in vivo antidiabetic drug discovery

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In vivo antidiabetic drug discovery Jian Luo Shaman Pharmaceuticals, South San Francisco, CA, USA All of the glucose-lowering agents available today for the treatment of diabetes resulted from the in vivo antidiabetic drug discovery approach. This is not surprising given the limited understanding of the biochemical basis of diabetes. With new developments in the elucidation of the biochemistry and physiology of diabetes, along with the ever-increasing number of drug discovery technologies, screening tests have shifted from in vivo to in vitro and from a cellular to a molecular level. However, there are concerns with this shift because diabetes, especially type 2 diabetes, has multiple and independent molecular defects and most of the molecular targets currently used await clinical validation. One approach (employed by Shaman) has used focused in vivo screening and has been successful in avoiding or minimising the drawbacks of in vivo testing, while maintaining the benefits. It is hoped that the combined use of in vivo and in vitro approaches will generate new breakthroughs in diabetes. Keywords: antidiabetic drugs, diabetes, drug discovery, in vitro, in vivo, type 2 diabetes Exp. Opin. Invest. Drugs (1998) 7(6):987-996 1. Introduction In general, strategies for drug discovery have changed dramatically over the recent decade. This has been due to new developments in chemistry and biochemistry, as well as progress in technology. On the chemistry side, the most prominent developments are combinatorial chemistry, molecular modelling, structure-based and computer-aided design, and QSAR and 3D QSAR [1]. On the biochemistry side, great advances have been made in understanding the biochemical basis of many diseases and the establish- ment of molecular targets for the treatment of these diseases [2]. As a general trend, biological screening tests have shifted from in vivo to in vitro and from a cellular to a molecular level, in order to increase the screening through-put and the specificity [1]. The antidiabetic drug discovery approach has progressed along the same track. There is no doubt that this change has many advantages; however, problems and concerns with this change also exist, especially in the field of type 2 diabetes. On the other hand, the in vivo approach has long been used as a tool for the discovery of antidiabetic drugs and continues to provide drug candidates for clinical development. The intent of this article is to emphasise the benefits of the in vivo antidiabetic drug discovery approach and hopefully provide some balance to the current molecular target paradigm. In this context, the historical aspects of antidiabetic drugs and the advantages and disadvan- tages of the in vivo approach are revisited, and some concerns with the shift from in vivo to in vitro assays are addressed. The drug discovery programme at Shaman is offered as an example, illustrating the benefits of the in vivo approach. 987 1998 © Ashley Publications Ltd. ISSN 1354-3784 Update 1. Introduction 2. Discovery history of antidiabetic drugs 3. In vivo antidiabetic testing 4. In vitro antidiabetic testing 5. Drawbacks of in vivo and in vitro test systems 6. Outcomes of in vivo and in vitro approaches 7. In vivo antidiabetic drug discovery at Shaman 7.1 The Shaman programme 7.2 Outcome of Shaman programme 8. Expert opinion Acknowledgement Bibliography http://www.ashley-pub.com Expert Opinion on Investigational Drugs Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by University of British Columbia on 10/29/14 For personal use only.

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Page 1: In vivo antidiabetic drug discovery

LuoIn vivo antidiabetic drug discovery In vivo antidiabetic drug discovery

Jian Luo

Shaman Pharmaceuticals, South San Francisco, CA, USA

All of the glucose-lowering agents available today for the treatment ofdiabetes resulted from the in vivo antidiabetic drug discovery approach.This is not surprising given the limited understanding of the biochemicalbasis of diabetes. With new developments in the elucidation of thebiochemistry and physiology of diabetes, along with the ever-increasingnumber of drug discovery technologies, screening tests have shifted fromin vivo to in vitro and from a cellular to a molecular level. However, thereare concerns with this shift because diabetes, especially type 2 diabetes, hasmultiple and independent molecular defects and most of the moleculartargets currently used await clinical validation. One approach (employedby Shaman) has used focused in vivo screening and has been successful inavoiding or minimising the drawbacks of in vivo testing, while maintainingthe benefits. It is hoped that the combined use of in vivo and in vitroapproaches will generate new breakthroughs in diabetes.

