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6-Benzhydryl-4-amino-quinolin-2-ones as Potent Cannabinoid Type 1 (CB1) Receptor Inverse Agonists and Chemical Modifications for Peripheral Selectivity Yuemei Zhang, Michael Greco, Mark J Macielag, Christopher A Teleha, Renee DesJarlais, YuTing Tang, George Ho, Cuifen Hou, Cailin Chen, Shuyuan Zhao, Jack Kauffman, Raul Camacho, Jenson Qi, William Murray, Keith Demarest, and James Leonard J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.8b01467 • Publication Date (Web): 19 Oct 2018 Downloaded from http://pubs.acs.org on October 21, 2018
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Journal of Medicinal Chemistry
6-Benzhydryl-4-amino-quinolin-2-ones as Potent Cannabinoid Type 1 (CB1) Receptor Inverse Agonists and Chemical Modifications for Peripheral Selectivity Yue-Mei Zhang,* Michael N. Grecoϯ, Mark J. Macielag, Christopher A. Teleha, Renee L. DesJarlais, Yuting Tangϯ, George Ho, Cuifen Houϯ, Cailin Chen, Shuyuan Zhao, Jack Kauffmanϯ, Raul Camacho, Jenson Qi, William Murrayϯ, Keith Demarestϯ, James Leonard Janssen Research & Development, 1400 McKean Road, Spring House, PA 19477-0776, United States. KEYWORDS cannabinoid type 1 receptor, CB1R antagonists/inverse agonists, peripheral restriction, brain penetration, P-gp substrates, quinoline-2-ones.
ABSTRACT
A novel series of 6-benzhydryl-4-amino-quinolin-2-ones was discovered as cannabinoid type 1 receptor (CB1R) inverse agonists based on the high-throughput screening hit, compound 1a. Structure-activity relationships were studied to improve in vitro/in vivo pharmacology and restrict distribution to the peripheral circulation. We adopted several strategies such as increasing topological polar surface area, incorporating discrete polyethylene glycol side chains and targeting P-glycoprotein (P-gp) to minimize access to the brain. Compound 6a is a P-gp substrate and a potent and highly selective CB1R inverse agonist, demonstrating excellent in vivo metabolic stability and a low brain to plasma ratio. However, brain receptor occupancy studies showed that compound 6a may accumulate in brain with repeat dosing. This was evidenced by compound 6a inhibiting food intake and inducing weight loss in diet-
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induced obese mice. Thus, a strategy based on P-gp efflux may not be adequate for peripheral restriction of the disclosed quinolinone series.
INTRODUCTION
Cannabinoid type 1 receptor (CB1R) is the most abundant 7-transmembrane, G protein-coupled receptor (GPCR) in the brain and is also widely expressed in peripheral tissues such as liver, adipose, pancreas and skeletal muscle.1 CB1R may be up-regulated in some disease states such as liver fibrosis and obesity.1 CB1R antagonists/inverse agonists (CB1RAs/CB1RIAs) have been shown in the clinic to induce weight loss and improve metabolism in obese dyslipidemic2 and diabetic patients.3 However, the occurrence of severe neuropsychiatric liabilities such as depression, anxiety, and suicidality, led to market withdrawal of the CB1RIA, rimonabant, as well as the termination of clinical development programs for several other brain penetrant CB1RIAs (ibipinabant, taranabant and otenabant).4 Nevertheless, the weight loss independent benefits of rimonabant on hepatic steatosis and improvement of other metabolic parameters,5 including elevation of HDL cholesterol and plasma adiponectin, reduction of plasma triglycerides and LDL cholesterol, and improvement of insulin sensitivity, suggest that a peripherally restricted CB1RIA could be of benefit in the treatment of type 2 diabetes. Moreover, a potential role of CB1R in the inflammatory response associated with non-alcoholic steatohepatitis (NASH) has been suggested by the reduction of liver inflammation in obese rats following treatment with CB1RIAs.6 A clinical case study also demonstrated improvement of liver enzymes, metabolic parameters, and hepatic mitochondrial function of a NASH patient treated with a CB1RIA.7 CB1R may also play a role in pathological renal conditions. Treatment with CB1RIAs dramatically reduced the development of renal fibrosis in mice.8 The contribution of the CB1R to the development of renal fibrosis was recently demonstrated in human nephropathies and correlates with kidney function.9 Thus, the potential utility of peripherally restricted CB1RAs or CB1RIAs for the treatment of metabolic disorders and its associated complications remains.10 Various CB1RIAs with low brain-penetration have been disclosed, including molecules designed around the 2,3-diarylpyrazole (rimonabant), 2,3-diaryl-
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Journal of Medicinal Chemistry
dihydropyrazole (ibipinabant), or diphenyl purine (otenabant) templates.11-14 The 2,3-diaryldihydropyrazole-based peripherally restricted CB1RIA JD5037 is to enter the PhI trial for the treatment of NASH.15 In an attempt to discover peripherally restricted CB1RIAs, a 4-styrylquinolin-2-one compound 1a (Figure 1, 1a) emerged from an internal high throughput screening (HTS) campaign as a highly selective and structurally distinct CB1RIA with modest in-vitro potency. Initial lead optimization around this scaffold (Figure 1, scaffold 1) focused on three aspects prior to enhancing peripheral restriction properties: 1) improving CB1R in vitro inverse agonism potency; 2) diminishing cytochrome P450 (CYP450) inhibition by replacing the imidazolyl group with a suitable R4 substituent16 (C6 position); and 3) removing the styryl moiety with potential chemical instability and in vivo metabolism liabilities (C4 position). The specific sites modified in SAR studies of scaffold 1 are outlined in Figure 1. N O Me
Cl
N
N NH
Ph 5
4
3 2 N1 O H
6
N Cl
Cl
7
8
1a Cl
rimonabant
R3
R4
N
CB1 EC50 = 165 nM
Cl
R
5
N
R
1
R2
1
CB2 EC50 >1000 nM
CYP450 IC50: 3A4, 2C9, 2C19
