Past approaches to discovering new medicines

, Indice ARS PHARMACEUTICA Volumen 36, número 3; 323-468, 1995 ISSN: 0004-2927 ESPINOSA, A.: Editorial .................................................................................. . GANELLIN, C. R.: Aproximaciones históricas al descubrimiento de nuevos fármacos ..................................................................... ...................... . RAVTÑA, E.: Antagonistas de los receptores de dopamina y de serotonÍlla. Síntesis de aminoalquil cic1anonas con perfil antipsicótico atípico .. . BRAÑA, F. M.: Mitonafide y amonafide ...................................................... . ARJONA, O. y PLUMET. 1.: Oxabicic1o vinil sulfonas: Rotura alquilante directa del puente con reactivos organolíticos .................................... . RONsTsvALLE, G., PREZZAVENTO, O., PASQUTNUCCI, L., MARRAZZO, A., VTTTORlO, F., PAPPALARDO, M. S. y BousQUET, E.: Investigaciones actuales en ligandos de receptores opiáceos .......................................................... .. ARJONA, O. y PLUMET, J.: Un ruta de acceso estereodivergente a ami nocarbazúcares naturales a partir de derivados (Fenilsulfonil)-7- oxabicido[2.2.1]heptane. Sintesis total de (5)-Validamina y de sus estereoisómeros en C 1 y C2 .............. .................................................. .. GANELLIN, C. R., FKYERAT, A., HOSSETNT, S. K., KHALAF, Y. S., PIRIPTTSI, A., TERTTUK, W., ARRANG, 1. M., GARBARG, M., LIGNEAU, X. y SCHWARTZ, J. c.: Estudios sobre estructura-actividad con ligandos del receptor histamina H3 .. 327-328 329-335 337-376 377-41 5 41 7-432 433-443 445-454 455-468 Past approaches to discovering new medicines Aproximaciones históricas al descubrimiento de nuevos fármacos GANELLIN, C. ROBIN Department of Chemistry. Christopher Ingold Laboratories. University College London. RESUMEN Se hace una breve historia de las principales aproximaciones al descubrimiento de nuevos fármacos. Se describen cuatro de las principales aproximaciones: productos naturales, uso de prototipos existentes, screening farmacológico y transmisores fisiológicos. Palabras clave: Nuevos fármacos. ABSTRACT A brief account is given of the main approaches to new drug discovery which have been taken during the twentieth century. Four main sources for new drugs are described and each of these is discussed in turn; they are: natural products, existing drugs, screens and physiological transmitters. Key words: New medicines. Recibido: 8-2-1995. Aceptado: 13-3-1995. BIBLID [0004-2927(1995) 36:3; 329-335] INTRODUCTION Nowadays the deve10pment of new medicines takes place in pharmaceutical companies and most of the new drugs are also discovered in their research laboratories. New drug discovery depends on a complex collaboration and interaction between various scientific disciplines drawn main1y from the chemical, biological and medical sciences. It has reached an extraordinary level of sophistication which is why most of the advances now come from the laboratories of the deve10ped industrial nations. To gain a historical perspective it is of interest to consider the main approaches to drug discovery which have be en taken during the twentieth century with the rise of the modem pharmaceutical industry. Ars Pharmaceutica, 36:3; 329-335, 1995 330 GANELLlN, C. ROBIN There have be en four main sources for new drugs. These are: -Natural products -Existing drugs -Screens -Physiological transrnitters and mechanisms involving them NATURAL PRODUCTS AS A SOURCE FOR NEW DRUGS Natural products provide the oldest. source for new medicines. Natural se1ection during evolution, and competition between the species, has produced powerful biologically active natural products which can serve as chemical leads. Thus, moulds and bacteria produce substances that prevent other organisms from growing in their vicinity. Extensive soil screening research prograrnmes have led to a wide range of antibiotics which have given rise to very potent life saving drugs. A recent example of the use of rnicrobial fermentation as a source for a drug lead was the discovery of a novel cholecystokinin (CCK) antagonist, asperlicin, from Aspergillus alliaceus (1) which served as the starting point for Merck scientists to develop the very specific and potent nonpeptide antagonists at CCK-A and CCK-B receptors respectively. Such fermentation broths are also a potentially rich source of novel enzyme inhibitors. Venoms and toxins are used by animal s as protection or to paralyse their prey; sorne are extremely potent, requiring only minute