Keywords:antidiabetic drugs, diabetes, drug discovery, in vitro, in vivo, type2 diabetes

Exp. Opin. Invest. Drugs (1998)7(6):987-996

1. Introduction

In general, strategies for drug discovery have changed dramatically over therecent decade. This has been due to new developments in chemistry andbiochemistry, as well as progress in technology. On the chemistry side, themost prominent developments are combinatorial chemistry, molecularmodelling, structure-based and computer-aided design, and QSAR and 3DQSAR [1]. On the biochemistry side, great advances have been made inunderstanding the biochemical basis of many diseases and the establish-ment of molecular targets for the treatment of these diseases [2]. As ageneral trend, biological screening tests have shifted from in vivo to in vitroand from a cellular to a molecular level, in order to increase the screeningthrough-put and the specificity [1]. The antidiabetic drug discoveryapproach has progressed along the same track. There is no doubt that thischange has many advantages; however, problems and concerns with thischange also exist, especially in the field of type 2 diabetes. On the otherhand, the in vivo approach has long been used as a tool for the discovery ofantidiabetic drugs and continues to provide drug candidates for clinicaldevelopment. The intent of this article is to emphasise the benefits of the invivo antidiabetic drug discovery approach and hopefully provide somebalance to the current molecular target paradigm. In this context, thehistorical aspects of antidiabetic drugs and the advantages and disadvan-tages of the in vivo approach are revisited, and some concerns with the shiftfrom in vivo to in vitro assays are addressed. The drug discoveryprogramme at Shaman is offered as an example, illustrating the benefits ofthe in vivo approach.

9871998 © Ashley Publications Ltd. ISSN 1354-3784

Update

1. Introduction

2. Discovery history ofantidiabetic drugs

3. In vivo antidiabetic testing

4. In vitro antidiabetic testing

5. Drawbacks of in vivo andin vitro test systems

6. Outcomes of in vivo andin vitro approaches

7. In vivo antidiabetic drugdiscovery at Shaman

7.1 The Shaman programme

7.2 Outcome of Shamanprogramme

8. Expert opinion

Acknowledgement

Bibliography

http://www.ashley-pub.com

Expert Opinion on Investigational Drugs

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2. Discovery history of antidiabetic drugs

Historically, insulin and oral glucose-lowering drugswere discovered by the in vivo approach. As early as1889, animal studies confirmed that the pancreas isthe critical organ which regulates blood glucoseconcentrations [3]. This stimulated effort to isolate theactive component as a possible treatment for diabetes.After numerous failures, insulin was discovered onthe basis of a series of animal experiments by aresearch team led by Banting and Macleod in 1922 [4].The hypoglycaemic activity of sulfonylureas wasaccidentally discovered by Janbon in 1942 [5].Following the extensive work of A Loubatires usingnormal or alloxan-induced diabetic dogs, it wasdiscovered that the hypoglycaemic activity of sulfony-lureas was associated with insulin secretion inducedby these compounds [6]. Biguanides are derived fromguanidine [6]. The latter is present at high concentra-tions (up to 0.5%) in Galega officinalis, a medicinalplant that was used to ‘cure’ type 2 diabetes [7].Guanidine was discovered to possess hypoglycaemicactivity when experimentally administered to rabbits[8]. These observations eventually led to the synthesisof biguanides with reduced toxicity and improvedefficacy [9]. The newest class of antidiabeticcompounds, thiazolidinediones, were originallytested for lipid-lowering activity in Japan. It wasdiscovered in the early 1980s that this class ofcompounds had glucose-lowering activity, which ledto its development in type 2 diabetes [10]. The firstcompound in this class, troglitazone, was put on theUS market in 1997. Taking into account the limitedunderstanding of the biochemistry and physiology ofdiabetes in the early and middle 20th century, it is notsurprising that the in vivo approach dominated thediscovery of glucose-lowering agents. In any event,history shows that the in vivo approach led to thediscovery of agents that tackled different aspects oftype 2 diabetes, including insulin deficiency, hepaticglucose over-production and insulin resistance.

