Discovery of C-(1-aryl-cyclohexyl)-methylamines as selective, orally available inhibitors of dipeptidyl peptidase IV.
The successful launches of dipeptidyl peptidase IV (DPP IV) inhibitors as oral anti-diabetics warrant and spur the further quest for additional chemical entities in this promising class of therapeutics. Numerous pharmaceutical companies have pursued their proprietary candidates towards the clinic, resulting in a large body of published chemical structures associated with DPP IV. Herein, we report the discovery of a novel chemotype for DPP IV inhibition based on the C-(1-aryl-cyclohexyl)-methylamine scaffold and its optimization to compounds which selectively inhibit DPP IV at low-nM potency and exhibit an excellent oral pharmacokinetic profile in the rat.
Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland. Electronic address: kenji.namoto@novartis.com.
Kenji
K
Namoto
Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Finton
F
Sirockin
Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Nils
N
Ostermann
Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Francois
F
Gessier
Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Stefanie
S
Flohr
Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Richard
R
Sedrani
Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Bernd
B
Gerhartz
Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Jörg
J
Trappe
Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Ulrich
U
Hassiepen
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
Alokesh
A
Duttaroy
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
Suzie
S
Ferreira
Argenta Discovery 2009 Ltd, Harlow CM19 5TR, UK.
Jon M
JM
Sutton
Argenta Discovery 2009 Ltd, Harlow CM19 5TR, UK.
David E
DE
Clark
Argenta Discovery 2009 Ltd, Harlow CM19 5TR, UK.
Garry
G
Fenton
Argenta Discovery 2009 Ltd, Harlow CM19 5TR, UK.
Mandy
M
Beswick
Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Daniel K
DK
Baeschlin
D000218:Adamantane / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D003500:Cyclization; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008744:Methylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology; D000077597:Vildagliptin
D054873:Dipeptidyl-Peptidase IV Inhibitors; D008744:Methylamines; D009570:Nitriles; D011719:Pyrazines; D011759:Pyrrolidines; D014230:Triazoles; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000077597:Vildagliptin; D000218:Adamantane; D000068900:Sitagliptin Phosphate
Dipeptidyl peptidase IV; Enzyme selectivity; Ex vivo plasma DPP IV inhibition; Pharmacokinetics; Protease inhibition; Structure-based drug design