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Organic & Biomolecular Chemistry COMMUNICATION Cite this: Org. Biomol. Chem., 2013, 11, 2075 Received 31st October 2012, Accepted 11th February 2013 DOI: 10.1039/c3ob27424a www.rsc.org/obc Novel N-indolylmethyl substituted olanzapine derivatives: their design, synthesis and evaluation as PDE4B inhibitorsDhilli Rao Gorja, a,b Soumita Mukherjee, a Chandana Lakshmi T. Meda, a Girdhar Singh Deora, a K. Lalith Kumar, a Ankit Jain, a,c Girish H. Chaudhari, a,c Keerthana S. Chennubhotla, a,c Rakesh K. Banote, a,c Pushkar Kulkarni, a,c Kishore V. L. Parsa,* a K. Mukkanti b and Manojit Pal* a A new strategy for converting antipsychotic drug olanzapine into PDE4 inhibitors is described via the design and Pd/C mediated synthesis of novel N-indolylmethyl olanzapine derivatives. One compound showed good inhibition (IC 50 1.1 μM) and >10 fold selectivity towards PDE4B over D that was supported by docking studies. This compound also showed signicant inhibition of TNF-α and no major toxicities in cell lines and a zebrash embryo model except the teratogenic eects to be re-assessed in rodents. Chronic obstructive pulmonary disease (COPD), a major health problem, is projected to be the 3rd leading cause of death globally by 2020 according to the WHO. 1 Asthma, on the other hand, aects 300 million people worldwide at present. 1 The search for improved therapies therefore is necessary. Among the emerging agents to treat COPD or asthma, phos- phodiesterase 4 (PDE4) inhibitors have attracted particular attention. 2 Additionally, evaluation of PDE4 inhibition for the potential treatment of a wider range of CNS related diseases including Parkinsons disease, 3 schizophrenia, 4 and Alzhei- mers disease 5 has underlined the importance of development of PDE4 inhibitors. The first-generation PDE4 inhibitor roli- pram suered from side eects including nausea and emesis. 1,2 Similar side eects delayed the market launch of the second generation inhibitors cilomilast and roflumilast. Encouragingly, roflumilast (Daxas®, Nycomed) was launched in Europe for the treatment of chronic bronchitis in 2009 and in US (Daliresp, Forest Lab) for exacerbations during COPD in 2012. Nevertheless, it is desirable to identify PDE4 inhibitors having fewer side eects. PDEs are a diverse family of enzymes that hydrolyze cyclic nucleotides and thus play a key role in regulating intracellular levels of the second messengers cAMP and cGMP, and hence cell function. 1 PDE4 is a cAMP-specific PDE and predominant isoenzyme in the majority of inflamma- tory cells, with the exception of platelets, implicated in inflam- matory airways disease. Since elevated levels of cAMP play a major role in relaxation of vascular smooth muscle, inhibition of PDE4 is beneficial for the treatment of respiratory diseases including asthma and COPD. 1,2 Among the four isoforms e.g. PDE4A, B, C, and D, the PDE4B plays a key role in inflamma- tory cell regulation and its inhibition suppresses TNF-α pro- duction via elevation of cAMP levels. 6 The inhibition of PDE4D on the other hand triggers the emetic response. 7 Thus, selec- tive inhibition of PDE4A and/or PDE4B was thought to provide a means to achieve ecacy while mitigating the adverse eects of the current PDE4 inhibitors. However, in spite of innumer- able eorts, only a few PDE4B selective inhibitors have been reported till date. 8,9 Olanzapine (Zyprexa®, Eli Lilly) (1, Fig. 1) that belongs to the thienobenzodiazepine class is a dopamine receptor anta- gonist and has been used as a second generation atypical anti- psychotic drug. It has proven ecacy against schizophrenia 10 and has shown anti-emetic eects in the treatment of refrac- tory nausea and vomiting in advanced cancer. 11 The indole derivatives 2 (Fig. 1), on the other hand, have been reported as Fig. 1 Design of an olanzapine based novel PDE4 inhibitor. Electronic supplementary information (ESI) available: 1 H and 13 C NMR, MS and HRMS data of all new compounds. See DOI: 10.1039/c3ob27424a a Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India. E-mail: manojitpal@redimail.com b Chemistry Division, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500072, India c Zephase Therapeutics Pvt. Ltd (An incubated company at the Institute of Life Sciences), University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India This journal is © The Royal Society of Chemistry 2013 Org. Biomol. Chem., 2013, 11, 20752079 | 2075 Downloaded by Cape Breton University on 08 March 2013 Published on 11 February 2013 on http://pubs.rsc.org | doi:10.1039/C3OB27424A View Article Online View Journal | View Issue