doses, e.g., bungarotoxin (from snake venom) which combines with acetylcholine receptors. CurrentIy, toxins from scorpions and snakes are providing important leads for the pharmacological exploration of potassium ion channels. Folk law medicines have provided another very important source of pharmacologically active natural products, e.g., aIkaloids such as morphine, atropine, reserpine and ergotarnine. EXISTING DRUGS AS A BASIS FOR NEW DRUG DISCOVERY Probably the most productive approach to the discovery of a new drug has been to start with an old drug. Obviously one can aim to improve existing drugs to improve dosage form or to avoid side effects. Less obvious is the approach which has exploited side effects arising from astute observation during studies in animal s or in patients. The discovery of sulphonarnide diuretics such as chlorothiazide in the 1950s followed from the observation that the antibacterial drug sulphanilarnide Ars Pharmaceutica, 36:3; 329-335, 1995 PAST APPROACHES TO DlSCOVERlNG NEW MEDICINES 331 in patients rendered the urine alkaline through inhibition of the enzyme carbonic anhydrase. The phenothiazine tranquilisers, which revolutionized the treatrnent of psychiatric patients, resulted from astute observation of the effects of an antihistamine. More recently, metoclopramide (a dopamine antagonist) which was found to be antiemetic in sorne patients led to the development of the new 5- ID3 antagonists as potent antiemetics, such as granisetron and ondansetron (2). SCREENS FOR NEW DRUGS As already mentioned, natural products can be screened to pro vide leads for antibiotics, receptor blockers, enzyme inhibitors and ion channel blockers. This can be supplemented with the screening of synthetic chemicals, obtained from chemical suppliers such as Aldrich or from company files (libraries) of compounds. In the past, the most successful screens provided drugs for use in chemotherapy but screens were also established for non-infectious diseases, e.g., anti-convulsants (useful in epilepsy), analgesics (in the hope of being non-addictive), anti-cancer, anti-hypertensives, anti-inflammatory, etc. There is an important distinction however between the anti-infective screens, and the screens which seek a treatrnent for a metabolically-based disease. In the anti-infective screens the drug has to be lethal to the pathogen, but leave the host unharmed, i.e., it is a search for selective toxicity between species. In the metabolically-based diseases, by contrast, it is a tissue selectivity which is sought within the same being. In the past, an animal model was used as a screening test, in which a clinical condition was induced in a laboratory animal such as a rabbit or rat, and compounds were tested to see whether they alleviate it. The model ofien simulated the disease by presenting similar syrnptoms, but it was ofien misleading if the under1ying causes were quite different. The modero approach to screening is to combine it with an understanding of physiological mechanisms (see below) . . PHYSIOLOGICAL MECHANISMS; THE MODERN "RATIONAL APPROACH" TO DRUG DESIGN As our understanding of physiological mechanisms has increased it has become possible to take a more mechanistic approach to research and start from a rationally argued hypothesis to design drugs. There are five main sites for drug action: -Enzymes -Receptors Ars Pharmaceutica, 36:3; 329-335, 1995 332 GANELLIN, C. ROBIN AMINE STRUCTURE RECEPTORS + muscle CH3CO.O.CH2CH2NMe3 ¡Nicotinic neuronal Ml, M2' M3' M4' MS ACETYL CHOLlNE DOPAMINE NORADRENALlNE, R=H ADRENALlNE, R=CH3 + SEROTONIN H0'O)CH2CH2NH3 (S-HYDROXYTRYPTAMINE I I � N H HISTAMlNE 5-HT1A-1F, 5-HT2A-2C 5-HT3,5-HT4,SHTSA_SB 5-HT6' S-HT7 Fig. l.-Chemical structures of the biogenic amines (shown as the most prevalent ionic species at pH 7.4) and receptor subtypes (see reference (5) for additional information on receptor subtypes). -Transport systems -Cell replication and protein synthesis -Storage sites Enzyrnes and receptors are highly specialised sites which recognise their appropriate substrates or chernical rnessengers and they possess a very high degree of selectivity. Hence they provide very good chemical starting points for drug designo Since the key to a successful drug lies in its selectivity of actioo, the rational approach has been especially effective in modem drug discovery when based 00 enzymes or hormone receptors, aod the past three decades have seeo sorne notable drug design successes based 00 the approach of using as leads, enzymes and their substrates, or receptors for biogenic amines. Ars Pharmaceutica, 36:3; 329-335, 1995 PAST APPROACHES TO DISCOVERING NEW MEDICINES AGONISTS :d'-0H � V CH3 HO I � r CH3 ,,¿ CH3 HO Salbutamol (�rstimulant) Sumatriptan (5-HT JD-agonist) ANTAGONISTS Pronethalol (�-blocker) Burimamide (H2-antagonist) Biogenic Amine OH HoifNHCH3 I� HO ,,¿ Adrenaline 5-Hydroxytryptamine (5-HT) OH HoifNHCH3 I� HO � Adrenaline Histamine 333 Fig. 2.