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. 2011 Nov 24;3(1):63–68. doi: 10.1021/ml200243g

Discovery of SCH 900271, a Potent Nicotinic Acid Receptor Agonist for the Treatment of Dyslipidemia

Anandan Palani †,*, Ashwin U Rao †,*, Xiao Chen †, Xianhai Huang †, Jing Su †, Haiqun Tang †, Ying Huang †, Jun Qin †, Dong Xiao †, Sylvia Degrado †, Michael Sofolarides †, Xiaohong Zhu †, Zhidan Liu †, Brian McKittrick †, Wei Zhou †, Robert Aslanian †, William J Greenlee †, Mary Senior †, Boonlert Cheewatrakoolpong ‡, Hongtao Zhang ‡, Constance Farley ‡, John Cook ‡, Stan Kurowski ‡, Qiu Li ‡, Margaret van Heek ‡, Gangfeng Wang §, Yunsheng Hsieh §, Fangbiao Li §, Scott Greenfeder ‡, Madhu Chintala ‡
PMCID: PMC4025820  PMID: 24900372

Abstract

graphic file with name ml-2011-00243g_0005.jpg

Structure-guided optimization of a series of C-5 alkyl substituents led to the discovery of a potent nicotinic acid receptor agonist SCH 900271 (33) with an EC50 of 2 nM in the hu-GPR109a assay. Compound 33 demonstrated good oral bioavailability in all species. Compound 33 exhibited dose-dependent inhibition of plasma free fatty acid (FFA) with 50% FFA reduction at 1.0 mg/kg in fasted male beagle dogs. Compound 33 had no overt signs of flushing at doses up to 10 mg/kg with an improved therapeutic window to flushing as compared to nicotinic acid. Compound 33 was evaluated in human clinical trials.

Keywords: Nicotinic acid receptor (NAR) agonist, flushing, dyslipidemia, FFA, LDL-C, VLDL-C, TG, HDL-C, CAD

Morbidity and mortality associated with coronary artery disease (CAD) are significant problems around the world. Elevated low-density lipoprotein cholesterol (LDL-C) and plasma triglycerides (TG) and low levels of high-density lipoprotein cholesterol (HDL-C) are considered risk factors for the development of CAD. An improvement in all of these risk factors would reduce the risk for developing CAD. Nicotinic acid (NA, niacin) has been used clinically for decades to favorably alter plasma lipids.1 NA reduces plasma free fatty acid (FFA), very low-density lipoprotein cholesterol (VLDL-C), LDL-C, plasma TG, and lipoprotein a (Lp-a), while increasing HDL-C.2−7 Despite this attractive profile, physician adoption and patient compliance with NA are limited due to intense cutaneous flushing at therapeutic concentrations, a difficult dose titration schedule to avoid this side effect, and large doses.8,9 An extended release formulation of NA (NIASPAN) is available by prescription.10 This formulation has a reduced incidence of flushing, but patients must undergo a complicated titration schedule to approach maximally efficacious doses and often do not achieve desired lipid goals due to tolerability issues. In addition, studies have shown that patients taking a combination of extended release NA and an antagonist of the prostaglandin D2 antagonist (DP) (TREDAPTIVE) show reduced flushing symptoms as compared to taking NA alone.11

The molecular target for NA was discovered in 2003. NA binds with high affinity to and activates the G-protein coupled receptor GPR109a, expressed primarily in human adipose tissue. NA also binds with low affinity to the homologous receptor GPR109b, which shares ∼95% identity to GPR109a and is only expressed in the human and chimpanzee.12−16 Activation of GPR109a in adipose tissue mediates an antilipolytic response by lowering intracellular 3′-5′-cyclic adenosine monophosphate (cAMP) levels, leading to reduced protein kinase A activity. This in turn results in a decrease in lipase activity and a reduction in intracellular TG hydrolysis. A reduction in intracellular lipolysis decreases FFA secretion into plasma and ultimately reduces the hepatic FFA pool available for TG resynthesis. It has been postulated that the decreased availability of FFA in the liver directly reduces the production of hepatic TG and VLDL.17−21 What is much less clear is whether the acute effects on plasma FFA and TG can eventually lead to an increase in HDL-C levels and other associated lipid and lipoprotein changes.22,23

