Zoektocht naar innovatieve geneesmiddelen voor de toekomst - Verslaving en ander gedrag in moleculair perspectief Prof. dr. Chris Kruse Swammerdam Institute, UvA Solvay Pharmaceuticals
Drug Discovery Assets Successful drug research relies on: innovative high quality compounds acting on disease relevant targets
Targets and Compounds What is a target? a (big) molecular entity inside the body interacting with a compound What is a compound? a (small) molecule interacting with a target
How to find Compounds? screening of hundreds of thousands of compounds design based upon: structures of known ligands structure of target protein (if available)
Discovery of ovel asses of Selective CB 1 Receptor Antagonists Chris Kruse Jos Lange Hein Coolen Arnoud Herremans
Chronology Use of Cannabis sativa for ~ 40 centuries medicinal/recreational purposes Discovery of active ingredient 9-THC 1964, Mechoulam et al. oning of CB 1 receptor 1990, Matsuda et al. Discovery of anandamide 1992, Mechoulam et al.
Locations of CB 1 -Receptors Substantia igra Globus Pallidus Caudate ucleus Putamen Basal Ganglia Amygdala Hippocampus Limbic System Hypothalamus Cerebral Cortex
Endocannabinoids Endogenous cannabinoid ligands: Fatty acid derivatives? Anandamide (AEA) 2-Arachidonyl glycerol oladin ether (porcine) Virodhamine ADA H H H H H H H 2 H H H Anandamide (1992) 2-Arachidonylglycerol (1995) oladin ether (2001) Virodhamine (2002) ADA (2002) Endocannabinoid signaling is altered in neurological, psychiatric, cardiovascular, gastrointestinal, reproductive and eating disorders and cancer Vandevoorde and Lambert, Curr. Pharm. Des. 2005, 11, 2647-2668 DiMarzo et al., BJP 141, 765 (2004) Lambert and Fowler, J. Med. Chem. 2005, 48, 5059-5087 Piomelli, at. Med. 10, 19 (2004) Di Marzo et al., at Rev. Drug Discov. 3, 771-784, 2004 Rodriguez de Fonseca, Alcohol Alcoholism 2005, 40, 2-14
CB1 antagonists: Potential Therapeutic Applications besity Addiction / smoking cessation Cognitive and memory disorders
Cannabinoids and feeding Endogenous cannabinoids Play a role in the natural reward pathways of the brain Modulation of the appetitive value of food: Mediation of behavioral, food searching effects Affect energy homeostasis Central: Leptin, CRH, MC 4, PY, others? Peripheral: lipogenic mechanisms, involved in FA oxidation? H! 9 -THC (Tetrahydrocannabinol) Consequently CB 1 agonists are useful for appetite stimulation Whereas The CB 1 antagonist rimonabant showed clinical efficacy in obesity / metabolic syndrome H Boyd and Fremming, Ann. Pharmacother. 2005, 39, 684-690 Fernandez and Allison, Curr. pin. Investig. Drugs 2004, 5, 430-435 Carai, Life Sc. 2005, 77, 2339-2350 Cox, Drugs Today 2005, 41 499-508 Rimonabant
CB 1 antagonists: Level of competitive R&D umber of patent applications 40 35 30 25 20 15 10 5 0 The yearly number of patents wherein CB 1 receptor antagonists have been claimed is increasing 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 Year Lange and Kruse, Drug Discov. Today 10, 693-702 (2005)
Examples of CB 1 receptor antagonists H Rimonabant (SR141716A) C C CP-272871 Review: Lange and Kruse, Curr. pin. Drug Discovery Dev. 2004, 7(4), 498-506 H LY-320135
Rimonabant blocks relapse Extinction of lever pressing for cocaine reward Reinstatement by reward associated stimuli Attenuated by Rimonabant (De Vries et al, 2001, nature med, 7, 1151-1154)
Rimonabant improves memory retention social recognition Rimonabant 70 0.7 investigation time (sec) 60 50 40 30 20 10 * * 0.6 0.5 0.4 0.3 0.2 0.1 recognition index First contact Second contact Recognition index (second/first) 0 0 0 1 3 10 Rimonabant (mg/kg po)
Lead Finding Strategies I. Conformationally Constrained Analogues of Rimonabant Lange et al. Chem. Pharm. Bull. 50, 1109 (2002) II. Bioisosteric Scaffolds. Analogues of Rimonabant Lange et al. J. Med. Chem. 48, 1823 (2005) III. Screening Lange et al., J. Med. Chem. 47, 627 (2004) Start research program in 1996
I. Conformationally Constrained Analogues H H Rimonabant (SR-141716A) = or Stoit et al., Chem. Pharm. Bull. 50, 1109 (2002); Ruiu et al., J. Pharmacol. Exp. Ther. 306, 363 (2003); ibid., Bioorg. Med. Chem. 13, 3309 (2005) Adam et al., Progress Med. Chem. 44, 2006, 207-329, Eds. King and Lawton.
II. Bioisosteric Scaffolds Replace central pyrazole moiety in rimonabant by other fivemembered ring heterocycles S H Thiazole bioisostere H H Rimonabant Imidazole bioisostere H Triazole bioisostere
Key compounds / In vivo results R BP TEMP H R (mg/kg/po) ED 50 (mg/kg, po) LED H 12 >30 H CH 3 2.4 10 C 2 H 5 16 30 ------------------------------------------ Rimonabant Rimonabant 5.5 3
III. Screening Limited set of compounds initially screened (~6000) ne relevant hit found: DU 513092 Source: Diversity library from stock (CADD) H 2 S Pharmacological activity DU 513092: DU513092 Moderately active in vitro as CB 1 antagonist But: completely inactive in vivo
Screening (2) bjectives Lead ptimization Improve pharmacodynamics * low nm range Improve pharmacokinetics * assure oral bioavailability
Lead optimisation program Ar 1 Ar 2 R4 S R3 R5 R1 R2 Ca. 950 compounds synthesized ~50/50 singles/libraries Result: Several compounds with CC potential
SLV326 and Rimonabant HCH 3 S H R R= CF 3 SLV326 Rimonabant
Pharmacological key results SLV 326 is also active in relapse models for cocaine, nicotine and alcohol
Receptor-docking alignment rimonabant
Protein model of CB1 receptor with antagonist
Conclusions Three independent approaches led to in vitro potent and selective CB 1 receptor antagonists Conformationally constrained rimonabant analogues showed poor Pharmacokinetic properties Scaffold exchange in rimonabant (1,5-pyrazole 1,2- imidazole) resulted in a bioisosteric analogue, both in Pharmacodinamic as in Pharmacokinetic Limited screening resulted in a lead from company stock; lead optimization offered several clinical candidates