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Discovery of Novel Imidazolines and Imidazoles As Selective TAAR1

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Discovery of Novel Imidazolines and Imidazoles As Selective TAAR1 Discovery of Novel Imidazolines and Imidazoles as Selective TAAR1 Partial Agonists for the Treatment of Psychiatric Disorders Giuseppe Cecere, pRED, Discovery Chemistry F. Hoffmann-La Roche AG, Basel, Switzerland Biological Rationale Trace amines are known for four decades Trace Amines - phenylethylamine p- tyramine p- octopamine tryptamine (PEA) Biogenic Amines dopamine norepinephrine serotonin ( DA) (NE) (5-HT) • Structurally related to classical biogenic amine neurotransmitters (DA, NE, 5-HT) • Co-localised & released with biogenic amines in same cells and vesicles • Low concentrations in CNS, rapidly catabolized by monoamine oxidase (MAO) • Dysregulation linked to psychiatric disorders such as schizophrenia & 2 depression Trace Amines Metabolism 3 Biological Rationale Trace Amine-Associated Receptors (TAARs) p-Tyramine extracellular TAAR1 Discrete family of GPCR’s Subtypes TAAR1-TAAR9 known intracellular Gs Structural similarity with the rhodopsin and adrenergic receptor superfamily adenylate Activation of the TAAR1 cyclase receptor leads to cAMP elevation of intracellular cAMP levels • First discovered in 2001 (Borowsky & Bunzow); characterised and classified at Roche in 2004 • Trace amines are endogenous ligands of TAAR1 • TAAR1 is expressed throughout the limbic and monoaminergic system in the brain Borowsky, B. et al., PNAS 2001, 98, 8966; Bunzow, J. R. et al., Mol. Pharmacol. 2001, 60, 1181. Lindemann L, Hoener MC, Trends Pharmacol Sci 2005, 26, 274. 4 Biological Rationale Electrical activity of dopaminergic neurons + p-tyramine Roche TAAR1 KO mice Increased firing rate of The TAAR1 agonist dopaminergic neurons of TAAR1 downregulates dopaminergic KO mice neurotransmission in neurons from WT but not from KO mice Working hypothesis based on electrophysiology and behavioral effects of cmpds in rodents -TAAR1 is a negative modulator of dopaminergic neurotransmission -TAAR1 full agonist lowers DA if is too high ( schizophrenia) -TAAR1 partial agonist / antagonist raises DA if too low ( depression) -TAAR1 partial agonist might normalize DA if too low ( bipolar disorder) Lindemann L, Meyer CA, Hoener CM et al., J Pharmacol Exp Ther 2008, 324, 948. 5 Medicinal Chemistry Programme Aim: Discovery of selective TAAR1 agonists Objectives: - Identify potent and selective TAAR1 agonists & partial agonists - Drug-like series with suitable phys.