title: 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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, 1000 Route 202, Raritan, New Jersey 08869, USA.
authors.forename: Weiqin
authors.initials: W
authors.lastname: Jiang
authors.forename: Jihua
authors.initials: J
authors.lastname: Guan
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Macielag
authors.forename: Suying
authors.initials: S
authors.lastname: Zhang
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Qiu
authors.forename: Patricia
authors.initials: P
authors.lastname: Kraft
authors.forename: Sheela
authors.initials: S
authors.lastname: Bhattacharjee
authors.forename: T Matthew
authors.initials: TM
authors.lastname: John
authors.forename: Donna
authors.initials: D
authors.lastname: Haynes-Johnson
authors.forename: Scott
authors.initials: S
authors.lastname: Lundeen
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Sui
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D006152:Cyclic GMP / Q000096:biosynthesis; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004285:Dogs; D004558:Electric Stimulation; D007172:Erectile Dysfunction / Q000188:drug therapy; D008253:Macaca mulatta; D008297:Male; D010413:Penis / Q000098:blood supply / Q000187:drug effects; D011758:Pyrroles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015363:Quinolones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C500079:1,2,3,4-tetrahydro-2-(5-(2-pyridinyl)pyrimidin-2-yl)-3-(3,4-dihydrobenzofuranyl)-9H-pyrrolo(3,4-b)quinolin-9-one; C500080:3-(2,3-dihydrobenzofuran-5-yl)-2-pyridin-2-yl-1,2,3,4-tetrahydropyrrolo(3,4-b)quinolin-9-one; D011758:Pyrroles; D015363:Quinolones; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D006152:Cyclic GMP