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. 2011 Nov 21;3(3):198–202. doi: 10.1021/ml200250t

Discovery of a Potent Thiadiazole Class of Histamine H3 Receptor Antagonist for the Treatment of Diabetes

Ashwin U Rao †,*, Ning Shao †, Robert G Aslanian †, Tin-Yau Chan †, Sylvia J Degrado †, Li Wang †, Brian McKittrick †, Mary Senior †, Robert E West Jr ‡, Shirley M Williams ‡, Ren-Long Wu ‡, Joyce Hwa ‡, Bhuneshwari Patel ‡, Shuqin Zheng ‡, Christopher Sondey ‡, Anandan Palani †
PMCID: PMC4025655  PMID: 24900450

Abstract

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A series of novel 2-piperidinopiperidine thiadiazoles were synthesized and evaluated as new leads of histamine H3 receptor antagonists. The 4-(5-([1,4′-bipiperidin]-1′-yl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)morpholine (5u) displayed excellent potency and ex vivo receptor occupancy. Compound 5u was also evaluated in vivo for antidiabetic efficacy in STZ diet-induced obesity type 2 diabetic mice for 2 or 12 days. Non-fasting glucose levels were significantly reduced as compared with vehicle-treated mice. In addition, 5u dose dependently blocked the increase of HbA1c after 12 days of treatment.

Keywords: Histamine, H3, antagonist, thiadiazole, type 2 diabetes, non-fasting glucose, HbA1c

Histamine receptors have been attractive drug targets, beginning with the development of classical antihistamines, which target the histamine H1 receptor for the treatment of allergic reactions. Antagonists of the histamine H2 receptor have been successful for the treatment of gastric acid-related disorders. Since the identification of a third subtype of histamine receptor, H3, as a presynaptic autoreceptor that inhibits histamine release,1 along with its subsequent recognition as a heteroreceptor that regulates the release of other important neurotransmitters,2−2c there has been considerable effort by both industry and academia to develop a potent and selective H3 receptor antagonist.3,4 A fourth member of the histamine receptor family, H4, has been identified that is expressed primarily in cells and tissues of the immune system, suggesting a novel therapeutic target for the regulation of immune function, particularly in allergy and asthma.5

The histamine H3 receptor is a G-protein coupled receptor (GPCR) and one of four subtypes (H1, H2, H3, and H4) of the histamine receptor family.6 By virtue of its unique central nervous system (CNS) localization (cerebral cortex, striatum, and hypothalamus),7 antagonists of the H3 receptor are sought for the potential treatment of a variety of disorders affecting cognition (attention deficit hyperactivity disorder, schizophrenia, and Alzheimer's disease),8−10d sleep disorder,11 as well as metabolic syndrome (MS, including obesity and diabetes).12−12e

A number of investigational H3 antagonists have been evaluated for anti-obesity effects in a variety of animal models.13 Obesity is a worldwide health crisis that contributes to a number of pathophysiologic conditions including type 2 diabetes, a disorder characterized by abnormally high blood glucose levels caused by a dysregulation in leptin and insulin signaling in the hypothalamus. Leptin and insulin signaling in the hypothalamus are supplemented by the action of neurotransmitters, including H3-mediated dopamine and serotonin, and directly influence glucose homeostasis.14 The use of compounds that enhance histamine release from nerve terminals such as H3 receptor antagonists may afford an effective therapeutic alternative. Indeed, several studies have shown that H3 receptor antagonists increase histamine release from the hypothalamus and reduce energy intake in normal and leptin-resistant mice with diet-induced obesity (DIO).15

The initial development of H3 receptor antagonists focused on imidazole-containing compounds (thioperamide, ciproxifan, and proxyfan) and has been reported effective.16 However, imidazole derivatives are associated with inhibition of cytochrome P450 enzymes and poor CNS penetration.17,17b More recently, several non-imidazole-based H3 antagonists have also been developed. However, clinical efforts have not yet yielded a marketed entity despite the high level of interest in this area.18−18e

We recently reported a non-imidazole-based series having antagonist activity at the H3 receptor.19 In our continuing efforts to identify structurally diverse H3 antagonists, we identified a high-throughput screen (HTS) lead with a novel thiadiazole (I) pharmacophore (Figure 1).20 This compound showed modest in vitro potency (hH3Ki = 49 nM and mH3Ki = 47 nM) in a [3H]-N-α-methylhistamine human and mouse recombinant assay. In this paper, we report on the synthesis and structure–activity relationships (SAR) of this 2-piperidinopiperidine-5-substituted thiadiazole class of histamine H3 receptor antagonists and its effect on glucose lowering in streptozotocin (STZ) DIO type 2 diabetic mice.

Figure 1.

Figure 1

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Target molecule of the study.