-chem. and PK properties - Use to probe behavioural pharmacology in animal models (POC) Challenges:- The natural ligands are not well suited as in vivo tool compounds due to their low metabolic stability (MAO substrates) - Selectivity vs. biogenic amine targets may be difficult to achieve Strategy: Screening a subset of the Roche library to find suitable starting points and optimise these hits in a medicinal chemistry programme 6 HTS of Roche Golden Library Numbers 52’757 cpds (Golden Library) HTS Confirmation of primary hits and counter screen 181 specific hits with EC50 < 10 M (372 specific hits with EC50 < 50 M) Similarity search looking for clusters of parent molecules 2’672 cpds to be tested Selecting and eliminating (partly manual) 191 new hits with EC50 < 10 M; 78 with EC50 < 1 M 7 TAAR1 Agonist Pharmacophore Starting point for screening activities basic head group β- phenylethylamine Tolazoline Naphazoline linker X HTS Rn p-tyramine aromatic Tetryzoline endogenous ligands pharmacophore model adrenergic basic pK = 10 a compounds Screening lead to identification of 2-benzylimidazolines as drug-like TAAR1 ligands Question: Can we find ligands that are selective vs. adrenergic receptor? 8 Benzylimidazolines and Benzylimidazoles Structure Activity and Selectivity Relationship 1) 2) N N H R1, R2 R1, R2 R1, R2 = H, F, Cl, Br, Me, Et, i t Pr, Bu, CF3, Ph, OH, MeO, PhO, NH , AcNH, MeSO ,… 1 2 K hTAAR1/Ki 2 2 2 R , R Ki hTAAR1 i Restricted SAR H 400 nM 4.7 No selectivity vs. o,o’-diMe 36 nM 4.5 2A Brain/Plasma <1 o,o’-diEt 24 nM 100 o,o’-diiPr 630 nM 14 Preliminary SAR within 2-Benzylimidazole series showed promising selective versus adrenergic receptors when two substituents were added in ortho- position on the phenyl ring 9 2-Benzyl-imidazoles Structure Activity and Selectivity RelationshipR: Me ~ Et > cBu ~ iPr > nPr, Ph, OH N N N R ≠ H: 0 or 1 o-substituent allowed: N o: H, F, Br, Cl, OMe, CF , Et N N 3 H H H m: Br, Cl, F, OMe, CF3 R N H disubstituted derivatives: NH mandatory o,m’: Cl/Cl, F/F oo' o,m: F/F, Me/Me mm' 2-Imidazole < 4-Imidazole R = H: at least 2 substituents on Ph ring o,o’: C1-C4 alkyl, C1-C3 alkyl/Halo, CF3, F, Cl, Et/OMe In functional assay with h/r o,m: Cl, Oalkyl2, CF3 TAAR1 o,m’: F/Me, Me, Me/F, F/CF 3 only H tolerated! m,m’: CF3 monosubstituted derivatives: based on Ki on h/rTAAR1 and hTAAR1 o: cPr, H, Et, OMe, OCF3 m: NO2, NH2, Aryl green < 0.5 M trisubstituted derivatives: 0.5 M < orange > 5 M o,o’,m: Et/Et/F, Et/Et/F, Et/Et/Br, Et/F/F, F/F/Me, Et/F/Cl red > 5 M 10 Profile of RO4992479 a Selective TAAR1 Full Agonist N N Frontrunner. Good selectivity vs. fromother GPCRs 4-Imidazole Series H . Good physicochemical properties . Low oral bioavailability in both mouse & rat TAAR1 Phys.-chem. Properties human mouse rat logD 2.62 MW 214 Sol. 410 g/ml EC50 46 nM 51 nM 324 nM pKa 7.31 PAMPA 3.42 x 10-6 cm/s H Effic. 87% 74% 62% 2a EC 7.13 M Effic. 17% SDPK 50 mouse rat CEREP (panel of 60 targets) clean i.v. dose 5 mg/kg 5 mg/kg hERGIC50 >10 M I1 IC50 0.66 CL 64 ml/min/kg 66 ml/min/kg Br./Pl. 2.4 1.6 Microsomal Stability human mouse rat p.o. dose 10 mg/kg 10 mg/kg 13 ClMic 59 -- cmax 303 ng/ml 97 ng/ml MAB 68% 37% -- t1/2 1.0 h 0.3 h Class MM-- Bioavail. F 21% 14% 11 Profile of RO4992479 a Selective TAAR1 Full Agonist N N Frontrunner. Active in antagonizing from cocaine-induced 4-Imidazole Series H hyperlocomotor activity in mouse . Anxiolytic-like effect in stress-induced hyperthermia (SIH) in mouse 8000 mTAAR1 7000 K 28 nM 6000 i EC 60 nM 5000 50 73% efficacy 4000 3000 2000 1000 Horizontal Activity (cm) Activity Horizontal 0 Tw 3 10 Tw 3 10 mg/kg RO No effect in TAAR1 KO mouse !! 