1,5-Substituted nipecotic amides: Selective PDE8 inhibitors displaying diastereomer-dependent microsomal stability Michael P. DeNinno  ,⇑ , Stephen W. Wright, Michael S. Visser à , John B. Etienne, Dianna E. Moore, Thanh V. Olson, Benjamin N. Rocke, Melissa P. Andrews, Cynthia Zarbo, Michele L. Millham, Brian P. Boscoe, David D. Boyer, Shawn D. Doran, Karen L. Houseknecht § Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA article info Article history: Received 14 January 2011 Revised 4 March 2011 Accepted 7 March 2011 Available online 11 March 2011 Keywords: Phosphodiesterase 8 Pancreas Diabetes Microsomal stability abstract The first highly potent and selective PDE8 inhibitors are disclosed. The initial tetrahydroisoquinoline hit was transformed into a nipecotic amide series in order to address a reactive metabolite issue. Reduction of lipophilicity to address metabolic liabilities uncovered an interesting diastereomer-dependent trend in turnover by human microsomes. Ó 2011 Elsevier Ltd. All rights reserved. Phosphodiesterase 8B is a cAMP-specific isoform of the broader class of phosphodiesterases (PDEs). 1–3 Although mRNA for the clo- sely related PDE8A has been found at low levels in most tissues, PDE8B is more highly expressed in the brain, thyroid, pancreas and adrenal cortex. 4,5 Expression of the enzyme in pancreatic b-cells 4 suggested that inhibition of PDE8B might have therapeutic utility in the treatment of diabetes. Such an agent could be used as a mono-therapy, or in combination with drugs which signal through cAMP such as those that act on the GLP-1 receptor. 6 Other PDE isoforms expressed in the pancreas include PDE1C, PDE3B, PDE4 and PDE10. 7 As no selective PDE8 inhibitors had been re- ported, a high throughput screen (HTS) was conducted with the goal of identifying selective tools for exploring the in vitro and in vivo phenotype of PDE8B inhibition. The majority of hits from the HTS contained classical PDE phar- macophores, such as the non-selective cAMP mimic inhibitor IBMX (Fig. 1). One hit (1) based on a tetrahydroisoquinoline (THIQ) scaf- fold looked particularly attractive due to its structural novelty. It was hoped that this structural novelty would result in greater specificity for derivatives of 1 against the PDE8B isozyme (Fig. 2). 8 A standard SAR campaign around 1 gave 2 which had high po- tency against PDE8B (IC 50 = 5 nM) and excellent selectivity. 9 How- ever, it was determined that multiple analogs were positive in a glutathione adduct-based reactive metabolite assay, presumably at least partially through compound 3 which was detected as one of the major products upon microsomal incubation (Fig. 3). 10 0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2011.03.022 ⇑ Corresponding author. Tel.: +1 858 404 6664; fax: +1 858 404 6719. E-mail address: mike_deninno@sd.vrtx.com (M.P. DeNinno).   Present address: Vertex Pharmaceuticals Inc., 11010 Torreyana Rd., San Diego, CA 92121, USA à Present address: Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Ave., Cambridge, MA 02139, USA § Present address: University of New England, 716 Stevens Ave., Portland, ME 04103, USA Figure 1. Structures of cAMP and IBMX. Figure 2. Structure of THIQ screening hit 1. Bioorganic & Medicinal Chemistry Letters 21 (2011) 3095–3098 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl