Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators

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Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators: Discovery of 2-Chloro-4-[1-(4-fluorophenyl)-2,5dimethyl-1H-imidazol-4-ylethynyl]-pyridine (Basimglurant, RO4917523), a Promising Novel Medicine for Psychiatric Diseases Georg Jaeschke, Sabine Kolczewski, Will Spooren, Eric Vieira, Nadia Bitter-Stoll, Patrick Boissin, Edilio Borroni, Bernd Büttelmann, Simona Ceccarelli, Nicole Clemann, Beatrice David, Christoph Funk, Wolfgang Guba, Anthony Harrison, Thomas Hartung, Michael Honer, Jörg Huwyler, Martin Kuratli, Urs Niederhauser, Axel Pähler, Jens-Uwe Peters, Ann Petersen, Eric Prinssen, Antonio Ricci, Daniel Rueher, Marianne Rueher, Manfred Schneider, Paul Spurr, Theodor Stoll, Daniel Tännler, Jürgen Wichmann, Richard H Porter, Joseph G Wettstein, and Lothar Lindemann J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/jm501642c • Publication Date (Web): 07 Jan 2015 Downloaded from http://pubs.acs.org on January 12, 2015

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Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators: Discovery of 2-Chloro-4-[1(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4ylethynyl]-pyridine (Basimglurant, RO4917523), a Promising Novel Medicine for Psychiatric Diseases Georg Jaeschke*1, Sabine Kolczewski1, Will Spooren2, Eric Vieira1, Nadia Bitter-Stoll1, Patrick Boissin1, Edilio Borroni2, Bernd Büttelmann1, Simona Ceccarelli3, Nicole Clemann4, Beatrice David1, Christoph Funk4, Wolfgang Guba5, Anthony Harrison4, Thomas Hartung6, Michael Honer2, Jörg Huwyler9, Martin Kuratli1, Urs Niederhauser4, Axel Pähler4, Jens-Uwe Peters1, Ann Petersen1, Eric Prinssen2, Antonio Ricci1, Daniel Rueher1, Marianne Rueher7, Manfred Schneider4, Paul Spurr6, Theodor Stoll1, Daniel Tännler1, Jürgen Wichmann1, Richard H. Porter8, Joseph G. Wettstein2, Lothar Lindemann2 Roche Pharmaceutical Research and Early Development, 1Discovery Chemistry, Therapeutic Modalities 2Discovery Neuroscience, Neuroscience, Ophthalmology & Rare Diseases (NORD), 3 Communications, 4Pharmaceutical Sciences, 5 Molecular Design and Chemical Biology, Therapeutic Modalities, 6Small Molecules Process Research and Synthesis, Therapeutic Modalities, 7 Infections Diseases, 8Operations for Neuroscience, Ophthalmology, and Rare Diseases (NORD), Innovation Center Basel, Grenzacherstrasse 124, CH-4070 Basel, Switzerland 9

University of Basel, Pharmaceutical Technology, Pharmacenter, Klingelbergstrasse 50, CH-4056 Basel, Switzerland. Corresponding Author. *Dr. Georg Jaeschke, F. Hoffmann-La Roche Ltd, Pharmaceutical Research and Early Development, Discovery Chemistry, Therapeutic Modalities, Grenzacherstrasse 124, CH-4070 Basel, Switzerland. Phone: +41 61 688 20 34. E-mail: [email protected].

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ABSTRACT: Negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(mGluR5) have potential for the treatment of psychiatric diseases including depression, fragile X syndrome (FXS), anxiety, obsessive-compulsive disorders and levodopa induced dyskinesia in Parkinson’s disease. Herein we report the optimization of a weakly active screening hit 1 to the potent

and

selective

ylethynyl]-pyridine

compounds (basimglurant,

chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-42)

and

2-chloro-4-((2,5-dimethyl-1-(4-

(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP, 3). Compound 2 is active in a broad range of anxiety tests reaching the same efficacy but at a 10-100-fold lower dose compared to diazepam and is characterized by favorable DMPK properties in rat and monkey as well as an excellent preclinical safety profile and is currently in phase II clinical studies for the treatment of depression and fragile X syndrome. Analogue 3 is the first reported mGlu5 NAM with a long halflife in rodents and is therefore an ideal tool compound for chronic studies in mice and rats. INTRODUCTION Glutamate is the principal excitatory neurotransmitter in the brain. Glutamate mediates its effects via ionotropic (iGlu) and metabotropic glutamate (mGlu) receptors. mGlu receptors are part of family III of G-protein-coupled receptors (GPCRs) which are classified into three clusters, Group I, II, and III, based on sequence homology, preferred signal transduction pathway, and pharmacology1, 2. The mGlu5 receptor belongs to Group I, is mainly expressed post-synaptically and found with high abundance in limbic brain areas including the hippocampal formation, forebrain, striatal regions and amygdala3. Evidences from non-clinical and clinical studies suggest that dysfunctions in glutamatergic systems may be involved in the pathophysiology of depression, and that interventions modulating glutamatergic neurotransmission may possess antidepressant effects4, 5. Glutamatergic approaches for the treatment of depression have increasingly been discussed which were in part triggered by reports of fast acting antidepressant effects of the N-methyl-D-aspartic acid (NMDA) channel blocking agent ketamine 6. While ketamine has limited clinical utility in view of its abuse potential and the risk of neurotoxicity, the prototypical mGlu5 antagonists 2-methyl-6-(phenylethynyl)ACS Paragon Plus Environment

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pyridine (MPEP, 4) and 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)-pyridine (MTEP, 5) are devoid of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

these liabilities and were reported to have antidepressant-like effects in the forced swim and tail suspension tests7, 8, two procedures used for the profiling of antidepressant drug candidates. On this background, the antidepressant potential of mGlu5 inhibitors warrants further examination. Compelling preclinical evidence indicates that the absence of fragile X mental retardation protein (FMRP) leading to increased mGlu5 receptor activity is important for the molecular pathophysiology of FXS9. Studies in Fmr1 knock-out mice have demonstrated that a reduction of the mGlu5 receptor activity by genetic or pharmacological means corrects a broad range of disease-related phenotypes10, 11

. Collectively, these data suggest a therapeutic, and even a disease modifying potential of mGlu5

antagonists in FXS. The need for chronic treatment is anticipated for both depression and FXS indications, and in the latter case, it is assumed that an early treatment start during childhood would be needed for the full therapeutic potential of mGlu5 inhibitors to unfold12. An excellent preclinical safety profile was therefore a key requirement. In addition, we were targeting a compound with a sufficiently long halflife amenable for once daily oral administration and high in vivo potency to achieve a low therapeutic dose. The first identified mGlu receptor antagonists were glutamate analogs targeting the orthosteric binding site13. These compounds were important tools for the understanding of mGlu receptor pharmacology. The in vivo use of these orthosteric ligands was however limited by their low brain penetration potential and insufficient selectivity towards the different metabotropic glutamate receptor subtypes13. Using functional assays based on recombinantly expressed receptors, antagonists with higher subtype selectivity targeting a non-competitive binding site were discovered14. These negative allosteric modulators (NAMs) are structurally unrelated to glutamate and bind within the transmembrane domain of the mGlu5 receptor15. As this binding site is less conserved among the different mGlu receptors than the orthosteric binding site, allosteric antagonists often have high subtype selectivity. The lipophilic nature of the allosteric binding site requires lipophilic ligands (i.e. molecules with positive logD), a feature which

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Cl N

N

N

N N Cl

R

O

R = F: 2 R = OCF3: 3

1

N H N

N N

N

NH

O

O

S

5

4

Cl

N

6

Fig. 1: mGlu5 negative allosteric modulators: Screening hit 1 and reference compounds 2-6.

also facilitates brain penetration. Allosteric antagonists offer therefore the potential to overcome the insufficient subtype selectivity and limited brain penetration of orthosteric antagonists16-19. Two potent, brain penetrant mGlu5 NAM compounds 420 and 521 were previously reported. Although both compounds are not suitable as drug candidates for clinical development, due to insufficient selectivity versus other targets, unsuitable PK properties or side-effect potential19, 4 and 5 have been studied in a wide range of preclinical animal models for different therapeutic indications and are regarded as prototypical mGlu5 NAMs. More

recently

we

reported

that

(3Z)-1-(3-chlorophenyl)-3-(1-methyl-2-oxo-imidazolidin-4-

ylidene)urea (fenobam, 6) is a potent and selective mGlu5 antagonist, acting through the same allosteric binding site as 4 and 522. In the late seventies, 6 was advanced to clinical studies in patients suffering from anxiety-disorders in an effort to identify non-benzodiazepine anxiolytics. Several double blind placebo-controlled clinical trials conducted with 6 have shown mixed results suggesting potential anxiolytic-like effect but limited tolerability which has been attributed to the erratic bioavailability of the compound23. Here we report the optimization of high-throughput screening hit 124 to 2, which is characterized by high target selectivity, high in vivo potency, long lasting action ACS Paragon Plus Environment

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and an excellent in vitro safety profile devoid of genotoxic or teratogenic potential which 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

distinguishes 2 from first generation acetylene-type mGluR5 NAMs. RESULTS AND DISCUSSION Scheme 1. Synthesis of 9a-g, 10

(b)

(a)

7

9a-g

8a-g

10 (from 9a)

8a: R = Ph 8e: R = 3-Me-2-Py 8b: R = o-Me-Ph 8f: R = 3-Py 8c: R = m-Me-Ph 8g: R = 3-Me-4-Py 8d: R = p-Me-Ph

no

9a

9b

9c

9d

9e

9f

9g

60

34

63

53

26

82

23

R

Yield [%] (from 7)

a

Reagents and conditions: (a) 8a-g (2 equiv), Et3N (3 equiv), (TPP)2PdCl2 (0.05 equiv), TPP (0.03 equiv), CuI (0.01 equiv), THF, 60°C, 4-16h, 23-82% yield. (b) n-BuLi (1.5 equiv), THF, -20°C, 10 min, then MeI (2 equiv), -70°C to -20°C, 2h, 78% yield.

Chemistry. Starting from precursor 725, the mGlu5 NAMs 9a-g were prepared under standard Sonogashira coupling conditions with the acetylene building blocks 8a-g in yields ranging from 23 to 82%. Introduction of the methyl group in the 2-position at the imidazole ring of 9a was achieved by deprotonation with n-BuLi and methylation with MeI which provided 10 in 78% yield.

The imidazole derivatives 15a-h were prepared following two slightly different synthetic routes: Starting from commercially available 2-methyl-4-iodoimidazole, a Sonogashira reaction with 11 led to the imidazole derivative 12, isolated in 59% yield. The intermediate 12 was directly Scheme 2. Synthesis of 15a-h

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Journal of Medicinal Chemistry (a)

12 11

(c)

13a: R = Ph 13b: R = m-CN-Ph 13c: R = p-CN-Ph 13d: R = m-SO2Me-Ph

(b) 13h: R = p-F-Ph

13a-g

13e: R = p-SO2Me-Ph 13f: R = m-F-Ph 13g: R = o-F,p-F-Ph

(d)

14: R = p-F-Ph

15a-h 11

no

15a

15b

15c

15d

15e

15f

15g

15h

41

14

17

40

27

14

76 (from 14)

R

Yield [%] 21 (from 12)

a

Reagents and conditions: (a) 11 (1.15 equiv), Et3N (1.0 equiv), (TPP)2PdCl2 (0.04 equiv), TPP (0.01 equiv), CuI (0.01 equiv), TBAF (1M in THF, 0.86 equiv), THF, 40-60°C, 16h, 59% yield. (b) 13a-g (2 equiv), Cu-TMEDA catalyst (0.035 equiv), 1bar O2 atm., THF, rt, 16h, 14-41% yield. (c) 13h (1.65 equiv), Cu(OAc)2 (1.2 equiv), Et3N (1.2 equiv), 1 bar O2 atm., THF, rt, 18h, 66% yield. (d) 11 (1.2 equiv), Et3N (1.5 equiv), (TPP)2PdCl2 (0.03 equiv), TPP (0.03 equiv), CuI (0.01 equiv), TBAF (1M in THF, 1.4 equiv), THF, 50°C, 16h, 76% yield.

