Imidazopyridazinones as novel PDE7 inhibitors: SAR and in vivo studies in Parkinson’s disease model Abhisek Banerjee, Sandip Patil, Mahesh Y. Pawar, Srinivas Gullapalli, Praveen K. Gupta, Maulik N. Gandhi, Deepak K. Bhateja, Malini Bajpai, Ramachandra Rao Sangana, Girish S. Gudi, Neelima Khairatkar-Joshi, Laxmikant A. Gharat ⇑ Glenmark Pharmaceuticals Limited, Navi Mumbai, Maharashtra 400709, India article info Article history: Received 4 May 2012 Revised 2 July 2012 Accepted 24 July 2012 Available online 8 August 2012 Keywords: PDE7 Imidazopyridazinone CNS penetration Parkinson’s disease MPTP Haloperidol abstract The synthesis and structure-activity relationship studies of a series of compounds from imidazopyridaz- inone scaffold as PDE7 inhibitors are disclosed. Potent analogs such as compounds 7 (31 nM), 8 (27 nM), and 9 (12 nM) were identified. The PDE selectivity and pharmacokinetic profile of compounds 7, 8 and 9 are also disclosed. The adequate CNS penetration of compound 7 in mice allowed it to be tested in the MPTP induced PD model and haloperidol induced catalepsy model to probe the differential pharmacology of PDE7 in the striatal pathway. Ó 2012 Elsevier Ltd. All rights reserved. Phosphodiesterase 7 (PDE7) an enzyme that selectively hydro- lyzes cAMP, has been extensively targeted for the treatment of a host of immunological and autoimmune conditions. 1 Recently, interest with PDE7 inhibitors has emerged in the context of Parkin- son’s disease (PD) 2 , considering the expression of PDE7A and 7B, the two isoenzymes of PDE7, in rodent and human brain. 1 The interest was further spurred by the findings that showed PDE7 inhibition can protect dopaminergic neurons against different in- sults in the lipopolysaccharide rat model of PD. 3,4 Furthermore, the dopamine receptors D1 and D2 signaling 5 has been proposed to be modulated by PDE7 via cAMP levels. It has been shown that PDE7 inhibitor alone or in combination with Levodopa (l-dopa) in- creased neuronal activation and restored paw stride length in MPTP treated mice model. 6 However, sub-optimal potency doses 7 were found to produce maximal efficacy and higher doses were re- ported to be sub-efficacious. 6 Interestingly, this observation can be correlated with the impact of PDE inhibition in the D1 receptor dependent ‘direct’ and D2 receptor dependent ‘indirect’ striatal pathways. Considering this background, our initial goal was to identify potent, selective, CNS-penetrating PDE7 inhibitors to eval- uate the potential of PDE7 inhibition as a novel target in the PD therapy. We have disclosed the structure-activity relationship of iso- thiazole and isoxazole fused pyrimidones (II) inspired from (I) as PDE7 inhibitors with adequate CNS penetration. 8 Additionally, we were also keen on exploring structurally diverse CNS penetrat- ing PDE7 inhibitors. Based on previous PDE7 SAR studies, 8,9 we hypothesized that an imidazopyridazinone scaffold (III)(Fig. 1) would allow us to explore alternate trajectory for essential/pre- ferred substituents. In this communication we describe the synthe- sis, SAR, PDE selectivity, and pharmacokinetic profile of a series of compounds from this scaffold. Moreover, we also wish to report our findings of the in vivo experiments in the MPTP treated mice model of PD and in the haloperidol induced catalepsy model. Synthetic access to imidazopyridazinone (III) where R 1 = H, has been previously reported by Gres’ko et. al. 10 We realized that we could access the desired PDE7 SAR by alkylation of compound 3 with various alkyl bromides to provide 4, at which point the syn- thesis could proceed to (III) (analogs 16–19 and 21) in a manner similar to that previously described (Scheme 1). 10 In the case where R 2 = –NO 2 , reduction to the amine (7) 11 could be effected with iron and ammonium chloride in methanol. Subsequent reac- tion of the amine (7) with phenylchloroformate, followed by treat- ment with methylamine hydrochloride provided 22. In the case where R 2 = –CN, the nitrile was readily hydrolyzed to the acid, esterified, reacted with hydrazine hydrate then followed by treat- ment with triphosgene to form the oxadiazolone analog 23. In the case where R 2 = methylacrylate, compound 24 could be readily 0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2012.07.077 ⇑ Corresponding author. Tel.: +91 022 6772 0000x3208. E-mail address: laxmikant_gharat@glenmarkpharma.com (L.A. Gharat). Bioorganic & Medicinal Chemistry Letters 22 (2012) 6286–6291 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl