Identification of a dual δ OR antagonist/μ OR agonist as a potential therapeutic for diarrhea-predominant Irritable Bowel Syndrome (IBS-d).
A small set of acyclic analogs 5 were prepared to explore their structure-activity relationships (SARs) relative to heterocyclic core, opioid receptor (OR) agonists 4. Compound 5l was found to have very favorable OR binding affinities at the δ and μ ORs (r K(i) δ=1.3 nM; r K(i) μ=0.9 nM; h K(i) μ=1.7 nM), with less affinity for the κ OR (gp K(i) κ=55 nM). The OR functional profile for 5l varied from the previously described dual δ/μ OR agonists 4, with 5l being a potent, mixed dual δ OR antagonist/μ OR agonist [δ IC(50)=89 nM (HVD); μ EC(50)=1 nM (GPI); κ EC(50)=1.6 μM (GPC)]. Compound 5l has progressed through a clinical Phase II Proof of Concept study on 800 patients suffering from diarrhea-predominant Irritable Bowel Syndrome (IBS-d). This Phase II study was recently completed successfully, with 5l demonstrating statistically significant efficacy over placebo.
Janssen Research and Development, L.L.C., Welsh and McKean Roads, PO Box 776, Spring House, PA 19477-0776, USA. HBreslin60@gmail.com
Henry J
HJ
Breslin
Craig J
CJ
Diamond
Robert W
RW
Kavash
Chaozhong
C
Cai
Alexey B
AB
Dyatkin
Tamara A
TA
Miskowski
Sui-Po
SP
Zhang
Paul R
PR
Wade
Pamela J
PJ
Hornby
Wei
W
He
D017322:Clinical Trials, Phase II as Topic; D003967:Diarrhea / Q000209:etiology*; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000150:complications / Q000188:drug therapy*; D015394:Molecular Structure; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013329:Structure-Activity Relationship
D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu