Synthesis of Spiropiperidine Lactam Acetyl-CoA Carboxylase Inhibitors

The synthesis of 4′,6′-dihydrospiro­[piperidine-4,5′-pyrazolo­[3,4-<i>c</i>]­pyridin]-7′(2′<i>H</i>)-one-based acetyl-CoA carboxylase inhibitors is reported. The hitherto unknown N-2 <i>tert</i>-butyl pyrazolospirolactam core was synthesized from ethyl 3-amino-1<i>H</i>-pyrazole-4-carboxylate in a streamlined 10-step synthesis requiring only one chromatography procedure. The described synthetic strategy provides pyrazolo-fused spirolactams from halogenated benzylic arenes and cyclic carboxylates. Key steps include a regioselective pyrazole alkylation providing the N-2 <i>tert</i>-butyl pyrazole and a Curtius rearrangement under both conventional and flow conditions to install the hindered amine via a stable and isolable isocyanate. Finally, a Parham-type cyclization was used to furnish the desired spirolactam. An analogous route provided efficient access to the related N-1 isopropyl lactam series. Elaboration of the lactam cores via amidation enabled synthesis of novel ACC inhibitors and the identification of potent analogues

Spirolactam-Based Acetyl-CoA Carboxylase Inhibitors: Toward Improved Metabolic Stability of a Chromanone Lead Structure

Acetyl-CoA carboxylase (ACC) catalyzes the rate-determining step in <i>de novo</i> lipogenesis and plays a crucial role in the regulation of fatty acid oxidation. Alterations in lipid metabolism are believed to contribute to insulin resistance; thus inhibition of ACC offers a promising option for intervention in type 2 diabetes mellitus. Herein we disclose a series of ACC inhibitors based on a spirocyclic pyrazololactam core. The lactam series has improved chemical and metabolic stability relative to our previously reported pyrazoloketone series, while retaining potent inhibition of ACC1 and ACC2. Optimization of the pyrazole and amide substituents led to quinoline amide <b>21</b>, which was advanced to preclinical development

Optimization of a Dicarboxylic Series for in Vivo Inhibition of Citrate Transport by the Solute Carrier 13 (SLC13) Family

Inhibition of the sodium-coupled citrate transporter (NaCT or SLC13A5) has been proposed as a new therapeutic approach for prevention and treatment of metabolic diseases. In a previous report, we discovered dicarboxylate <b>1a</b> (PF-06649298) which inhibits the transport of citrate in in vitro and in vivo settings via a specific interaction with NaCT. Herein, we report the optimization of this series leading to <b>4a</b> (PF-06761281), a more potent inhibitor with suitable in vivo pharmacokinetic profile for assessment of in vivo pharmacodynamics. Compound <b>4a</b> was used to demonstrate dose-dependent inhibition of radioactive [¹⁴C]­citrate uptake in liver and kidney in vivo, resulting in modest reductions in plasma glucose concentrations