The 4-piperidinopiperidine thiadiazole moiety was constructed relatively straightforward by the bromination of commercially available 1,3,4-thiadiazol-2-amine 1 to afford 2, which was then converted to intermediate 3. The bromine of dibromo intermediate 3 was then easily displaced with 4-piperidinopiperidine under refluxing conditions. The reaction can be controlled to afford 4 exclusively, since the amino substitution deactivates further addition. The 2-piperidinopiperidine-5-bromothiadiazole 4 was subsequently coupled with both commercially available and custom synthesized amines under microwave conditions to afford the desired products 5 in 50–80% yields (Scheme 1).

Scheme 1.

Scheme 1

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In earlier studies, it was envisioned that the urea moiety would hinder entry into the brain due to its multiple H-bond donor and acceptor characteristics. Replacement of the urea with aryl groups improved brain penetration and absorption.21 Encouraged by these findings, we used this lead compound as a starting point for modification of the urea moiety. Because H3 activity is centrally mediated, we focused on removing the H-bond donors to improve CNS penetration and pharmacokinetic properties. Table 1 shows the binding affinities in a [3H]-N-α-methylhistamine human and mouse recombinant assay. In compounds 5a and 5b, removal of the H-bond donors afforded moderate to no improvement in the binding affinities. Replacement of the urea moiety with piperidinone (5c) displayed a 2–3-fold drop in potency. The change of piperidinone to 3,3-difluoropyrrolidine (5d) showed improved H3 binding affinity by 2-fold in both species when compared to 5c. Interestingly, the 4,4-difluoropiperidine 5e (hH3Ki = 15 nM, mH3Ki = 18 nM) displayed a 4-fold improvement in affinity as compared to 5d. The effect of substitution on the piperidine ring was next investigated. Substitution at the 3-position of the piperidine ring with phenyl (5f) was over 5-fold weaker for both human and mouse H3 receptor than 5e. Attempts to replace the phenyl group with methoxy (5g), hydroxy (5h), or fluoro (5i) gave no improvement in human or mouse H3 binding affinities. Replacement of the piperidine group with morpholine (5j) had weaker H3 binding affinities in both species. However, basic compounds such as pyrrolidine (5d), piperidine (5e), and morpholine (5j) showed a promising interaction with the H3 receptor and were deemed more appropriate for further optimization due to their better pharmacokinetic profile.22

Table 1. Binding Affinities of 2-Piperidinopiperidine Thiadiazole Derivatives.

graphic file with name ml-2011-00250t_0008.jpg

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a

Binding affinity in a [3H]-N-α-methylhistamine human and mouse recombinant assay. H3 binding Ki values are the average of at least two independent determinations ± standard deviations.

Encouraged by these findings and on the basis of knowledge acquired from prior SAR studies, we then undertook a detailed study of the piperidine moiety by incorporating appropriate structural modifications (Table 2). Replacement of the phenyl ring with heterocycles such as pyridine (5k) and pyrimidine (5l) showed a 6-fold improvement in human and a 2–3-fold improvement in mouse H3 affinity. A breakthrough in potency was achieved when pyridine (5m) (hH3Ki = 3 nM and mH3Ki = 5 nM) showed single digit nanomolar range in human and mouse H3 receptor binding affinity. However, methoxy (5n) and hydroxy (5o) substitution at the 3-position of piperidine displayed an 18-fold drop in binding affinity in both species with the exception of 5n (hH3Ki = 11 nM). Exchange of the hydroxy with a fluoro substituent (5p) (hH3Ki = 4.0 nM and mH3Ki = 7.0 nM) evoked high affinity at the human and mouse H3 receptor. Replacement of the pyridine (5o) with pyrimidine (5q) displayed a decrease in potency. When the hydroxy pyridine (5o) was replaced with morpholine (5r), the binding affinity improved 11-fold with Ki = 5.0 nM in human and 5-fold with Ki = 11 nM in mouse. Replacement of the pyridine heterocycle with pyrazine (5s) resulted in no significant improvement in binding affinity.

Table 2. Binding Affinities of 2-Piperidinopiperidine Thiadiazole Derivatives.

graphic file with name ml-2011-00250t_0009.jpg

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a

Binding affinity in a [3H]-N-α-methylhistamine human and mouse recombinant assay. H3 binding Ki values are the average of at least two independent determinations ± standard deviations.

To determine the importance of the stereogenic chiral center on affinity, the enantiomers of 5r were separated by super critical fluid chromatography (SFC), and their single isomers (5t and 5u) were tested individually.23 The slower eluting enantiomer 5u was found to have greater binding affinity at both human and mouse H3 receptor as compared to the faster eluting enantiomer 5t.