-Chemical structures of sorne agonists and antagonists at biogenic arnine receptors where the design was based on the amine structure as a ternplate. Ars Pharmaceutica, 36:3; 329-335, 1995 334 GANELLlN, C. ROBIN Enzymes have active sites which specifically recognise the substrates which they act upon and one can interrupt this process with enzyme inhibitors which may be designed using the chemistry of the substrate as a starting point. Altematively, it may be possible to characterise the enzyrne active site. For example, angiotensin converting enzyme (ACE) was characterised as a metalloenzyme containing zinc at the active site, and this led to the design of the inhibitor captopril for treatment of hypertension (3). Or, the substrate specificity may be studied using dipeptides as probes which may then be con verted into potent inhibitors, as was effected in the design of the enkephalinase inhibitor, thiorphan (4). Many substances circulate as chemical messengers and combine with their own receptors, e.g., amino-acids, biogenic amines, peptides, prostaglandins, purines, steroids; they are remarkably specific since the messengers are not normally recognised by other receptors. With biogenic amines (Fig. 1), for example, it has been possible to differentiate between sites for the same messenger, suggesting sub-populations of receptors to provide further opportunities for achieving selectivity of drug action. There are several classic examples where se1ective antagonist drugs have been designed to block a particular receptor population using the chemistry of the natural messenger as alead (6-9). Well known drugs (Fig. 2) such as propranolol (adrenergic l3-blocker), cirnetidine (H2-receptor histamine antagonist), salbutamol (adrenergic 132-stirnulant) and sumatriptan (5-HTID agonist) have been derived from compounds whose design was based on the natural biogenic amine transmitter. Thus, modification of the biogenic amine structure and addition of appropriate chemical groups have given rise to compounds which may either selectively stirnulate, or selectively block, a sub-population of receptors. There are many potential sites for drug intervention to affect biogenic amine action especially in their role as neurotransmitters (Fig. 3). In addition to blocking post-synaptic receptors (R¡, R2 etc.), there are presynaptic autoreceptors which may modulate transmitter release or synthesis, storage sites and reuptake mechanisms which modulate free transmitter concentration, and enzymes which can be blocked to alter the rate of transmitter tumover, e.g., inhibit biosynthesis to deplete the transmitter or inhibit metabolism to prolong its existence. Furthermore, the amine receptor is coupled to a second messenger system, e.g., an enzyme (protein kinase) or an ion channel, so that its influence may be modified by drug interference with the amplifying transducing mechanism. It has been much more difficult to design drugs to act on transporter proteins or ion channels, or on storage sites, mainly because too líttle was known about the nature of these specialised units in cells. With the advent of molecular biology, and the future prospect of isolating many of the protein units involved in these functions, it is like1y that progress will greatly accelerate for drug design based on these mechanisms. A current example is the considerable Ars Pharmaceutica, 36:3; 329-335, 1995 PAST APPROACHES TO DlSCOVERING NEW MEDICINES 335 BIOSYNTHESIS AUTORECEPTOR R RECEPTORS R 1 METABOLI sr� AMPLI F 1 CAT IO�J � t I EFFECT EFFECT Fig. 3.-Biogenic amine transmission can be modified by drug intervention at various stages and sites using enzyme inhibitors, or selective receptor blockers or stimulants. 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(1976): Pharm. J., 217:303. (7) BLACK, J. W. (1989): Science, 245:486. (8) JACK, D. (1976): Pharm. J., 217:229. (9) JACK, D. (1991): Br. J. CUno Pharmacol., 31:50 1. (10) UHL, G. R. and HARTIG, P. R. (1992): Trends Pharm. Sci., 13:421. (11) GANELLIN, C. R. (1993), in Medicinal Chemistry, 2nd Edition, Eds. Ganellin, C. R. and Roberts, S. M. Academic Press, Ch. 7, pp. 121-140. Ars Pharmaceutica, 36:3; 329-335, 1995