title: 1,5-Substituted nipecotic amides: selective PDE8 inhibitors displaying diastereomer-dependent 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.
authors: Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. mike_deninno@sd.vrtx.com
authors: Michael P
authors: MP
authors: DeNinno
authors: Stephen W
authors: SW
authors: Wright
authors: Michael S
authors: MS
authors: Visser
authors: John B
authors: JB
authors: Etienne
authors: Dianna E
authors: DE
authors: Moore
authors: Thanh V
authors: TV
authors: Olson
authors: Benjamin N
authors: BN
authors: Rocke
authors: Melissa P
authors: MP
authors: Andrews
authors: Cynthia
authors: C
authors: Zarbo
authors: Michele L
authors: ML
authors: Millham
authors: Brian P
authors: BP
authors: Boscoe
authors: David D
authors: DD
authors: Boyer
authors: Shawn D
authors: SD
authors: Doran
authors: Karen L
authors: KL
authors: Houseknecht
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008861:Microsomes / Q000187:drug effects*; D008958:Models, Molecular; D015394:Molecular Structure; D009557:Nipecotic Acids / Q000737:chemistry*
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D008024:Ligands; D009557:Nipecotic Acids; C030278:nipecotic acid; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C112770:PDE8A protein, human