H N—C CH CH NM Br (CH3)2CHO—P-S—CH2CH2NMe3 Br ,1 3 Q 2 2 3 7i20 “‘7‘2 8%“? +12 5e13msl 7 F5 (CH ) CHC') +a+ “0"” H :B AHESC—‘ig H r AD 5 l' —————!>~ up ‘5 “0-H 3 2 - 3 Maw <— W J <— s .2 - Lmlfifils f‘bWacciy/{mjjme- acafilenmme/ w MW U \J ”W WEWM “(Math Mamw wig? L3 W . II. (20 pointsf/djy ' WWW WWMXW A. (5 points) Do ONE of the following two parts. These two compounds are useful in the treatment of parkinsonism, and the mechanism through which each yields a useful pharmacological response is through a covalent attachment to an important biological target. For ONE of them, indicate its biological target and write a rational chemical mechanism accounting for its activity. 1. carbidopa biological target: 2. selegeline p MFAWW CH ;1CH3 Ho Cc — 9A,: 2‘C—iit—CHZ—CECH , 0 f“ | \ + ’1, R CH3 fl HO ~+H H1]; CH3R, R; l /H._a FIH DH Llrll r’ H3N+ Cd“ L)“ ksH‘ CI“; ff ‘3 \ ___> —-x+‘” 'H C1544W | < / > \ Q A (/14 lt“ _ R) " \ \ \M i | 5 R +E t p, HT ‘ ‘10 ”C‘HZC—ral ”‘4'“ B. (15 points) The following molecules are associated with important pharmacological and/or physiological effects and each may be used as a drug. For each provide a partial structure showing how the compound exists at physiological pH (pH 7.4) and classify each in terms of pharmacological category and therapeutic use in 10 words or less. (More than one word categories are expected.) pharmacological category/ structure at H 7.4 theraeutic use ‘q/ WW OAC / W3 M 55W N+ j \ flax W- , CHz—CH=CH2 g“ me B; E ,1, M4} W ”W €113 Br— . / ‘ MW 3 (5' OH 5’ dW i ’ CH3 1; @WW) Wfl— aw. C] A” H O /_\/ CH—N‘ N—CHz-CHzo-CHZE-OH WW % W G \_/ Cup“ 5 - III. (26 points) A. (20 points) Draw minor modifications to the structures of fosphenytoin and carbamazepine (shown below) that satisfy the following criteria. No R groups unless stated. Q 0 02— || )LN—CHZ -O—P—O N N ' O , _§o 0 2+ (l H Na 0“" \NH3 1. The active product to which fosphenytoin is 2. A succinimide used to treat petit mal. converted. 0 R—groups OK H K / \ . / <D></ \NH‘ Plxrmllo‘A K ...... CL”?— </:\> Ht) : O // \ /\ O ..__. O E 3. A highly teratogenic oxazolidinedione. 4. A long—acting barbiturate useful as a sedative and R groups OK """' anticonvulsant Ealr/ Pk o \/ \ ¢O K _0 ~ \l l KilO\N/l\\o H“ N‘+(C'+ l K o 5. A circulating metabolite of carbamazepine often 6. A carbamazepine analog designed to bypass the associated with adverse effects to the drug. adverse side-effects thought to be caused by v. 0 O \ g7; ** \_\{/‘\l Ekw/i \/ I/ l l C—‘D "3 H'z/ Cori) Lil B. (6 points) Provide an arrow-pushing mechanism for the conversion of fosphenytoin to phenytoin. Hg) 0 W o \ 4‘1 n, \ /0 l \ , "a ——cH- o-— 9-0 /? N LCHZEED )1 H + HQ 2. / K“ ‘oH- / D \+ gfblrirwpoog IV. (21 points) A. (10 points) Draw a-to explain the synergistic interaction of the hypnotic drug, chloral hydrate — Cl3C—CH(OH)2 — with. alcohol. Be sure to identify the enzymes involved. lot-l- .4420 ”o ”0 Cl C—c:l+ ________A C' C’c NAfibl+ (REC/\H 3 \ .3 \ H ()H ’l" O “WWW chit“ geolwm‘vfi mWSblLSM 5; cum? 4% game Mctxdmemmei m BAQ I5 CauQprl 4a “rt/e we‘d“ get anthem/L M - \ gzykvx M SM 221%”: web-i) 5&de 030020” W36) 0305M Culc WOLAe/Ljd aézfl/ 'chlemcmgl, B. (6 points) Flurazepam, shown low, has been marketed for use as a sedative-hypnotic. What would be a likely side—effect? Why? What positive property of flurazepam might allow one to defend its use as a sedative— hypnoflc? N'CQRVMCIKVRM Ea/ éomZCIDM/t 68th cc leflg’lifid Qc’lf‘v-e mommfi ,- ‘ N’d25allfi—l lu/AZ amA/ W‘ARCAA lilac 0046144 lam Cew'l'wllouk; +0 (messiwfl grade“ (ll/\wgndfjh) ((44% %M My m [Md/{A liipcflultofi, 9}; réwchw MSJl+S M WML £405me C. (5 points) Identify the receptor subtypes, enzymes or transporters with which the following drugs interact to produce their therapeutic effect. Ramelteon (hypnotic) Melatonin / HTl Eszopiclone (hypnotic) Oé l SQanl—l— {afiefi/l‘A. Tiagabine (anticonvuslant) (3945/4 ngw (\‘6 am lull/Li bLW> Ketamine (anesthetic) M M fi/Jr WM Remifentanil (anesthetic) ,_ 9 l3) A )5L {9 WM \555 V. (26 points) A. (3 points) List 3 limitations of the older antieplileptic drugs. u...» u f“ flat,» (“as \r: y 8535‘ 3 {\sztrtélss‘PL fi‘LCyoxi L‘W \_ . i 9 l ‘3‘- ‘I 5-?“ F51 *O’UI'L‘TJ-A.‘ v’f ‘ «.ka , » \ ’ \ flit d i" ‘ 4 A t t , \ .9» ‘ 10w?\_ny~ ?Qvi&vqfl) i \‘ m» .‘ ~21, ALA» agfi-“w— “at m Cw a kbw. 3‘ch (.33 51.21”“ 53 new" “Lad 1*): (:1 ~35? w ‘ , L 2 \ \ i y! \ ‘ r by a , ' . t I a,“ "P ‘94:. T" «a, (.0 .x , \A~E._.“‘~1" ~.. 9;; LUru 9. -‘Dr wax “Nuke-7 ”rev: 100 can.) 9 has“; A‘ (23'th an. K \V“, . . . . . Nit 0“ M B. (8 points) In rare cases, valprorc ac1d can cause a fatal hepatotoxrcrty. Outline a metabolic sequence that converts this anticonvulsant intQAIWeS that may bind to liver mitochondrial nucleophiles. Be sure to identify the enzymes involved "1/ ‘f,i‘$g‘pgiw4mwéc:°4, CDmL-i COZH ?‘\'§ ’3 CD? u énowrkw‘ “oak a ”~25;th A; i; ‘ : -. \ flaw 33>” ‘“ W ”C93 //‘\/i\/‘\ M ‘W?’ / v “N /-:z ’1’. r S 7* QwaWuN‘ti ix.) 1. regal?