Since the discovery of NA receptors (NAR), extensive efforts have been devoted to NAR agonists.24−27 Our lead identification strategy, which involved an extensive structure–activity relationship (SAR) investigation of the C-2 region of a thiobarbituric acid core, had been shown to activate the receptor and has been reported previously.28 Further screening and elaboration of both the C-2 and the C-5 regions provided a pyranopyrimidinedione series suitable for optimization as NAR agonists. A comparison of the in vitro activity data of the compounds synthesized is shown in Table 1. When the thiol group (vide supra) was changed to a carbonyl group (1), while maintaining the ethyl group at the C-5 position, significant improvement in potency was observed. Compounds 2 and 3, incorporating methyl and n-propyl groups, respectively, were 3–9-fold less active in the cAMP assay. Interestingly, the n-butyl analogue 4 showed moderate activity equivalent to that of 1. Changing R1 from ethyl (1) to isopropyl (5) was less tolerated, with 7-fold loss in activity. Fluoroalkyl derivatives were less tolerated with significant loss in activity (6 and 7). When R1 was substituted with phenyl (8) or an ester (9), there was complete loss in activity. One carbon homologation of 8 and 9 as in 10 and 11 or introduction of polar functional group (12) resulted in decreased activity.

Table 1. Potency of Compounds in the hu-GPR109a cAMP Assay.

graphic file with name ml-2011-00243g_0007.jpg

compd R1 EC50 (nM)a compd R1 EC50 (nM)a
1 Et 31 ± 18 7 CH2CF3 1600 ± 720
2 Me 290 ± 14 8 Ph >10000
3 n-Pr 99 ± 58 9 CO2Me >10000
4 n-Bu 17 ± 5.0 10 CH2CO2Me 930 ± 230
5 i-Pr 220 ± 44 11 4–F-C6H4CH2 170 ± 54
6 CF3 >10000 12 CH(OH)Me 1300 ± 240
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a

Data represent an average of multiple determinations (n ≥ 3) ± standard deviations.

Having identified the optimal R1 linker length, we undertook additional SAR studies on the C-5 region having longer side chain with different alkyl and aryl substituents (Table 2). Although the phenyl group in 13 had a negative effect on activity, the thiophene derivatives (14 and 15) retained better in vitro activity. Compounds 16 and 17 with longer alkyl side chains retained activity similar to that of 4. Introduction of heteroatoms, for example 18, showed much weaker activity, whereas the thio analogue 19 showed excellent activity. However, oxidation of 19 to the sulfone 20 was detrimental to activity. Meanwhile, the effect of branching on compound 4 was studied, which showed some interesting results. The α- and β-methyl group (with respect to C-5) in 21 and 22 showed significant loss in potency, while the γ-methyl improved the potency in the hu-GPR109a assay by 4-fold (23, EC50 = 4.0 nM). Introduction of another methyl substituent at the gamma position (24) resulted in complete loss of activity, indicating the role of steric hindrance in cAMP activity. Homologation of 23 to 25 retained the best in vitro activity with an EC50 of 5.0 nM. Interestingly, fluoroalkyl derivatives 26 and 27 showed good activity with the difluoromethyl analogue (26) having an EC50 of 3.0 nM. An attempt was made to introduce small cycloalkyl groups given the promising data of analogues 23 and 25. The cyclopropyl ring (28) was 3-fold less potent than 23. However, the cyclobutyl ring (29) showed excellent activity (EC50 = 1.0 nM). Increasing the linker length had an opposite effect on activity (30, EC50 = 4.0 nM, vs 31, EC50 = 39 nM). Further extending the linker length (32) led to decreased activity. Elaboration of SAR on compound 30 with substituents on the cyclopropyl ring was investigated with the identification of compound SCH 900271 (33) with excellent activity (EC50 = 2.0 nM). The substitution on the ipso position of cyclopropyl played an important role in activity, although the ethyl (34) and the halogens (35 and 36) showed a slight decrease in activity. SAR studies of the C-5 region eventually led to the discovery of several compounds with potent in vitro activity. Compounds tested active as GPR109a agonists are full agonists and showed much weaker agonist potency for the GPR109b (vide infra). The presence of the NH is important for GPR109a activity, and the acidic N1–H bond mimics the role of NA. The substitution of small alkyl groups on either N1 or N3 led to several fold loss in agonist potency.29