3. In vivo antidiabetic testing

In the absence of the biochemical or molecular basisfor a disease, animal testing using disease models isthe only basis available for drug discovery. In the earlydays, random screening of a large series of syntheticcompounds or compounds from natural sources inseveral or many different animal models was carriedout in many pharmaceutical companies [1]. Later on, a

more rational approach was adopted; compoundswere synthesised with a distinct chemical rationale(e.g., similarity to a natural substance) and screenedfor activity [11]. In fact, the first generation of sulfony-lureas and metformin stem from the latter strategy[9,12]. Type 2 diabetes is a chronic metabolicsyndrome with multifactorial causes and abnormali-ties on many organs, including pancreas, liver andperipheral tissues (muscles and fat) [13]. The in vivoapproach to discover innovative, new, and usefuldrugs uses a complete biological system that allowssimultaneous testing of a variety of mechanisms ofaction to potentially correct a disease state. Thecorrection of diabetes will likely require a drug thathas more than one mechanism of action. It is known,e.g., that the oral antidiabetic drugs, sulfonylureas,metformin and troglitazone seem to possess multiplemechanisms of action [14-16]. For type 2 diabetes, forwhich the pathophysiology is still largely unknown,use of an in vivo approach could potentially detectsubstances acting by a novel mechanism of action andmay further our understanding of the disease. Thediscovery of the thiazolidinediones is one of the mostappropriate examples of this. These drugs represent anew approach to treating type 2 diabetes, reducinginsulin resistance [17]. They were developedoriginally without any knowledge of their effects atthe molecular level. With extensive mechanisticstudies, it is now known that thiazolidinediones act asPPAR-g agonists to reduce insulin resistance [18].Meanwhile, PPAR-g has been recognised to play asignificant role in insulin resistance [18]. This is one ofthe most compelling examples of the success of the invivo approach and has had a great impact on theantidiabetic drug discovery process, and somepharmaceutical companies have started to identifyPPAR-g agonists for the treatment of type 2 diabetes.

Efficacy in animal models has to be proven before anycompound progresses into the development stage.The in vivo approach provides this informationinstantly. The in vitro to in vivo chasm for activitycould be very frustrated and is the bottleneck of the invitro drug discovery approach. Only a very smallportion of in vitro hits will be confirmed in in vivosystems. This is not surprising because, in biology, thewhole is more than the sum of its parts. More than 30years ago, Irwin S stated: “Analysis to ever-finer levelsof structure does not necessarily reveal the nature ofrelations between the parts and may actually destroythe relations. Although the dynamics and mechanismsof drug action are most readily studied in isolated

© Ashley Publications Ltd. All rights reserved. Exp. Opin. Invest. Drugs(1998)7(6)

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situations, the reliability of knowledge as a basis forclinical prediction tends to decrease as we proceedfrom the whole to isolated tissue, single functionalunits, or subcellular levels of activity” [19]. Kety SS alsostated: “We do not always get closer to the truth as weslice and homogenise and isolate” [20]. Thesestatements are still valid today and this obstacle for invitro drug discovery has yet to be overcome. Inaddition, the in vivo approach offers a variety ofinformation. For example, during the screening ofantidiabetic compounds, information on foodconsumption, body weight, body temperature, bloodlipid concentrations and general animal appearancecan be obtained in addition to blood glucose concen-trations. Monitoring the changes of body weight andfood intake as well as the appearance of the animalsmay help to distinguish specific glucose-loweringeffects from non-specific effects, e.g., reduced plasmaglucose through decreased food intake and bodyweight. Body temperature is a reflection of bodyenergy expenditure. Hypertriglyceridaemia is usuallyaccompanied by type 2 diabetes. Compounds thatexhibit both glucose and triglyceride-lowering activitywould be more beneficial for use in type 2 diabetes.These end-points are easy to obtain while at the sametime providing a more complete profile for thecompound tested.

4. In vitro antidiabetic testing

The establishment of in vitro assays dramaticallyreduces the amount of test material required forbiological testing, is less labour intensive for bothchemists and biologists, and reduced the cost for eachtest. With molecular targets, the advantages are evenmore significant since high through-put screeningassays can be established. A miniaturised assay isanother favourable trend since it provides muchhigher through-put and requires minimum amountsof test materials [21]. These developments coincidedwith the needs of combinatorial chemistry, which cangenerate huge compound libraries in a short period oftime [22]. Similarly, screening of materials from anatural source has the same requirements. Thisapproach should improve the efficiency and speed ofdrug discovery. Over the years many moleculartargets have been selected or proposed for antidia-betic drug discovery. As previously mentioned,PPAR-g is of interest because of the fact that

thiazolidinediones reduce insulin resistance, at leastpartly, by activating this receptor [23]. GlaxoWellcome is screening compounds that have highaffinity for the PPAR-g. There are at least three bigpharmaceutical companies, including Bristol-MyersSquibb, SmithKline Beecham and Eli Lilly, working onthe b-3 adrenoceptor agonist for the treatment of bothobesity and type 2 diabetes [24]. Insulin receptortyrosine phosphatase is another target of interest, withNovo Nordisk, Sugen and Kinetek looking for inhibi-tors for this enzyme. Other interesting moleculartargets include: carnitine palmitoyltransferase I(CPT-I) inhibitors (Norvartis), tumour necrosis factoralpha (TNF-a) inhibitors (T-Cell Sciences) andglucose-6-phoshatase inhibitors (Hoechst). Inaddition, there have been significant efforts to identifygenes and regulators of gene expression that arethought to play a role in type 2 diabetes, and whichserve as new targets for drug discovery [25].

5. Drawbacks of in vivo and in vitro testsystems

Both in vivo and in vitro approaches have theirdrawbacks. For in vivo testing, the most significant isthe requirement for a large quantity of test material.This is an obvious obstacle for combinatorialchemistry and some natural sources to providesufficient test materials. Labour-intensive methodsand low through-put are among the disadvantages.Obviously, using this approach to screen randomlyselected compounds from large chemical librariesfaces significant challenges, namely, low hit rate andthe financial burden. In addition, the compoundsdiscovered by the in vivo approach may not have thespecific mechanisms of action that the investigatordesired or preferred. The current in vitro testsovercome the drawbacks that in vivo tests have.However, in vitro testing fails to provide what an invivo test can, namely, treatment novelty, instant invivo activity, and a variety of in vivo information. Inaddition, there are concerns with the relevance of asingle in vitro mechanistic assay to discovertreatments for type 2 diabetes. The in vitro discoveryapproach relies on the understanding of thebiochemical basis of a disease. Type 2 diabetes is achronic metabolic syndrome, characterised by insulinresistance and relative insulin deficiency [26]. Despitegreat advances in the understanding of the

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pathophysiology of the disease, the mechanisms formany of the underlying defects are unknown andneed to be defined [26]. Although controversycontinues to exist [27,28], there is considerableevidence that insulin resistance develops beforerelative insulin deficiency ensues [29-31]. As a result,great efforts have been devoted to the study of thepathophysiology of insulin action. Although far fromcomplete, the current understanding of normal insulinaction is illustrated in Figure 1 [32]. In patients withtype 2 diabetes, there are several independent defectsin the process of insulin action. For example, theinsulin-stimulated tyrosine kinase (IRTK) of theb-subunit is markedly altered [33] and the insulinstimulation of both insulin receptor substrate 1 (IRS-1)and phosphatidylinositol 3¢-kinase (PI3K) activitiesare reduced [34]. In addition, other signallingabnormalities, e.g., G-protein, exist in type 2 diabetes[35]. In other words, there are multiple independentpathophysiological defects at the molecular level inthe process of insulin action. Other molecular aspectsrelated to the liver and pancreas also contribute to thepathophysiology of type 2 diabetes [36]. Furthermore,the knowledge base for an in vitro mechanistic assay

