Discovery, structure-activity relationship, and pharmacological evaluation of (5-substituted-pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidines as potent dipeptidyl peptidase IV inhibitors.
A series of (5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine (C5-Pro-Pro) analogues was discovered as dipeptidyl peptidase IV (DPPIV) inhibitors as a potential treatment of diabetes and obesity. X-ray crystallography data show that these inhibitors bind to the catalytic site of DPPIV with the cyano group forming a covalent bond with the serine residue of DPPIV. The C5-substituents make various interactions with the enzyme and affect potency, chemical stability, selectivity, and PK properties of the inhibitors. Optimized analogues are extremely potent with subnanomolar K(i)'s, are chemically stable, show very little potency decrease in the presence of plasma, and exhibit more than 1,000-fold selectivity against related peptidases. The best compounds also possess good PK and are efficacious in lowering blood glucose in an oral glucose tolerance test in ZDF rats.
Pei
Zhonghua
Z
Department of Exploratory Pharmacokinetics and Pharmaceutics, Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-3500, USA. zhonghua.pei@abbott.com
Li
Xiaofeng
X
Longenecker
Kenton
K
von Geldern
Thomas W
TW
Wiedeman
Paul E
PE
Lubben
Thomas H
TH
Zinker
Bradley A
BA
Stewart
Kent
K
Ballaron
Stephen J
SJ
Stashko
Michael A
MA
Mika
Amanda K
AK
Beno
David W A
DW
Long
Michelle
M
Wells
Heidi
H
Kempf-Grote
Anita J
AJ
Madar
David J
DJ
McDermott
Todd S
TS
Bhagavatula
Lakshmi
L
Fickes
Michael G
MG
Pireh
Daisy
D
Solomon
Larry R
LR
Lake
Marc R
MR
Edalji
Rohinton
R
Fry
Elizabeth H
EH
Sham
Hing L
HL
Trevillyan
James M
JM
D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001786:Blood Glucose / Q000032:analysis; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004355:Drug Stability; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D019440:Anti-Obesity Agents; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D009570:Nitriles; D011480:Protease Inhibitors; D011759:Pyrrolidines; D018819:Dipeptidyl Peptidase 4