2 PRINCIPLES OF ORGANIC MEDICINAL CHEMISTRY The drug/protein complex does not permeate through phospholipid bilayers,including capillary membranes,glomerular membranes in the nephrons,and the blood brain barrier. Bound drugs are also less available to the enzymes involved in first-pass metabolism After the metabolic and excretory processes have eleared much ofthe free drug the reversible drug/protein complex serves as a depot to replenish the concentration in vivo. Por thesdrug with high protein binding activity vaeedtha 6 half-life c om fraction able of crossing cell mem tein hindine bindin of the tion rises:the potency of the drug may as a ce.This may have and therapeutic consequences in some cases. BIOISOSTERISM The term isosterism wa s introduced by I.La ngmuir in 1919 who postulated that molec ions or radicals ha two Accor ingly isosters should be isoelectric i.e.they should p same total charge Ex (CO and NO (ii)CO,and N.o (ii)Na and NCO (iv)CH N,and CH,CO that qual molecular shapes and volumes,a ss nearl which exhibit simila 4 te that do not necessarily have the same size or volume,but ha physical properties,produce broadly similar biological properties.Traditionally bioise have been classified into two groups.They are: 1.Classical bioisosteres.Classical repla cement is like for like in term um atoms.valeney de and er of may be univalent at and groups ((a)-CH..-NH OH,-F,-Cl(6)-Cl,-NH,-SH (e)-Br L,一p and (d)-t-Ba)-tert-butyl,bivalent atoms and gr (()CH -Se-;(6)-COCH-,CONH-,-C0O-,-COS-),trivalent atoms and groups ((a)-CH 子r furan,tetrahy drothiphene.cyclopentan.pyrrolidine)
PHYSICO-CHEMICAL PROPERTIES OF ORGANIC MEDICINAL AGENTS 29 (i)Flurine vs Hydrogen replacement.The substitution of hydrogen by fluorine is one of the more commonly employed monovalent isosteric replacement. The antineoplastic agent 5-fl l repre ts a class stitution of a normal enzyme s an r sult in a derivative,w can alter s orine sub tive enzyme proc (ii)Divalent replacements involving double bonds.The replacement of C=S with an aldose reductase in nd in vivo tic neuropathy,resu CH,COOH X=CN CH x H.Co CE. (iii)Trivalent ring commonly u equivalents.The trivalent substitution of-CH=with rin CH ith N-is antibacterial agent norfloxacin resulted in enoxacin which is also in clinical use for its antibacterial activity. Me R=H.X=CH,norfloxacin CH.CH.N >Me R=OMe,X=N.enoxacin Non-classical bioisosteres.The non-classical bioisosteres comprise groups which are structurally similar but do not meet the electronic and steric requirements in the rigorous sense.These is ty by the retention of their properties such as pk,electro static po in a derivative,which can alter s ctive enz ne proc ational analysis me thodology can aid in rationalization They are albuterol (3-CHOH),soterenol (3-NHSO,CH)and carbuterol (3-NH CONH,). Isoproterenol(3-OH)is the prototype of the B-adrenergie agonist and is widely used as bronchodialator;however it is not a B,-selective agent. -CH CH, CH, CH(OHCH NHCH CH(OH)CH NH- CH. CH(OH)CH NHCH CH. CH. CH, OH CH,OH NHSO,CH, OH OH OH Albuterol Soterenol
30 PRINCIPLES OF ORGANIC MEDICINAL CHEMISTRY which cataly e m-h oxy group 2.Peptide bonds and peptide fragments have been replaced with a wide variety of struc -CONH-,NHCN-.CH,NHCO- -COCH,- -NHCONH-,-CH NH-, NHCO,-NHCOS CO,-,NHSO-,-CH(OH)CH2,ete. 3.In search for improved antihyperlipidemie agents the tetrazolyl analogue of nicotinic acid was found to be three times as active in lowering blood cholesterol r1eadepresents ists for the na antageous appl tively
4 Chemistry of Prodrugs THE PRODRUG CONCEPT mical d alter the r ness and/or to decrease associated toxicity C.d +se eaesea Pro+Drug Drug This is done in the laboratory. (Chemistry)
The prodrug concept was first proposed by Albert in 1958. Albert and his co-workers described prodrugs as pharmacologically inactive chemical derivatives that could be used to alter the physicochemical properties of drugs, in a temporary manner, to increase their usefulness and/or to decrease associated toxicity. “Enzyme” + Drug + Cap = Prodrug (synthesis in the lab) (released at the site of action) Drug Cap This is done in the laboratory. (Chemistry) Pro + Drug Pro Drug 4 Chemistry of Prodrugs 31
32 PRINCIPLES OF ORGANIC MEDICINAL CHEMISTRY Drug Drug Pro Enzy matic or Pro Drug Pro Drug This is happening in the body. (In vivo) bioreversible derivatives,and conge converte rug as so as the derivative re: the site of act wed by rapid elimination of the released derivatizi ing group without causing side effects in the process. Ex: (CH.CCC )》-CH-CH-NH一CH (CH).cco OH Dipivefrin(Prodrug) (inactive) Esterase H0○-CH-CH,-N-CH, OH H0 Epinephrine(Drug) Prodrugs are pharmacologically inactive derivatives of active drugs.They are designed to maximize the amount of active drug that reaches its site of action,through manipulation of the physicochemical,biopharmaceutical or pharmacokinetic properties of the drug
32 PRINCIPLES OF ORGANIC MEDICINAL CHEMISTRY C-8—N-CHEMI\CHE4-1.PM5 Drug Drug Pro Normally this is the situation Pro Drug Pro Drug Enzymatic or chemical transformation This is happening in the body. ( ) In vivo Biological Barrier They have also been called ‘latentiated drugs’, ‘bioreversible derivatives’, and ‘congeners’. Ideally, the prodrug is converted to the original drug as soon as the derivative reaches the site of action, followed by rapid elimination of the released derivatizing group without causing side effects in the process. Ex: (CH ) CCO— 3 3 HO— (CH ) CCO 3 3 HO Dipivefrin (Prodrug) (inactive) Epinephrine (Drug) Esterase —CH—CH —NH—CH 2 3 —CH—CH —NH—CH 2 3 OH O O OH Prodrugs are pharmacologically inactive derivatives of active drugs. They are designed to maximize the amount of active drug that reaches its site of action, through manipulation of the physicochemical, biopharmaceutical or pharmacokinetic properties of the drug