“ ”mu. {asri C. (15 points) GABA-T is a pyridoxal—phosphate (PLP) dependent enzyme that metabolizes GABA. Vinylgaba is a mechanism-based inhibitor of GABA-T. The two PLP-imine structures shown below are normal intermediates in the processing of GABA and vinylgaba by GABA—T. Contrast the fate of these two intermediates. Be sure to show the final products in each case. Arrow pushing is expected. / is g) l O H “P‘\\ ‘9 /\/COZH > /\\/C 2 "5/ ‘4} r‘fs» (‘ + KN fl ‘ l i A“ y+ “ f HNé / H- Wt “ , w HN / CH2 ‘ (l 19“ I CH2 - R *g \ \ \ i i i g ‘ {J‘ M154 i i fl % 4’ ‘fi/ +/ “A in H D1 I «LL. ‘ u ‘ (“flax/Ci“: vjfifid’hlfifi , qt { ”Hating“; V «#3 (rt/(D: a l V- ,f’M ‘14-): y A t, M- ~."~ 0A kn w“...- a IE: '12 - mCi‘r’.’ v ,u“$«‘~“m a )‘N/‘M" G) / “- v' E 5' A}; ‘1“ Id " "‘3 / /w‘:‘? 2 1’4 ’" w. l i ae.. .\ / \i ”I: g/ ‘ [ r ,7, : Li \ "a :7 ,’ /’/ , _ / q l v i V “Cl 3 \v 1:7 ~ Mm m claw”; g Q‘VbUa’C EL: Zn)?" \ ’2 _ F” ’1‘; (r: F o /\ O {i ‘ at \rffr- w K ’1’ ‘ \ Z- \ / jY \l k) ‘?‘l“ 7 .'1: L§(>:}I‘JM (5’0“ M) l't ‘ “ r‘ w . ‘1 ‘1 a l i \ ...‘ "‘x “‘x ~ Ni.” Hi4»- ~~~~ _ 1:; L 1 a y » <0 5 x $52 U” m ~11)? ‘I- ”filuuv L‘s LA 1M 1/ ‘ F “a N M I fix mum _ a 14 eunua e (Era/1% ‘ A i, ‘F .2" 3 f.) Jig P7} ’1 1. F» l \ O \_\ Ni“! V 51th was? W» a e. diam. m...m1 T/ a; 4L. XMF' .L. .31 , .5 a , l /_\“_4 931?” F F" ”W“ ’ i ,1» as “A ‘- tow”. TFM 4m“ . "\ \ \ \ t x ‘ _, \\ 3. ‘ , J: ‘ F. 17. M1115 L; §\%,L,'-tt,,\ a“ 1M ”wank vL. 1- .«4’ 2,0. A :3 r tag 1 bx r Q- Q:‘" F m / M: 7. n .. 1 ' . , , f' “(if " of"? “'31" { .v. “X a a \I", \ ‘9 \e ‘ MA) (rtki‘ r 6 ch ru 1nd1cate above: .m “ ' ‘ ‘ “‘ ‘ ‘ F0 a d g 53‘ V0} M '37:? "5:: any?!” ’.._ '1..1n.n...1.,.. Q FQE; . . ' . . ‘ 5' $-11tg1w-r; an no?‘ 1“\er«‘.a.u 1) What the pH 15 of the 1ntravenous solution of each dm 54 —~ 1 ‘ 1 1 1 . ‘” , ii) The structure of the salt form at that pH. (4114 J m" "r" ' 5 1"" “3‘" ‘ '3“ 111) How the1r durat1on of act1on lS terminated. 1], L, 7;» t1\ B. (3 points) Based 1Wof barbiturate SAR, what would you expect thiamylal’s pKa to be? 4.5 :'\ 7.5 "EU...” 8.5 . i C. (3 points) What three structural features of thiamylal act together to increase lipophilicity relative to a ‘classical’ barbiturate like pentobarbital? “3.," e’. .3 i: if, '1 .~ “I 9“" "’3 wk... a"? Li“; (¥ f.fl“{..»’fl " Xi‘an 5 i053 1.." 1mm ,3 bezutmwav/ ’ (A e 7) \y \ w 79"”va \p t“ 2 «A m‘x .Q 9F\.. at; x) v" fitg‘xnfi { m\ {‘33} 6U}; )4 3' I' i 11* A“ i “I v— . I” __ 3‘) \Jffiqf” 3 JF \ i R ‘1 I A F 2"” “7 W; VI. (21 points) A. (15 points) Midazolam and thiamylal can form water—soluble salts suitable for their use as intravenous anesthetics. CH3\fN ‘ o s .. a O , NH Cl " N 21.. 4 :1 ...
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