could be easily challenged by new and clinicallyrelevant information generated in this largelyunknown field [12]. The development of b3 adreno-ceptor agonists serves as an example. The first-timesynthesis of a b3-adrenoceptor agonist was more thana decade ago. Those that have been taken forward toclinical trials had either limited efficacy or significantside-effects. The fundamental problem is that thereare a low number of b3-adrenoceptors relative to b1-and b2-adrenoceptors in those tissues mediatingthermogenesis in humans [37].

6. Outcomes ofin vivo and in vitroapproaches

A successful discovery approach should lead to theidentification of lead chemical entities and shouldultimately be judged by the number of compoundsthat reach the patient population as approved drugs. Itis difficult to obtain a discovery history of eachcompound under clinical development. However,compounds with specific molecular targets orunknown cellular or molecular mechanisms can be

© Ashley Publications Ltd. All rights reserved. Exp. Opin. Invest. Drugs(1998)7(6)

990 In vivo antidiabetic drug discovery

Figure 1: Molecules known to be involved in action of insulin. Adapted from [32].

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identified. Clearly, for glucose lowering, there are nocompounds with specific molecular targets on themarket yet. Etomoxir, a carnitine palmitoyltransferaseinhibitor [38], is in Phase II clinical trials. It is the mostadvanced candidate among a few compounds inclinical development, acting against specific, knownmolecular targets. Compounds with more attractivemolecular targets, e.g., PPAR-g, TNF-a and insulintyrosine phosphatase are still in the preclinical stages.In contrast, in vivo approaches have led to thediscovery of approved drugs, such as insulin, sulfony-lureas, biguanides and thiazolidinediones.Furthermore, there are several compounds presentlyin clinical development, whose in vivo activities werereported before in vitro studies were. BTS-67582(Knoll) is in Phase II clinical trials; it was originallydescribed as a hypoglycaemic agent, stimulatinginsulin secretion. Later studies revealed the blockadeof ATP-sensitive potassium channel activity via adifferent binding site to that of glibenclamide [39].JTT-501 (Japan Tobacco) is also in Phase II clinicaltrials. It acts as an insulin sensitiser and decreasesplasma glucose, insulin and triglyceride in animalmodels of type 2 diabetes. SP-134101 (Shaman) willbe discussed below.

Clearly, in vivo approaches still play an important rolein the drug discovery process. This can be explainedby the fact that the history of using of moleculartargets for drug discovery is still very short ascompared to the in vivo approach.

7. In vivo antidiabetic drug discovery atShaman

The in vivo approach has steadily providedcompound leads and resulted in approved drugs.However, the use of in vivo testing to screen largenumbers of randomly selected compounds can nolonger be justified. Shaman’s approach of focusedscreening has been successful in avoiding orminimising the drawbacks of in vivo testing, whilemaintaining the benefits [40,41].

7.1 The Shaman programme

The hit rate or number of hits that can be generatedwithin a period of time is crucial in a drug discoveryprogramme. There are at least two ways to insure anadequate rate. One is to increase the through-put ofthe screening, which is the current mainstreammethod. The other is to select compound sources thatare likely to give high hit rates. The latter is theShaman approach. In the case of Shaman’s diabetesdrug discovery programme, only plants beingindicated for the treatment of diabetes or plantsmeeting Shaman’s internal selection criteria arechosen. The selection gives a highly focused source ofscreening materials, while maintaining great chemicaldiversity. Since the number of compounds or extractsto be screened is dramatically reduced, the lowthrough-put nature of the in vivo assay is less relevant.

