IV. Discovery of CXCR3 antagonists substituted with heterocycles as amide surrogates: improved PK, hERG and metabolic profiles.
The structure-human CXCR3 binding affinity relationship of a series of pyridyl/pyrazinyl-piperazinyl-piperidine derivatives were explored with a focus to improve PK, hERG and metabolic profiles. Several small heterocycles were identified as amide surrogates, which minimized many potential metabolite issues. During the course of SAR development, we have observed the additive effect of desirable functional groups to improve hERG and PK profiles which lead to the discovery of many clinically developable CXCR3 antagonists with excellent overall profile.
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: gopinadhan.anilkumar@Merck.com.
Anilkumar G
AG
Nair
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Michael K C
MK
Wong
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Youheng
Y
Shu
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Yueheng
Y
Jiang
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Chung-Her
CH
Jenh
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Seong Heon
SH
Kim
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
De-Yi
DY
Yang
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Qingbei
Q
Zeng
Ligand Pharmaceuticals, 3000 Eastpark Boulevard, Cranbury, NJ 08512, USA.
Yuefei
Y
Shao
Ligand Pharmaceuticals, 3000 Eastpark Boulevard, Cranbury, NJ 08512, USA.
Lisa Guise
LG
Zawacki
Ligand Pharmaceuticals, 3000 Eastpark Boulevard, Cranbury, NJ 08512, USA.
Jingqi
J
Duo
Ligand Pharmaceuticals, 3000 Eastpark Boulevard, Cranbury, NJ 08512, USA.
Brian F
BF
McGuinness
Ligand Pharmaceuticals, 3000 Eastpark Boulevard, Cranbury, NJ 08512, USA.
Carolyn Diianni
CD
Carroll
Ligand Pharmaceuticals, 3000 Eastpark Boulevard, Cranbury, NJ 08512, USA.
Doug W
DW
Hobbs
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Neng-Yang
NY
Shih
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Stuart B
SB
Rosenblum
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Joseph A
JA
Kozlowski
D000577:Amides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D006571:Heterocyclic Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D051381:Rats; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000577:Amides; C515187:CXCR3 protein, human; D051638:Ether-A-Go-Go Potassium Channels; D006571:Heterocyclic Compounds; D054367:Receptors, CXCR3
CXCR3