Novel N-indolylmethyl substituted olanzapine derivatives: their design, synthesis and evaluation as PDE4B inhibitors

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Page 1: Novel N-indolylmethyl substituted olanzapine derivatives: their design, synthesis and evaluation as PDE4B inhibitors

Organic &Biomolecular Chemistry

COMMUNICATION

Cite this: Org. Biomol. Chem., 2013, 11,2075

Received 31st October 2012,Accepted 11th February 2013

DOI: 10.1039/c3ob27424a

www.rsc.org/obc

Novel N-indolylmethyl substituted olanzapinederivatives: their design, synthesis and evaluation asPDE4B inhibitors†

Dhilli Rao Gorja,a,b Soumita Mukherjee,a Chandana Lakshmi T. Meda,a

Girdhar Singh Deora,a K. Lalith Kumar,a Ankit Jain,a,c Girish H. Chaudhari,a,c

Keerthana S. Chennubhotla,a,c Rakesh K. Banote,a,c Pushkar Kulkarni,a,c

Kishore V. L. Parsa,*a K. Mukkantib and Manojit Pal*a

A new strategy for converting antipsychotic drug olanzapine into

PDE4 inhibitors is described via the design and Pd/C mediated

synthesis of novel N-indolylmethyl olanzapine derivatives. One

compound showed good inhibition (IC50 1.1 μM) and >10 fold

selectivity towards PDE4B over D that was supported by docking

studies. This compound also showed significant inhibition of

TNF-α and no major toxicities in cell lines and a zebrafish embryo

model except the teratogenic effects to be re-assessed in rodents.

Chronic obstructive pulmonary disease (COPD), a majorhealth problem, is projected to be the 3rd leading cause ofdeath globally by 2020 according to the WHO.1 Asthma, on theother hand, affects ∼300 million people worldwide at present.1

The search for improved therapies therefore is necessary.Among the emerging agents to treat COPD or asthma, phos-phodiesterase 4 (PDE4) inhibitors have attracted particularattention.2 Additionally, evaluation of PDE4 inhibition for thepotential treatment of a wider range of CNS related diseasesincluding Parkinson’s disease,3 schizophrenia,4 and Alzhei-mer’s disease5 has underlined the importance of developmentof PDE4 inhibitors. The first-generation PDE4 inhibitor roli-pram suffered from side effects including nausea andemesis.1,2 Similar side effects delayed the market launch of thesecond generation inhibitors cilomilast and roflumilast.Encouragingly, roflumilast (Daxas®, Nycomed) was launchedin Europe for the treatment of chronic bronchitis in 2009 andin US (Daliresp, Forest Lab) for exacerbations during COPD in2012. Nevertheless, it is desirable to identify PDE4 inhibitorshaving fewer side effects. PDEs are a diverse family of enzymes

that hydrolyze cyclic nucleotides and thus play a key role inregulating intracellular levels of the second messengers cAMPand cGMP, and hence cell function.1 PDE4 is a cAMP-specificPDE and predominant isoenzyme in the majority of inflamma-tory cells, with the exception of platelets, implicated in inflam-matory airways disease. Since elevated levels of cAMP play amajor role in relaxation of vascular smooth muscle, inhibitionof PDE4 is beneficial for the treatment of respiratory diseasesincluding asthma and COPD.1,2 Among the four isoforms e.g.PDE4A, B, C, and D, the PDE4B plays a key role in inflamma-tory cell regulation and its inhibition suppresses TNF-α pro-duction via elevation of cAMP levels.6 The inhibition of PDE4Don the other hand triggers the emetic response.7 Thus, selec-tive inhibition of PDE4A and/or PDE4B was thought to providea means to achieve efficacy while mitigating the adverse effectsof the current PDE4 inhibitors. However, in spite of innumer-able efforts, only a few PDE4B selective inhibitors have beenreported till date.8,9