© Ashley Publications Ltd. All rights reserved. Exp. Opin. Invest. Drugs(1998)7(6)

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Figure 2: Shaman antidiabetic drug discovery approach.

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As part of the efforts to minimise the drawbacks of thein vivo approach, mouse models were chosen inconsideration of test material needs, and housing andhandling requirements. In fact, there are severalstrains of mice, e.g., ob/ob, db/db and yellow KK, thatare generally accepted as models of type 2 diabetes[42]. These models have been used extensively fordrug discovery purposes, although they are not ideal.For example, the extreme degree of obesity, hyperin-sulinaemia and genetic defects is not typical inpatients with type 2 diabetes [42,43]. It is critical thatthe animal model represents the human disease asclosely as possible, including responses to currentlyavailable antidiabetic drugs. There are, however,non-genetic mouse models of type 2 diabetes that areinduced by feeding diets enriched in fat or fructosethen injecting small doses of streptozotocin (STZ) [44].These mouse models are more likely to simulatehuman disease and are less expensive.

Figure 2 illustrates the Shaman antidiabetic drugdiscovery approach. The first step is the identificationand collection of plants indicated for the treatment ofdiabetes. This is followed by the use of an appropriateanimal model to screen plant extracts and guide theactive compound isolation from active plant extracts.The active compounds serve as leads for preclinicaland clinical development or are subjected to syntheticmodification, leading to the generation of new leads.The latter is assisted with in vivo testing.

7.2 Outcome of Shaman programme

In Shaman’s programme, 45.7% of the plants screenedto date were active for glucose lowering. Clearly, thehit rate of this compound source is high. Moreimportantly, the hit rate has been quite consistent,indicating that the quality of the plants collected overtime has been maintained. Select active plants havebeen subjected to active compound isolation andmore than 20 series of patentable, orally activecompounds have been isolated. These compoundsare chemically distinct from each other and differ fromthe currently available oral antidiabetic agents. Someof them are known compounds, while others are newchemical entities. Limited studies of the mechanismsof action with a few of these compounds indicate thatthey may possess a variety of mechanisms of action,e.g., reduce insulin resistance, mimic the insulin effectand decrease liver glucose output. Many of thesecompounds have been selected as leads for furtherdevelopment. One of the most advanced compounds,SP-134101 (masoprocol), is in a Phase I clinical trial.The compound is isolated from the creosote bush,concoctions of which have long been used by nativeAmericans in southwestern North America as aremedy to type 2 diabetes. Oral administration ofSP-134101 to db/db and ob/ob mice significantlyreduced plasma glucose concentrations and accentu-ated the ability of insulin to lower plasma glucoseconcentrations (Figure 3 and Figure 4)[45]. In fat-fedSTZ-injected rats, which are insulin resistant,

© Ashley Publications Ltd. All rights reserved. Exp. Opin. Invest. Drugs(1998)7(6)

992 In vivo antidiabetic drug discovery

Figure 3: Plasma glucose concentrations indb/dbmice receiving either vehicle or masoprocol orally over a 12 day treatment period.

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hyperglycaemic, and hypertriglyceridaemic, oralSP-134101 significantly lowered plasma glucose,triglyceride and free fatty acid concentrations.Insulin-mediated glucose disposal, as assessed by thesteady state plasma glucose concentration during aconstant glucose/insulin infusion, improved by 30%.Plasma insulin concentrations did not change withSP-134101 treatment. Studies in isolated adipocytesshowed that SP-134101 enhanced glucose disposal (inthe presence or absence of insulin) and inhibitedisoproterenol-stimulated lipolysis [unpublished data].These data demonstrate that SP-134101 lowers bothplasma glucose and triglyceride concentrations,presumably as a result of its ability to both increaseglucose disposal and decrease lipolysis. It is a uniquecompound.

