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SAT-5-1 An overview of CNS drug discovery at Eli Lilly and Company
254 was significantly higher with imipramme than with venlafaxme begmmng at the first week of therapy(Shrivastava el al, 1994) Dose-related side effects included headache, insomnia, nausea somnolence, dry mouth, and sexual dysfunction (Danjeu and Hackett, 1995) Interestingly. in the study of Benkert and associates (1994), the incidence of adverse effects remained low and relatively constant throughout the study despite rapid dosage escalation, and f e w patients discontinued for adverse effects. In dose4itration studies, the incidence of side effects markedly de creased when the venlafaxine dosage was reduced to maintenance levels A small, but significant rise in blood pressure occurred with venlafaxme in clinical trials, most o{ten at doses above 200 mg daily, but hypertensive patients were not at increased risk for elevated blood pressure. At the usual venlafaxine dose of 75 mg gFve twbce daily, clinically significant blood pressure changes occurred with a similar frequency as with placebo Overdose have been reported in 14 of over 3.000 patients administered venlafaxine in clinical trials The maximum amount of venlafaxine ingested at one time was 6.75 g. Overdoses of veniafaxme induced mainly drowsiness and lethargy, In one patient, 2.75 g of venlafaxine that was ingested together with thyroxine (05 mg) and naproxen(lO g). The patient experienced generalized convulsions and coma but recovered fully with supportive measures No deaths have been reported following venlafaxine overdoses.
References Benkert O, Hackett D, Realini R, et al A randomlsed, double-bhnd comparison of a rapidly escalating dose of venlafax~neand imlpramme m inpatients with malor depression and melancholia (abstract)Neuropsychopharmacology 1994; 10(supplL 165S Daniou R Hackett D Safety and tolerance profile of venlafaxine Int Clin Psychopharmacol 1995;10(suppl 2):15-20 Dierick M, Martin A, Ravizza L, Realmi R A double-blind comparison el venlafaxIne and fluoxetine for treatment of malor depression pn outpatients Prog NeuroPsychopharmaco11995 (in press) Nierenberg A, Feighner JR Rudolph R, et al Venlafaxmelot treatment-resistant unrpolar depression J Clm Psychopharmaco11994;14 419-423 Rudolph R. Entsuah R. Denvan A A low relapse rate confirms the long-term efficacy of venlafaxine in the treatment of major depression labstract} Neuropsychopharmacology 1994;10{suppl) 105 Scnweizer E, Feighner J. Mandos L. Rickels K Comparison o1 venlafaxins and ~mipramme in the acute treatment of major depression in outpatients J Clin Psychatry 1994;55:104-108 Shrivastava R. Cohn C, Crowder J. et al Long-term safety and clinical acceDtabdnv of venlafaxine and imlpramine in outpatients with major depresston J Clin Psychopharmaco1194;14:322 329
SAT-5 Lilly: Advancing CNS research into the twenty-first century I SAT-5-1 I An overview of CNS drug discovery at Eli Lilly and Company S.M. Paul Lilly Research Laboratories, Eli lJ//y and Company, /ndlanapo#s, /ndiana 46285 Revolutionary advances in the neurosclences which have occurred over the past decade make it an extremely opportune time to be discovering drugs for treating a variety of CNS disorders The coalescence of a num ber of scientific disciplines - - ranging from molecular biology and genet,cs to structural biology and combinatorial chem stry - - has resulted in an un. precedented research environment for CNS drug discovery At Lrrly, we have integrated our medicinal chemistry and neurobielogy expertise in :he put suit of drug candidates for a variety of different neuropsychiatric d sorders InterdiscJphnary groups of scientFsts thematically linked (by target) work together to discover potential drugcandicates The more recentimplemen tation of combinatoria} chemistry and h gn t~'roughput (robotic) screening has greatly enhanced "lead generation" -.- and shortened the time to de lineating an actual drug candidate. A closely aligned group of clmrcal investigators (our Decision Phase Medical group) carry out innovative chmcal s t u d i e s - - ranging from Phase I I B ("proof of concept") through Phase il rnvestrgations. The close working relationship between our discovery sclentrsts and clinical investigators has proven Invaluable. A general descnpt,orof the various research efforts lby Actron Group) will be presented, a!oqg with some representative examples of recent scientific accomplishments that have resulted (or will result) in innovative CNS drugs An overview o+ our CNS drug pipeline, including our Phase II and Phase III compounes, wdl also be presented
SAT-5 Lilly:Advancing CNS research into the twenty-first century
discovery and pharmacology of xanomeline, ISAT-5-21 The a muscarinic M1 receptor agomst for Alzheimer's disease
H.E Shannon, F.R Bymaster, D.O. Calligaro, N.W. DeLapp, C.H. Mitch, J.S Ward, R Olesen, M.J. Sheardown. M.D.B. Swedberg, R Sauerberg.
