Pyrroloquinolone PDE5 Inhibitors with Improved Pharmaceutical Profiles for Clinical Studies on Erectile Dysfunction

Abstract

We previously reported a series of potent and selective pyrimidinyl pyrroloquinolone PDE5 inhibitors such as 2a for potential use in male erectile dysfunction (MED) (Sui, Z.; Guan, J.; Macielag, M. J.; Jiang, W.; Zhang, S.; Qiu, Y.; Kraft, P., Bhattacharjee, S.; John, T. M.; Craig, E.; Haynes-Johnson, D.; Clancy, J. J. Med. Chem. 2002, 45, 4094-4096). Unfortunately, the low aqueous solubility and poor oral bioavailability rendered them undesirable development candidates. To address this issue, we designed a series of analogues using two approaches: increasing the overall basicity and reducing molecular weight of the lead. Through earlier SAR studies, we discovered that the PDE5 potency of the pyrroloquinolones is insensitive to substitution on the pyrrole nitrogen. Basic functional groups such as pyridines and benzimidazoles were appended via the aromatic ring connected to the pyrrole nitrogen. Several truncated analogues were also designed and synthesized to improve oral absorption. These modifications allowed us to identify analogues with good oral bioavailability in rats, dogs, and monkeys while the high potency against PDE5 and desirable selectivity versus other PDE isozymes were maintained. Compounds R-11e and R-11l were selected as development candidates for MED and other indications.

Biaryl Phosphane Ligands in Palladium‐Catalyzed Amination

“…[175] At Johnson & Johnson [176] 1 has been used as the ligand in the low yield synthesis of PDE 5 inhibitors for the treatment of erectile dysfunction (Scheme 22).…”

Biarylphosphanliganden in der palladiumkatalysierten Aminierung

“…[175] Bei Johnson & Johnson [176] wurde 1 als Ligand in der Synthese eines PDE-5-Inhibitors zur Behandlung der Potenzstörung eingesetzt (Schema 22).…”

Phosphodiesterase 5 Inhibitors - Drug Design and Differentiation Based on Selectivity, Pharmacokinetic and Efficacy Profiles

“…Another group [25] discovered a completely new class of PDE5Is, belonging to the pyrroloquinolone polycyclic ring system, with their best inhibitor (IC 50 of 0.40 nM) shown in structure 12. Some other congeners of this compound are subnanomolar inhibitors of the target PDE, and show good selectivity for inhibiting PDE5 over other isoforms, including PDE6.…”