Olanzapine (Zyprexa®, Eli Lilly) (1, Fig. 1) that belongs tothe thienobenzodiazepine class is a dopamine receptor anta-gonist and has been used as a second generation atypical anti-psychotic drug. It has proven efficacy against schizophrenia10

and has shown anti-emetic effects in the treatment of refrac-tory nausea and vomiting in advanced cancer.11 The indolederivatives 2 (Fig. 1), on the other hand, have been reported as

Fig. 1 Design of an olanzapine based novel PDE4 inhibitor.†Electronic supplementary information (ESI) available: 1H and 13C NMR, MSand HRMS data of all new compounds. See DOI: 10.1039/c3ob27424a

aInstitute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad

500046, India. E-mail: [email protected] Division, Institute of Science and Technology, JNT University, Kukatpally,

Hyderabad 500072, IndiacZephase Therapeutics Pvt. Ltd (An incubated company at the Institute of Life

Sciences), University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India

This journal is © The Royal Society of Chemistry 2013 Org. Biomol. Chem., 2013, 11, 2075–2079 | 2075

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Page 2: Novel N-indolylmethyl substituted olanzapine derivatives: their design, synthesis and evaluation as PDE4B inhibitors

promising inhibitors of PDE4.12 We anticipated that a combi-nation of the structural features of 1 and 2 in a single molecu-lar species 3 (Fig. 1) could be helpful for the selectiveinhibition of PDE4B with reduced emetic side effects. Ourdesign was primarily based on the fact that (i) the catalyticpocket of PDE4B is more hydrophobic9a in nature than PDE4Dand (ii) the buried pocket volume available for an inhibitor tobind within the PDE4B binding site is greater than that ofPDE4D.9b Thus the hydrophobic and bulky nature of 3 wasexpected to be favorable for PDE4B selectivity. Furthermore,docking studies performed using a series of molecules basedon 3 indicated a favorable effect of an N-sulfonyl moiety (Z =SO2R), the oxygen of which may have H-bonding interactionwith the surrounding amino acids in the PDE4 binding pocketthereby enhancing the binding affinity of the resulting mole-cule towards PDE4. Herein, we report the design, synthesisand pharmacological evaluation of a novel series of potentialPDE4B inhibitors13 based on the scaffold 3 derived from olan-zapine. Notably, no PDE4 inhibitory properties have beenreported for olanzapine or its analogues. Moreover, since anumber of potent but non-selective inhibitors have beenreported earlier1,2 thus achieving PDE4B selectivity rather thanpotency was the major goal of this research.

The designed compounds were conveniently prepared fol-lowing a Pd/C-mediated coupling–cyclization strategy.14 Thekey starting material i.e. the terminal alkyne 4 required foraccessing our target compound 3 (mainly 3a–j) was syn-thesized by treating olanzapine (1) with propargyl bromide inthe presence of NaH in THF (Scheme 1).15 Initially, the alkyne4 was reacted with N-(4-bromo-2-iodophenyl)-methanesulfona-mide 5a in the presence of 10%Pd/C–PPh3–CuI and Et3N inEtOH at 70 °C for 4 h (Table 1). While the expected product 3awas isolated in 81% yield (Table 1, entry 1) the increase in reac-tion time however improved the product yield (Table 1, entry2). The use of K2CO3 in place of Et3N (Table 1, entry 3) or omis-sion of Pd/C (Table 1, entry 4) was found to be ineffective. Theuse of Pd(PPh3)2Cl2 (Table 1, entry 5) afforded satisfactoryyield (65%) whereas omission of CuI (Table 1, entry 6) reducedthe yield to 14%. Thus, 10% Pd/C–PPh3–CuI and Et3N in EtOHwas used to prepare other analogues of 3 (Scheme 1, Table 2).A number of o-iodosulphanilides (5a–j) were reacted withalkyne 4 under the optimized conditions. The reaction pro-ceeded well irrespective of the presence of an electron releas-ing [e.g. Cl (5h), Br (5a, 5i) and Me (5e)] or withdrawing group

[e.g. CN (5d), NO2 (5c) and COCH3 (5f, 5j)] affording thedesired products in good yields.