Lilly Research Laboratones, Eli Lffly and Company, indianapolis, IN U.S,A and Nero Nordisk, Pharmaceuticals Division, Drug Discove~ M~/ov, Denmark A substantial body of evidence suggests that an M1 receptor agonist might provide neurotransmitter rel31acement therapy in Alzheimer's disease. Xanomeline is a potent and selective muscarinic cholinergic M1 receptor agonist which crosses the blood-brain barrier and is orally bioavailable. As such, xanomeline may have therapeutic utility in Alzheimer's disease. Xanomeline has high affinity for M1 receptors (ICso = 7 nM) as measured by inhibition of [3H]-pirenzepine binding in hippocampal and conical membranes. Xanomeline also has high affinity for inhibiting the binding of the muscarinic agonist [3H]-oxotremorine-M (IC50 = 3 nM), but is 10-to 20-fold less potent in inhibiting [3H]-QNB binding (IC50 = 70 nM) at M2 receptors in brain stem and forebrain membranes, Xanometine does not interact appreciably with other receptors at concentrations well in excess of those required for M1 receptor occupancy. Thus, in receptor binding studies, Xanomeline shows a high degree of specificity for muscarinic M1 receptors Results in isolated tissue preparations support the specificity of Xanomeline for M1 receptors in functional assays, At M1 receptors in the rabbit vas deferens, Xanomeline had an EC50 of 0.008 nM. In the guinea pig atria, which contains only M2 receptors, Xanomeline produced a negative motrop~c response, but with an ECs0 of approximately 5 #M. At M3 receptors in the guinea pig bladder, Xanomeline was without appreciable agonist or antagonist activity at concentrations up to 10 /zM. In the guinea pig ileum, which contains multiple muscarinic receptor subtypes, Xanomeline had an EC50 of 71 nM. Thus, Xanometine exhibited a very high degree of specificity for M1 muscarinic receptors m isolated tissue preparations. Xanomeline also was selective for M1 receptors in cultured cells. Xanomeline increased phosphoinositoJ (PI) hydrolysis in three cell lines expressing human ml receptors, CHO, A9L and BHK, with EC50 values of 0004 /zM, 0,2 /zM and 20 /zM. respectively. The maximal stimulation of PI hydrolysis produced by Xanomeline, expressed as percent of the effect produced by the nonselective agonist ca rbachol, was 100%. 55% and 70% in CHO, A9L and BHK cells, respectively. Moreover, xanomeline increases APPs secretion from CHO cells, and is 1000-fold more potent than carbachol n this regard. Although Xanomeline also is an agonist at other muscarinic receptors in cloned cells, its rank order of efficacies is ml > m5 > m4 >_ m2 > m3. The effects of XanomeJine on neurochemical parameters in rat brain prowde m vivo evidence for its M1 specificity Xanomeline increased DOPAC levels in rat striatum to as much as 165% of control, presumably by acting at M1 heteroreceptors on dopamine neurons. Moreover, the ex v/re inhioltion of [3H]-pirenzepine binding in brain tissue after oral administration of Xanemeline closely paralleled the changes in DOPAC levels. In con:rast, Xanomeline produced only modest increases in acetylcholine levels m striatum which were of short duration (<1 hour). Thus, as measured by neurochemical parameters, Xanomeline is a selective, orally available M1 agonlst in vJvo. Taken together, these data indicate that xanomeline is a potent and se,ectwe M1 receptor agonist, and as such it may have therapeutic utility in AJzheimer's disease. Xanomeline is currently in Phase tl clinical trials.