12 Synthesis of 2-Benzyl Imidazoles o,o’-disubstituted required an ad-hoc synthetic route ethylenediamine Swern [O] S8, 200°C, W (43-84%) (17-80%) i. EtLi (2.6 eq.) Ph3P, CBr4 THF, -10 °C CH2Cl2, 0°C to rt p-TsOH, toluene ii. 4 M aq. HCl (60% ) reflux, 40 min THF, reflux (99%) (93% ) ethylenediamine Swern [O] CH Cl , rt, 18 h 2 2 (75% ) (60%) Galley G, Stalder, H, Goergler A, Hoener CM, Norcross RD, BMCL 2012, 22, 5244. 13 Benzylimidazolines and Benzylimidazoles Structure Activity and Selectivity Relationship 1) 2) N 3) N NH R N H R1, R2 R1, R2 R1, R2 R1, R2 = H, F, Cl, Br, Me, Et, i t Pr, Bu, CF3, Ph, OH, MeO, Restricted SAR 1 2 PhO, NH2, AcNH, MeSO2,… R , R K hTAAR1 Ki hTAAR1/Ki 2 i Low selectivity vs. 2 Restricted SAR H 400 nM 4.7 Often high clearance in PK No selectivity vs. 2 Submicromolar inhibition o,o’-diMe 36 nM 4.5 of CYP (expecially at 2C9) Brain/Plasma <1 o,o’-diEt 24 nM 100 o,o’-diiPr 630 nM 14 • All three series show a very restricted structure-selectivity-relationship • Metabolite ID studies on RO4992479 showed extensive oxidation of o,o’- ethyl residues and GSH adduct formation 14 Discovery of the 2-atom linker 4-Imidazole series Successful Application of a SOSA N ApproachNH NH 1 65 nM vary 11 nM 48 nM (5.3) (1.6) sidechain (1.6) h 2a Ki = 18 nM N N NH NH N N 32 nM (3.9) 2 22 nM 55 nM (24) (5.9) hTAAR1 Ki h 2a Ki = 40 nM (2a Ki/hTAAR1 Ki) Aminomethyl imidazoles are known adrenergic ligands – SOSA approach* Selectivity for TAAR1 could be achieved by variation of substituents* Wermuth CG: Selective Optimisation of Side Activities. DDT 2006, 11, 160. 15 4-Aminomethyl-Imidazoles Structure Activity and Selectivity EC hTAAR1 Relationship 50 R 5 nM m-Cl N NH 10 nM H m,m'-di-F m-Cl,p-F m,p-di-F p-NHC(O)Aryl m-Me N p-Cl m-F m-Cl-m'-F m-OCF CF H R m-OMe m-Cl,o'-F p-F,m-Me 2 2 m,p-di-Cl m-Cl,p-F m-[1-pyrrole] Broader SAR allowed 50 nM p-Br, m-F m-F,o'-F m-OBn m,m'-di-Cl Good selectivity vs alpha m-[-naphthyl] p-F m-OCHF2 m-OPh 2 100 nM p-Cl,m-CF Good PK possible p-OBn p-Cl,m-OMe 3 selectivity vs. 2a o-F m-OEt m-NH 2 p-OPh m-c-Pr (based on EC50 and IC50) i m-CF3 m-O Pr m-OCF3 p-F,m-OMe m-O-[3-pyridine] green > 200 200 > orange > 50 m-CHOH-Ph p-F,m-OPh p-Cl,m-F red < 50 300 nM p-Cl,o-F p-OMe,m-F m-Ph m-Br m-OH 16 RO5073012 – a TAAR1 partial agonist Frontrunner from 4-Imidazole Series . Balanced TAAR1 efficacy profile across species . Good selectivity vs. other GPCRs . Good physicochemical properties . Good oral PK profile in both mouse & rat TAAR1 Phys.-chem. Properties human mouse rat logD 3.3 MW 250 Sol.
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