Most of the compounds synthesized (3a–j) were evaluatedfor their PDE4B and PDE4D inhibitory properties in vitro usingenzyme based assays (Table 2). The PDE4B isolated from Sf9cells and commercially available PDE4D were used for thispurpose. Rolipram, a well known inhibitor of PDE4, was usedas a reference compound. In general, compounds containingan N-mesyl moiety showed significant inhibition (>60%) ofPDE4B than those possessing an N-tosyl group e.g. 3g–j whentested at 30 μM. Compounds 3a–e showed superior inhibitionof PDE4B compared to PDE4D. Based on these initial data, adose–response study was performed with three representativecompounds e.g. 3a–c (and their precursor olanzapine). TheScheme 1 Synthesis of N-indolylmethyl substituted olanzapine derivatives 3.

Table 1 Effect of reaction conditions on coupling of terminal alkyne 4 with 5aa

Entry Pd-catalysts Base Time (h) Yieldb (%)

1. 10% Pd/C–PPh3 Et3N 4 812. 10% Pd/C–PPh3 Et3N 6 893. 10% Pd/C–PPh3 K2CO3 10 154. PPh3

c Et3N 12 No product5. Pd(PPh3)2Cl2 Et3N 8 656. Pd(PPh3)2Cl2

d Et3N 12 14

a All reactions were carried out using 5a (1 equiv.), alkyne 4 (1 equiv.),a Pd-catalyst (0.016 equiv.), PPh3 (0.125 equiv.), CuI (0.02 equiv.), anda base (2 equiv.) in EtOH (5.0 mL), at 70 °C. b Isolated yield. c Thereaction was carried out without Pd/C. d The reaction was carried outwithout CuI.

Table 2 Preparationa of compound 3 (Scheme 1) and its in vitro evaluationagainst PDE4B and PDE4D

Entry R1 =; Z = (5) 3b Yieldc

% inhibition @ 30 μM

PDE4B PDE4D

1. Br; Ms (5a) 3a 89 68.9 ± 1.7 35.3 ± 6.22. H; Ms (5b) 3b 90 87.1 ± 0.6 70.0 ± 1.23. NO2; Ms (5c) 3c 87 72.6 ± 1.1 47.8 ± 2.04. CN; Ms (5d) 3d 85 86.7 ± 2.0 64.1 ± 1.75. Me; Ms (5e) 3e 81 61.9 ± 1.5 41.2 ± 0.86. COMe; Ms (5f) 3f 82 69.5 ± 0.8 ND7. H; Ts (5g) 3g 72 37.0 ± 6.9 23.1 ± 0.98. Cl; Ts (5h) 3h 85 13.5 ± 1.9 ND9. Br; Ts (5i) 3i 76 30.0 ± 1.5 ND10. COMe; Ts (5j) 3j 78 22.4 ± 0.8 ND

a All the reactions were carried out using 5 (1 equiv.), alkyne 4 (1equiv.), 10% Pd/C (0.016 equiv.), PPh3 (0.125 equiv.), CuI (0.02 equiv.),and Et3N (2 equiv.) in EtOH at 70 °C for 6 h. b Identified by 1H and 13CNMR, IR, and MS. c Isolated yields. Ms = mesyl, Ts = p-tosyl, ND = notdetermined.

