Design and synthesis of indane-ureido-thioisobutyric acids: A novel class of PPARalpha agonists.
A series of aminoindane derivatives were synthesized and shown to be potent PPARalpha agonists. The compounds were obtained as racemates in 12 steps, and tested for PPARalpha activation and PPARalpha mediated induction of the HD gene. SAR was developed by variation to the core structure as shown within. Oral bioavailability was demonstrated in a Sprague-Dawley rat, while efficacy to reduce plasma triglycerides and plasma glucose was demonstrated in db/db mice.
Matthews
Jay M
JM
Drug Discovery, Johnson & Johnson, East Coast RED, Spring House, PA 19477-0776, USA. jmatthew@prdus.jnj.com
Chen
Xiaoli
X
Cryan
Ellen
E
Hlasta
Dennis J
DJ
Rybczynski
Philip J
PJ
Strauss
Kim
K
Tang
Yuting
Y
Xu
June Z
JZ
Yang
Maria
M
Zhou
Lubing
L
Demarest
Keith T
KT
D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D002087:Butyrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D006801:Humans; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D047493:PPAR alpha / Q000819:agonists*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D000596:Amino Acids; D002087:Butyrates; D007189:Indans; D047493:PPAR alpha; D014508:Urea