transformed to the desired products 15a-g by copper catalyzed couplings of the corresponding boronic acids 13a-g in the presence of oxygen26, 27. In this reaction, the formation of regioisomeric side products was observed in which the boronic acids reacted with the sterically more hindered imidazole nitrogen. Although only small amounts of the isomeric products were formed, the yields of the desired products themselves were poor to moderate (14-41%), and the separation of the isomeric mixtures by column chromatography was quite laborious. However, an improved yield was achieved by reversing the reaction sequence. This was exemplified by the preparation of product 15h, acquired by coupling imidazole 10 first with 4-fluoroboronic acid 13h to form imidazole 14, followed by a Sonogashira reaction to generate the desired product 15h in 76% yield. ACS Paragon Plus Environment

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To access the dimethyl substituted imidazole derivatives 2, 3 and 22c, the β-keto ester 16, was treated with NaNO2 under acidic conditions and the oxime intermediate produced was condensed Scheme 3. Synthesis of 2, 3, 22c (a)

16

17a-c

(b)

18a-c

20a-c 19

(d)

17a-21a, 2: R = p-F-Ph 17b-21b, 3: R = p-OCF3-Ph 17c-22c:

(c)

R = o-F,p-F-Ph 2, 3, 22c

21a-c

a

Reagents and conditions: (a) i) NaNO2 (1.1 equiv), AcOH (2.2 equiv), H2O, 0-5°C, rt, 1h. ii) 17a-c (1 equiv), pyridinium p-toluenesulfonate (0.05 equiv), toluene, 75°C, 6h. iii) MeC(OEt)3 (3.5 equiv), p-TsOH.H2O (0.02 equiv), Pd/C, 1 bar H2, rt, 1h, 37-75% yield. (b) 19 (1.2 equiv), KHMDS (2.5 equiv), toluene, 0-5°C, 1h, 29-92% yield. (c) (chloromethylene)dimethyliminium chloride (2.5 equiv), CH2Cl2, 0-5°C, 1h, 83-100% yield. (d) KOtBu (2.2 equiv), H2O (1.1 equiv), THF, 0-5°C, 1h, 39-93%.

with anilines 17a-c to generate the corresponding imines. These were, without isolation, directly reduced, acylated and cyclized in situ with triethylorthoacetate furnishing the imidazole esters 18a-c in 37-75% yield. 2-Chloropicoline (19) was deprotonated and treatment of the imidazoles 18a-c with the anion under optimized conditions cleanly produced the desired ketones 20a-c. Reaction with (chloromethylene)dimethyliminium chloride (Vilsmeier’s salt) followed by a Grob-type fragmentation process of the chloro-eneal products 21a-c, mediated by KOH-tBuOK, gave the desired products 2, 328, and 22c in yields ranging from 39 to 93%. The entire procedure for the preparation of compound 2 from inexpensive commercially available materials is efficient and a high overall yield of ca. 50% is attainable. Pharmacology. In an HTS campaign based on a Ca2+ mobilization assay followed by a confirmatory MPEP binding assay, benzodiazepine 1 was identified as a moderately active mGlu5 NAM. Imidazole derivative 1 originates from a former Roche GABA-A agonist program24 and displayed ACS Paragon Plus Environment

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the expected high potency (1 nM, Table 1) in rat cortex 3H-flumazenil radioligand (BDZ) binding. In 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

an effort to increase mGlu5 affinity and decrease GABA-A activity, further available acetylene analogs24,

29

were screened. Benzodiazepine 23 indicated that mGlu5 affinity could be slightly

improved by changing the size and position of the substituent on the western aromatic moiety. Table 1. In vitro and in vivo data of 1, 9a and 23-24 1

23

24

9a

X 2 1

R1

Cl

H

H

H

2

H

F

F

H

R

Ki / IC50 (nM)a compd

MPEP binding

Ca2+ BDZ mobilization binding

hERGb

rat CLintc (µL/min/mg)

human CLintc (µL/min/mg)

1440 1 1 872 123 3160 3160 3160 11 3160 28 3160 29 3160 20 3160 13 3160 > 10000 14 1000 10