Communication Organic & Biomolecular Chemistry

2076 | Org. Biomol. Chem., 2013, 11, 2075–2079 This journal is © The Royal Society of Chemistry 2013

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IC50 values are presented in Table 3. While all these com-pounds showed some selectivity towards PDE4B the com-pound 3a was identified as most potent (IC50 ∼ 1.1 μM) andselective (>10 fold towards PDE4B) among them (Fig. 2).Notably, olanzapine did not inhibit PDE4B across the dosestested. With respect to the initial in vitro data the compound3a seemed to be comparable with phase 2 clinical candidate16a

CC-1088 (PDE4 IC50 = 1.1 μM) and possesses better PDE4Bselectivity than the marketed drug roflumilast [IC50 = 1.3 nM(PDE4B) and 0.2 nM (PDE4D)]16b and other advanced com-pounds17 e.g. cilomilast [IC50 = 86 nM (PDE4B) and 12 nM(PDE4D)], oglemilast [IC50 = 2.5 nM (PDE4B) and 1.7 nM(PDE4D)], etc. To understand the nature of interactions of 3a–cwith PDE4B and D, docking studies were performed (Table 3,see also ESI†). All these compounds (i.e. 3a, 3b and 3c) showedbetter interactions with PDE4B compared to D in silico.

The compound 3a was further evaluated for its anti-inflam-matory effects. Consequently, pre-incubation of RAW 264.7cells with 10 μM of compound 3a before stimulation with bac-terial endotoxin caused ∼50% inhibition of TNF-α synthesis.The toxicity of the 3a–c was also evaluated in cell lines and azebrafish embryo model. The compounds 3a and 3c did notcause major toxicity in RAW 264.7 cells (Fig. 3) and HEK 293Tcells (Fig. S2 in ESI†). Further, compounds 3a and 3c were tol-erated up to 10 and 50 μM, respectively, without any apparenthepatotoxicity in 4 day old zebrafish embryos (Fig. 4). More-over, 3a did not induce any changes in the heart rate.However, 3a–c along with rolipram showed teratogenic effectsat 50 μM (lower concentrations for 3a) in zebrafish embryos(Fig. S15A and S15B in ESI†). While its precursor i.e. olanzapineis not an animal teratogen in two species (rats and rabbits) itsdose related embryo and fetal toxicity (decreased fetal weightand related skeletal ossification) is known in the literature.18

Table 3 In vitro data of compounds 3a–c and their glide scores after dockinginto the PDE4B and D

Entry Compound

IC50a (μM) Glide score

PDE4B PDE4D PDE4B PDE4D

1. 3a 1.1 ± 0.1 >10 −5.11 −2.982. 3b 2.3 ± 0.4 8.2 ± 0.9 −5.47 −2.903. 3c 7.9 ± 2.2 51.7 ± 11.6 −5.10 −2.524. Rolipram 0.94 ± 0.2 0.88 ± 0.3 −6.66 −5.0

aData are represented as mean ± SD of at least 3 independentexperiments.

Fig. 2 Dose dependent inhibition of PDE4B and PDE4D by 3a.

Fig. 3 Cytotoxicity of 3a–c in RAW 264.7 cells.

Fig. 4 Hepatotoxicity of 3a–c in zebrafish embryos.

Organic & Biomolecular Chemistry Communication

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Page 4: Novel N-indolylmethyl substituted olanzapine derivatives: their design, synthesis and evaluation as PDE4B inhibitors

Thus observed teratogenic effects of 3a in zebrafish embryosneed to be assessed in appropriate animal models.

To assess the in silico binding mode of compounds 3a–c inhuman D2 dopamine19 receptor docking studies were per-formed using a homology model of the catalytic site of ahuman D2 dopamine receptor. While these compoundsshowed differences in the binding mode with that of olanza-pine their docking scores (though lower than that of olanza-pine) indicated significant interactions with the receptor (seeESI†). While the larger volume of these molecules compared toolanzapine was responsible for their lower docking scoresoverall, these molecules appeared to have potential to bindwith a dopamine receptor. Further in vitro studies20 are in pro-gress towards this direction.

In conclusion, a new strategy is presented for convertingthe antipsychotic drug (and a non-PDE4 inhibitor) olanzapineinto PDE4 inhibitors via the design and synthesis of novelN-indolylmethyl olanzapine derivatives. These compoundswere elegantly prepared by using a Pd/C mediated coupling–cyclization strategy as a key step. Some of the synthesized com-pounds showed encouraging PDE4 inhibition. The compound3a showed good inhibition (IC50 1.1 μM) and >10 fold selectiv-ity towards PDE4B over D and was supported by the dockingstudies. This compound also showed significant inhibition ofTNF-α, no major toxicities in RAW 264.7 cells and no hepato-toxicities up to 10 μM in a zebrafish embryo model except theteratogenic effects which need to be re-assessed in rodents.Overall, the synthetic strategy described here could be usefulin constructing a library of small molecules based on anN-indolylmethyl olanzapine framework. Additionally, our studysuggests that this framework could be an attractive templatefor the identification of novel and selective inhibitors ofPDE4B.

The authors thank Prof. J. Iqbal and DBT (Grant BT/01/COE/07/02) for support. DRG thanks DST, India for a ResearchFellowship. SM thanks CSIR, India for a ResearchAssociateship.

Notes and references

1 A. Kodimuthali, S. L. Jabaris and M. Pal, J. Med. Chem.,2008, 51, 5471.

2 M. D. Houslay, P. Schafer and K. Y. J. Zhang, Drug DiscoveryToday, 2005, 10, 1503.

3 L. Yang, N. Y. Calingasan, B. J. Lorenzo and M. F. Beal, Exp.Neurol., 2008, 211, 311.

4 J. K. Millar, B. S. Pickard, S. Mackie, R. James, S. Christie,S. R. Buchanan, M. P. Malloy, J. E. Chubb, E. Huston,G. S. Baillie, P. A. Thomson, E. V. Hill, N. J. Brandon,J.-C. Rain, L. M. Camargo, P. J. Whiting, M. D. Houslay,D. H. R. Blackwood, W. J. Muir and D. J. Porteous, Science,2005, 310, 1187.

5 A. Blokland, R. Schreiber and J. Prickaerts, Curr. Pharm.Des., 2006, 12, 2511.

6 S.-L. C. Jin, L. Lan, M. Zoudilova and M. Conti, J. Immunol.,2005, 175, 1523.

7 A. Robichaud, P. B. Stamatiou, S.-L. C. Jin, N. Lachance,D. MacDonald, F. Laliberte, S. Liu, Z. Huang, M. Conti andC.-C. Chan, J. Clin. Invest., 2002, 110, 1045.

8 (a) A. F. Donnell, P. J. Dollings, J. A. Butera, A. J. Dietrich,K. K. Lipinski, A. Ghavami and W. D. Hirst, Bioorg. Med.Chem. Lett., 2010, 20, 2163; (b) K. Naganuma, A. Omura,N. Maekawara, M. Saitoh, N. Ohkawa, T. Kubota,H. Nagumo, T. Kodama, M. Takemura, Y. Ohtsuka,J. Nakamura, R. Tsujita, K. Kawasaki, H. Yokoi andM. Kawanishi, Bioorg. Med. Chem. Lett., 2009, 19, 3174;(c) M. Kranz, M. Wall, B. Evans, A. Miah, S. Ballantine,C. Delves, B. Dombroski, J. Gross, J. Schneck, J. P. Villa,M. Neu and D. O. Somers, Bioorg. Med. Chem., 2009, 17,5336.

9 (a) P. Srivani, D. Usharani, E. D. Jemmis and G. N. Sastry,Curr. Pharm. Des., 2008, 14, 3854; (b) H. Wang, M.-S. Peng,Y. Chen, J. Geng, H. Robinson, M. D. Houslay, J. Cai andH. Ke, Biochem. J., 2007, 408, 193.

10 K. H. Littrell, R. G. Petty and N. M. Wolf, Expert Rev.Neurother., 2006, 6, 811.

11 (a) S. D. Passik, J. Lundberg, K. L. Kirsh, D. Theobald,K. Donaghy, E. Holtsclaw, M. Cooper and W. Dugan, J. PainSymptom Manage., 2002, 23, 526; (b) M. Srivastava, N. Brito-Dellan, M. P. Davis, M. Leach and R. Lagman, J. PainSymptom Manage., 2003, 25, 578.

12 C. Hulme, K. Moriarty, B. Miller, R. Mathew,M. Ramanjulu, P. Cox, J. Souness, K. M. Page, J. Uhl,J. Travis, F.-C. Huang, R. Labaudiniere and S. W. Djuric,Bioorg. Med. Chem. Lett., 1998, 8, 1867.