Table 3 summarizes the in vitro, ex vivo, and pharmacokinetic properties of compounds 5m, 5p, and 5u. Compounds 5p and 5u exhibited significantly lower potential for human ether-à-go-go related gene (hERG) channel inhibition as measured using a high-throughput rubidium efflux assay.24 These compounds showed no inhibition for 3A4, 2D6, and 2C9 under pre- or co-incubation conditions. Particularly noteworthy is that the compounds are potent in the ex vivo receptor occupancy study in imprinting control region (ICR) mouse. Four hours following oral administration of compounds at 30 mg/kg, the total brain concentrations were measured. Compounds 5m and 5p showed modest brain concentrations with good plasma exposure. The low brain concentration of compound 5u may in part be due to their low lipophilicity (cLogP = 1.23).

Table 3. Pharmacokinetic Properties and ex Vivo and in Vitro Profiles of Representative Diamines.

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For assessment of the antihyperglycaemic effect, STZ-induced (STZ at 80 mg/kg, ip) diabetic ICR mice (blood glucose; 250–500 mg/dL) were used to evaluate the capacity of 5p and 5u to lower blood glucose. The non-fasting glucose was monitored daily before quaque die (QD) dosing of 5p and 5u (30 mg/kg). Figure 2 illustrates the change in blood glucose level. Compound 5u (−104.5 mg/dL) significantly decreased non-fasting glucose on day 2 when compared to 5p (−67.91 mg/dL). The pharmacokinetic profile of compounds 5p and 5u revealed that the brain/plasma ratios were not important to achieve efficacy in the diabetes model. For example, compound 5p had a brain/plasma ratio of 0.227, demonstrating only moderate efficacy. On the other hand, compound 5u with a brain/plasma ratio of just 0.016 was fully efficacious in the diabetes model. The link between exposure and efficacy is dependent on a number of factors in combination including the binding of the compound in blood and in the CNS, blood–brain barrier (BBB) permeability, the concentration–time (c-t) profile of the compound in blood, the distribution within the brain parenchyma, and the clearance out of the CNS. Indeed, there seem to be many CNS discovery programs that have identified compounds, which despite a very low brain/plasma ratio demonstrate the desired efficacy in animal models or human.25

Figure 2.

Figure 2

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Antihyperglycemic effect of 5p and 5u in STZ-induced diabetic ICR mice. Data are expressed as the mean ± SEM (n = 12/group). **P < 0.01 as compared with the control (0) group.

Glycated hemoglobin (HbA1c) is routinely used as a marker for long-term glycemic control. Elevated HbA1c has been regarded as an independent risk factor for coronary heart disease (CHD) and stroke in subjects with diabetes. In view of this, it was rationalized to testify the potential of compound 5u in a chronic study with the change of HbA1c as the end point. Compound 5u dose dependently blocked the increase of HbA1c following a 12 day treatment in STZ DIO mice (Figure 3).

Figure 3.

Figure 3

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Dose–response effect of 5u on HbA1c levels in type 2 diabetic mice (10 and 30 mg/kg). **P < 0.01 as compared with the control (0) group.

In conclusion, we have synthesized and evaluated a new series of 2-piperidinopiperidine thiadiazole derivatives as H3 receptor antagonists. Compound 5u was identified as having excellent potency and ex vivo receptor occupancy. We also found that treatment with 5u improves glycemic control in the STZ-induced diabetic mouse model. These findings indicate that 5u may be a new therapeutic agent for the treatment of type 2 diabetes. The role of the H3 receptor in type 2 diabetes needs to be further investigated.

Acknowledgments

We thank the Drug Metabolism and Pharmacokinetics group of the Schering-Plough Research Institute for providing the pharmacokinetic data. Thanks are also due to Dr. Christopher Boyce for comments on the preparation of the manuscript and Dr. Malcolm MacCoss for his support and encouragement.

Glossary

Abbreviations

GPCR

G-protein coupled receptor

CNS

central nervous system

MS

metabolic syndrome

HTS

high-throughput screen

SAR

structure–activity relationship

SFC

super critical fluid chromatography

hERG

human ether-à-go-go related gene

ICR

imprinting control region

STZ

streptozotocin

DIO

diet-induced obesity

QD

quaque die

BBB

blood–brain barrier

c-t

concentration–time

CHD

coronary heart disease

HbA1c

glycated hemoglobin

Supporting Information Available

Experimental procedures for assay protocols and synthesis and characterization of compounds 2–5a–u. This material is available free of charge via the Internet at http://pubs.acs.org.

The authors declare no competing financial interest.

Supplementary Material

ml200250t_si_001.pdf (3.4MB, pdf)

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Associated Data

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Supplementary Materials

ml200250t_si_001.pdf (3.4MB, pdf)

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