Regioselective Synthesis of 2<i>H</i>‑Indazoles Using a Mild, One-Pot Condensation–Cadogan Reductive Cyclization

An operationally simple and efficient one-pot synthesis of 2<i>H</i>-indazoles from commercially available reagents is reported. <i>Ortho</i>-imino-nitrobenzene substrates, generated via condensation, undergo reductive cyclization promoted by tri-<i>n</i>-butylphosophine to afford substituted 2<i>H</i>-indazoles under mild reaction conditions. A variety of electronically diverse <i>ortho</i>-nitrobenz­aldehydes and anilines were examined. To further extend the scope of the transformation, aliphatic amines were also employed to form <i>N</i>2-alkyl indazoles selectively under the optimized reaction conditions

Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents

The optimization of a new class of small molecule PCSK9 mRNA translation inhibitors is described. The potency, physicochemical properties, and off-target pharmacology associated with the hit compound (<b>1</b>) were improved by changes to two regions of the molecule. The last step in the synthesis of the congested amide center was enabled by three different routes. Subtle structural changes yielded significant changes in pharmacology and off-target margins. These efforts led to the identification of <b>7l</b> and <b>7n</b> with overall profiles suitable for in vivo evaluation. In a 14-day toxicology study, <b>7l</b> demonstrated an improved safety profile vs lead <b>7f</b>. We hypothesize that the improved safety profile is related to diminished binding of <b>7l</b> to nontranslating ribosomes and an apparent improvement in transcript selectivity due to the lower strength of <b>7l</b> stalling of off-target proteins

Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents

The optimization of a new class of small molecule PCSK9 mRNA translation inhibitors is described. The potency, physicochemical properties, and off-target pharmacology associated with the hit compound (<b>1</b>) were improved by changes to two regions of the molecule. The last step in the synthesis of the congested amide center was enabled by three different routes. Subtle structural changes yielded significant changes in pharmacology and off-target margins. These efforts led to the identification of <b>7l</b> and <b>7n</b> with overall profiles suitable for in vivo evaluation. In a 14-day toxicology study, <b>7l</b> demonstrated an improved safety profile vs lead <b>7f</b>. We hypothesize that the improved safety profile is related to diminished binding of <b>7l</b> to nontranslating ribosomes and an apparent improvement in transcript selectivity due to the lower strength of <b>7l</b> stalling of off-target proteins

Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents

The optimization of a new class of small molecule PCSK9 mRNA translation inhibitors is described. The potency, physicochemical properties, and off-target pharmacology associated with the hit compound (<b>1</b>) were improved by changes to two regions of the molecule. The last step in the synthesis of the congested amide center was enabled by three different routes. Subtle structural changes yielded significant changes in pharmacology and off-target margins. These efforts led to the identification of <b>7l</b> and <b>7n</b> with overall profiles suitable for in vivo evaluation. In a 14-day toxicology study, <b>7l</b> demonstrated an improved safety profile vs lead <b>7f</b>. We hypothesize that the improved safety profile is related to diminished binding of <b>7l</b> to nontranslating ribosomes and an apparent improvement in transcript selectivity due to the lower strength of <b>7l</b> stalling of off-target proteins

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

Evolution of the Synthesis of AMPK Activators for the Treatment of Diabetic Nephropathy: From Three Preclinical Candidates to the Investigational New Drug PF-06409577

Indole acids <b>1</b>, <b>2</b>, and <b>3</b> are potent 5′-adenosine monophosphate-activated protein kinase (AMPK) activators for the potential treatment of diabetic nephropathy. Compounds <b>1</b>–<b>3</b> were scaled to supply material for preclinical studies, and indole <b>3</b> was selected for advancement to first-in-human clinical trials and scaled to kilogram quantities. The progression of the synthesis strategy for these AMPK activators is described, as routes were selected for efficient structure–activity relationship generation and then improved for larger scales. The developed sequences employed practical isolations of intermediates and APIs, reproducible cross-coupling, hydrolysis, and other transformations, and enhanced safety and purity profiles and led to the production of 40–50 g of <b>1</b> and <b>2</b> and 2.4 kg of <b>3</b>. Multiple polymorphs of <b>3</b> were observed, and conditions for the reproducible formation of crystalline material suitable for clinical development were identified

Evolution of the Synthesis of AMPK Activators for the Treatment of Diabetic Nephropathy: From Three Preclinical Candidates to the Investigational New Drug PF-06409577

Indole acids <b>1</b>, <b>2</b>, and <b>3</b> are potent 5′-adenosine monophosphate-activated protein kinase (AMPK) activators for the potential treatment of diabetic nephropathy. Compounds <b>1</b>–<b>3</b> were scaled to supply material for preclinical studies, and indole <b>3</b> was selected for advancement to first-in-human clinical trials and scaled to kilogram quantities. The progression of the synthesis strategy for these AMPK activators is described, as routes were selected for efficient structure–activity relationship generation and then improved for larger scales. The developed sequences employed practical isolations of intermediates and APIs, reproducible cross-coupling, hydrolysis, and other transformations, and enhanced safety and purity profiles and led to the production of 40–50 g of <b>1</b> and <b>2</b> and 2.4 kg of <b>3</b>. Multiple polymorphs of <b>3</b> were observed, and conditions for the reproducible formation of crystalline material suitable for clinical development were identified

Optimization of Metabolic and Renal Clearance in a Series of Indole Acid Direct Activators of 5′-Adenosine Monophosphate-Activated Protein Kinase (AMPK)

Optimization of the pharmacokinetic (PK) properties of a series of activators of adenosine monophosphate-activated protein kinase (AMPK) is described. Derivatives of the previously described 5-aryl-indole-3-carboxylic acid clinical candidate (<b>1</b>) were examined with the goal of reducing glucuronidation rate and minimizing renal excretion. Compounds <b>10</b> (PF-06679142) and <b>14</b> (PF-06685249) exhibited robust activation of AMPK in rat kidneys as well as desirable oral absorption, low plasma clearance, and negligible renal clearance in preclinical species. A correlation of in vivo renal clearance in rats with in vitro uptake by human and rat renal organic anion transporters (human OAT/rat Oat) was identified. Variation of polar functional groups was critical to mitigate active renal clearance mediated by the Oat3 transporter. Modification of either the 6-chloroindole core to a 4,6-difluoroindole or the 5-phenyl substituent to a substituted 5-(3-pyridyl) group provided improved metabolic stability while minimizing propensity for active transport by OAT3