13 For our earlier effort, see: (a) G. R. Reddy, T. R. Reddy,S. C. Joseph, K. S. Reddy, L. S. Reddy, P. M. Kumar,G. R. Krishna, C. M. Reddy, D. Rambabu, R. Kapavarapu,C. L. T. Meda, K. K. Priya, K. V. L. Parsa and M. Pal, Chem.Commun., 2011, 47, 7779; (b) P. M. Kumar, K. S. Kumar,C. L. T. Meda, G. R. Reddy, P. K. Mohakhud, K. Mukkanti,G. R. Krishna, C. M. Reddy, D. Rambabu, K. S. Kumar,K. K. Priya, K. S. Chennubhotla, R. K. Banote, P. Kulkarni,K. V. L. Parsa and M. Pal, Med. Chem. Commun., 2012, 3,667; (c) R. Adepu, D. Rambabu, B. Prasad, C. L. T. Meda,A. Kandale, G. R. Krishna, C. M. Reddy, L. N. Chennuru,K. V. L. Parsa and M. Pal, Org. Biomol. Chem., 2012, 10, 5554.

14 (a) M. Pal, Synlett, 2009, 2896; (b) M. Layek, U. Lakshmi,D. Kalita, D. K. Barange, A. Islam, K. Mukkanti and M. Pal,Beilstein J. Org. Chem., 2009, 5, DOI: 10.3762/bjoc.5.46;(c) M. Pal, S. Venkataraman, V. R. Batchu and I. Dager,Synlett, 2004, 1965.

15 J. Fairhurst, T. M. Hotten, D. E. Tupper and D. T. Wong, USPatent, Application No US006034078A, March 7, 2000.

16 (a) G. W. Muller, M. G. Shire, L. M. Wong, L. G. Corral,R. T. Patterson, Y. Chen and D. I. Stirling, Bioorg. Med.Chem. Lett., 1998, 8, 2669; (b) R. W. Chapman, A. House,J. Richard, D. Prelusky, J. Lamca, P. Wang, D. Lundell,P. Wu, P. C. Ting, J. F. Lee, R. Aslanian and J. E. Phillips,Eur. J. Pharmacol., 2010, 643, 274.

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17 J. M. McKenna and G. W. Muller, Medicinal Chemistry ofPDE4 Inhibitors, in Cyclic Nucleotide Phosphodiesterase inHealth and Disease, ed. S. H. Francis, J. A. Beavo andM. D. Houslay, CRC Press, 2006, Print ISBN: 978-0-8493-9668-7, DOI: 10.1201/9781420020847.ch33.

18 G. Briggs, R. Freeman and S. Yaffe, in Drugs in pregnancyand lactation: A reference guide to fetal and neonatal risk,Lippincott Williams & Wilkins, 8th edn, 2008, p. 1355.

19 (a) The dopamine D2 receptor occupancy by olanzapine isknown in the literature, see: L. S. Pilowsky, G. F. Busatto,M. Taylor, D. C. Costa, T. Sharma, T. Sigmundsson, P. J. Ell,V. Nohria and R. W. Kerwin, Psychopharmacology, 1996,124, 148; (b) We thank one of the reviewers for bringingthis to our notice.

20 In a preliminary study, the binding affinities of olanzapineand 3a–c were assessed and found to be Ki = 68 ± 7 and500–1000 nM respectively in standard in vitro radioligandbinding assays that were run under the conditionsdescribed earlier, see: (a) M. Durand, S. Aguerre,F. Fernandez, L. Edno, I. Combourieu, P. Mormède andF. Chaouloff, Neuropharmacology, 2000, 39, 2464 and(b) G. Campiani, S. Butini, C. Fattorusso, F. Trotta, S. Gemma,B. Catalanotti, V. Nacci, I. Fiorini, A. Cagnotto, I. Mereghetti,T. Mennini, P. Minetti, M. A. Di Cesare, M. A. Stasi, S. DiSerio, O. Ghirardi, O. Tinti and P. Carminati, J. Med. Chem.,2005, 48, 1705. The Ki values represent the concentrationgiving half maximal inhibition of [3H]-spiperone binding to aD2 receptor of rat tissue homogenate.

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