i
Xanomeline in mild and moderate Alzheimer's ISAT-5-31 disease; the effects of a novel M1 agonist on I
behavior
Ned C Bodick, Walter Often. Lilly Research Laboraton'es, Eh' Lilly and
Company, b/ly Corporate Center, indianapolis, iN 46285, USA The clinical relevance of behaviors in Alzheimer's Disease is increasingly recognized in the literature (Teri et al., 1992). Disruptive psychotic symptoms are a significant source of stress and burden for the caregiver (Mohr et al., 1993), and aggressive behavior is reported to be the major reason for institutionalization (Ferbs et al., 1985). Previous studies indicate that a modest improvement in psychotic behavior results in a substantial improvement m functionality and quality of life (Ferris et al., 1985). Amelioration of psychotic symptoms may defer institutionalization and reduce its substantial economic consequence, yet behavioral demise has largely been ignored in experimental therapy and drag development (Mohr et al., 1993).
References Benkert O, Hackett D, Realini R, et al A randomlsed, double-bhnd comparison of a rapidly escalating dose of venlafax~neand imlpramme m inpatients with malor depression and melancholia (abstract)Neuropsychopharmacology 1994; 10(supplL 165S Daniou R Hackett D Safety and tolerance profile of venlafaxine Int Clin Psychopharmacol 1995;10(suppl 2):15-20 Dierick M, Martin A, Ravizza L, Realmi R A double-blind comparison el venlafaxIne and fluoxetine for treatment of malor depression pn outpatients Prog NeuroPsychopharmaco11995 (in press) Nierenberg A, Feighner JR Rudolph R, et al Venlafaxmelot treatment-resistant unrpolar depression J Clm Psychopharmaco11994;14 419-423 Rudolph R. Entsuah R. Denvan A A low relapse rate confirms the long-term efficacy of venlafaxine in the treatment of major depression labstract} Neuropsychopharmacology 1994;10{suppl) 105 Scnweizer E, Feighner J. Mandos L. Rickels K Comparison o1 venlafaxins and ~mipramme in the acute treatment of major depression in outpatients J Clin Psychatry 1994;55:104-108 Shrivastava R. Cohn C, Crowder J. et al Long-term safety and clinical acceDtabdnv of venlafaxine and imlpramine in outpatients with major depresston J Clin Psychopharmaco1194;14:322 329
SAT-5 Lilly: Advancing CNS research into the twenty-first century I SAT-5-1 I An overview of CNS drug discovery at Eli Lilly and Company S.M. Paul Lilly Research Laboratories, Eli lJ//y and Company, /ndlanapo#s, /ndiana 46285 Revolutionary advances in the neurosclences which have occurred over the past decade make it an extremely opportune time to be discovering drugs for treating a variety of CNS disorders The coalescence of a num ber of scientific disciplines - - ranging from molecular biology and genet,cs to structural biology and combinatorial chem stry - - has resulted in an un. precedented research environment for CNS drug discovery At Lrrly, we have integrated our medicinal chemistry and neurobielogy expertise in :he put suit of drug candidates for a variety of different neuropsychiatric d sorders InterdiscJphnary groups of scientFsts thematically linked (by target) work together to discover potential drugcandicates The more recentimplemen tation of combinatoria} chemistry and h gn t~'roughput (robotic) screening has greatly enhanced "lead generation" -.- and shortened the time to de lineating an actual drug candidate. A closely aligned group of clmrcal investigators (our Decision Phase Medical group) carry out innovative chmcal s t u d i e s - - ranging from Phase I I B ("proof of concept") through Phase il rnvestrgations. The close working relationship between our discovery sclentrsts and clinical investigators has proven Invaluable. A general descnpt,orof the various research efforts lby Actron Group) will be presented, a!oqg with some representative examples of recent scientific accomplishments that have resulted (or will result) in innovative CNS drugs An overview o+ our CNS drug pipeline, including our Phase II and Phase III compounes, wdl also be presented
SAT-5 Lilly:Advancing CNS research into the twenty-first century
discovery and pharmacology of xanomeline, ISAT-5-21 The a muscarinic M1 receptor agomst for Alzheimer's disease
H.E Shannon, F.R Bymaster, D.O. Calligaro, N.W. DeLapp, C.H. Mitch, J.S Ward, R Olesen, M.J. Sheardown. M.D.B. Swedberg, R Sauerberg.
Lilly Research Laboratones, Eli Lffly and Company, indianapolis, IN U.S,A and Nero Nordisk, Pharmaceuticals Division, Drug Discove~ M~/ov, Denmark A substantial body of evidence suggests that an M1 receptor agonist might provide neurotransmitter rel31acement therapy in Alzheimer's disease. Xanomeline is a potent and selective muscarinic cholinergic M1 receptor agonist which crosses the blood-brain barrier and is orally bioavailable. As such, xanomeline may have therapeutic utility in Alzheimer's disease. Xanomeline has high affinity for M1 receptors (ICso = 7 nM) as measured by inhibition of [3H]-pirenzepine binding in hippocampal and conical membranes. Xanomeline also has high affinity for inhibiting the binding of the muscarinic agonist [3H]-oxotremorine-M (IC50 = 3 nM), but is 10-to 20-fold less potent in inhibiting [3H]-QNB binding (IC50 = 70 nM) at M2 receptors in brain stem and forebrain membranes, Xanometine does not interact appreciably with other receptors at concentrations well in excess of those required for M1 receptor occupancy. Thus, in receptor binding studies, Xanomeline shows a high degree of specificity for muscarinic M1 receptors Results in isolated tissue preparations support the specificity of Xanomeline for M1 receptors in functional assays, At M1 receptors in the rabbit vas deferens, Xanomeline had an EC50 of 0.008 nM. In the guinea pig atria, which contains only M2 receptors, Xanomeline produced a negative motrop~c response, but with an ECs0 of approximately 5 #M. At M3 receptors in the guinea pig bladder, Xanomeline was without appreciable agonist or antagonist activity at concentrations up to 10 /zM. In the guinea pig ileum, which contains multiple muscarinic receptor subtypes, Xanomeline had an EC50 of 71 nM. Thus, Xanometine exhibited a very high degree of specificity for M1 muscarinic receptors m isolated tissue preparations. Xanomeline also was selective for M1 receptors in cultured cells. Xanomeline increased phosphoinositoJ (PI) hydrolysis in three cell lines expressing human ml receptors, CHO, A9L and BHK, with EC50 values of 0004 /zM, 0,2 /zM and 20 /zM. respectively. The maximal stimulation of PI hydrolysis produced by Xanomeline, expressed as percent of the effect produced by the nonselective agonist ca rbachol, was 100%. 55% and 70% in CHO, A9L and BHK cells, respectively. Moreover, xanomeline increases APPs secretion from CHO cells, and is 1000-fold more potent than carbachol n this regard. Although Xanomeline also is an agonist at other muscarinic receptors in cloned cells, its rank order of efficacies is ml > m5 > m4 >_ m2 > m3. The effects of XanomeJine on neurochemical parameters in rat brain prowde m vivo evidence for its M1 specificity Xanomeline increased DOPAC levels in rat striatum to as much as 165% of control, presumably by acting at M1 heteroreceptors on dopamine neurons. Moreover, the ex v/re inhioltion of [3H]-pirenzepine binding in brain tissue after oral administration of Xanemeline closely paralleled the changes in DOPAC levels. In con:rast, Xanomeline produced only modest increases in acetylcholine levels m striatum which were of short duration (<1 hour). Thus, as measured by neurochemical parameters, Xanomeline is a selective, orally available M1 agonlst in vJvo. Taken together, these data indicate that xanomeline is a potent and se,ectwe M1 receptor agonist, and as such it may have therapeutic utility in AJzheimer's disease. Xanomeline is currently in Phase tl clinical trials.
i
Xanomeline in mild and moderate Alzheimer's ISAT-5-31 disease; the effects of a novel M1 agonist on I
behavior
Ned C Bodick, Walter Often. Lilly Research Laboraton'es, Eh' Lilly and
Company, b/ly Corporate Center, indianapolis, iN 46285, USA The clinical relevance of behaviors in Alzheimer's Disease is increasingly recognized in the literature (Teri et al., 1992). Disruptive psychotic symptoms are a significant source of stress and burden for the caregiver (Mohr et al., 1993), and aggressive behavior is reported to be the major reason for institutionalization (Ferbs et al., 1985). Previous studies indicate that a modest improvement in psychotic behavior results in a substantial improvement m functionality and quality of life (Ferris et al., 1985). Amelioration of psychotic symptoms may defer institutionalization and reduce its substantial economic consequence, yet behavioral demise has largely been ignored in experimental therapy and drag development (Mohr et al., 1993).