The other aspect of the drug discovery programme isthe synthetic modification of active compoundsisolated from plants, with the aim of improvingefficacy and potency, minimising toxicity. Takingadvantage of the structure template, this compoundsource also gives high hit rates. Many leads have beenidentified and two of the leads are under considera-tion for development.

8. Expert opinion

As reported in The World Health Report 1997 [46], thenumber of diabetic patients is estimated to be about135 million and this number is expected to rise toalmost 300 million by the year 2025. While the rise incases will exceed 40% in developed countries, it willbe on the order of 170% in developing countries. Theepidemic of diabetes is attributed to populationageing, unhealthy diets, obesity and a sedentarylifestyle, which are mainly the outcome of improvedeconomic condition and urbanisation. Among all thediabetic patients, 90 - 95% of them are type 2diabetics. This disease is one of the most dauntingchallenges posed by a chronic disease, since it resultsin many severe complications, e.g., heart disease,stroke, hypertension, blindness and kidney failure[47]. Despite four classes of oral antidiabetic agentsavailable for the treatment of type 2 diabetes, there is agreat need for better drugs [48-51].

Using molecular targets as a means to discoverantidiabetic drugs is an exciting approach, since itpromises accelerated drug discovery [52]. There is notyet enough information to judge the success or failureof this approach, since most of the compounds are in

© Ashley Publications Ltd. All rights reserved. Exp. Opin. Invest. Drugs(1998)7(6)

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Figure 4: Plasma glucose clearance following insulin (0.5 U/kg iv.) administration in vehicle and masoprocol treateddb/dbmice(n = 5).

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the early development stage. It is an approach worthexploring and is likely to result in new treatments fortype 2 diabetes. However, this approach bears a greatrisk of failure because the biomedical basis of type 2diabetes is still largely unknown; multiple andindependent molecular defects exist in the process ofinsulin action [27] and most of these molecular targetsawait clinical validation. Secondly, the approach maynot be able to provide what it promises: increasedefficiency and speed of drug discovery. This isbecause there has in general been a steady decline inthe number of drugs introduced into human therapy[1,53], despite the fact that fundamental biomedicalknowledge has grown greatly in the last three decadesand the pharmaceutical industry has applied thisknowledge and the techniques of molecular andcellular biology to the drug discovery process [53].Whether it is true or not, Persson attributed this drugdiscovery slow down to a failure in understanding theimportance of exploratory in vivo approaches in drugdiscovery [54]. Nowadays, the pharmaceuticalindustry reacts very fast to new developments,especially those that help to cut down costs [51].However, one should not sacrifice the biochemicalprinciple (validity of biological testing) to accommo-date the new developments in technology. Newtechnologies should be integrated into the drugdiscovery process. Shaman’s approach does not relyon any sophisticated new technologies, however,new developments or technologies could be used tomake the process more efficient.

Certainly, all the different approaches used indiabetes drug discovery are worth considering. It islikely that in vivo approaches will continue to play arole in antidiabetic drug discovery, and the in vivoapproach together with in vitro testing will generatemagic bullets for diabetes.

Acknowledgement

The author would like to thank Dr Richard F Hectorfor his critical comments and suggestions.

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Papers of special note have been highlighted as:• of interest•• of considerable interest

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• Comprehensive review on drug discovery strategies andnew technologies

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3. MACFARLANE IA: The millennia before insulin. In : Text-book of Diabetes. Pickup J, Williams G (Ed.), Blackwell Sci-entific Publications, London, UK (1991):3-9.

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• Interesting discussion on approaches to drug discovery

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Jian LuoShaman Pharmaceuticals, Inc. 3 East Grand Avenue, South SanFrancisco, CA 94080-4812, USA(Tel: +1 415 952 7070; Fax: +1 415 873 8377)

© Ashley Publications Ltd. All rights reserved. Exp. Opin. Invest. Drugs(1998)7(6)

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