Table 2. Potency of Compounds in the hu-GPR109a cAMP Assay.

graphic file with name ml-2011-00243g_0008.jpg

graphic file with name ml-2011-00243g_0001.jpg

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a

Data represent an average of multiple determinations (n ≥ 3) ± standard deviations.

The synthetic route to pyranopyrimidinedione 33 as a representative example is summarized in Scheme 1. Starting with ethyl 5-methylhex-5-enoate 37, cyclopropanation followed by basic hydrolysis afforded 4-(1-methylcyclopropyl)butanoic acid 39. The acid 39 was then converted to the β-keto ester 40 followed by condensation of barbituric acid 41 in refluxing acetic acid to afford 33. This sequence was adopted to prepare most of the analogues in this series.

Scheme 1. Synthesis of Compound 33.

Scheme 1

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Reagents and conditions: (a) Et2Zn, CH2I2, TFA, CH2Cl2, 0 °C to room temperature, 12 h, 99%. (b) NaOH, EtOH, room temperature, 12 h, 93%. (c) Ethyl potassium malonate, CDI, MgCl2, THF, room temperature, 12 h, 99%. (d) Compound 41, glacial AcOH, 110 °C, 24 h, 15%.

Following these initial studies, several compounds were dosed orally in a rat in vivo model designed to measure reductions in FFA and TG (Table 3). Compound 4 demonstrated excellent efficacy in vivo (rat FFA, −29%; TG, −40%, 1 h post 1.0 mg/kg po dosing). Compound 4 also exhibited a dose-dependent reduction in plasma FFA and achieved 90% FFA reduction at 0.3 mg/kg dose in dogs. Only a very modest reduction of FFA and TG was observed following oral administration of 3.0 mg/kg of 23, which was not statistically significant. Excellent in vivo efficacy was observed with compound 26 (TG, −59%, 1 h post 1.0 mg/kg po dosing). In dogs, 26 suppressed plasma FFA (80%); however, 4 h postdosing, FFA rebounded to levels markedly above baseline, a phenomenon not seen with other compounds in this series. The observed FFA reduction was also accompanied by modest flushing seen at 3.0 mg/kg also not seen with other compounds in this series. It is of interest to note the potential link between flushing and FFA rebound with compound 26, which is reminiscent of the clinical profile of niacin. The reason for flushing behavior shown by compound 26 is not clear, and we speculate that it could be due to differences in free drug concentration in plasma.30 Reduction of FFA and TG levels by 29 and 30 was also measured in rats and dogs. Significant reductions in plasma FFA and TG were observed that were essentially equal in magnitude to the response elicited by a 10 mg/kg dose of NA. However, further evaluation of compound 4 was discontinued as it was found to cause acute renal necrosis in mice. Serum blood urea nitrogen (BUN) and creatinine were markedly elevated in mice at 100 mg/kg. Profound nephrotoxicity was also observed with a few other compounds in this series, including compounds 29 and 30. Similar toxicity was not observed in rats, thereby suggesting that this phenomenon is likely species specific. The mechanism of this observed side effect is yet to be determined. Compound 33 was profiled further to assess its potential as a drug candidate.

Table 3. In Vitro and in Vivo Potencies of NAR Agonists and NA.

  4 23 26 29 30 33 NA
hu-GPR109a EC50 (nM)a 17 4.0 3.0 1.0 4.0 2.0 99 ± 15
hu-GPR109b EC50 (nM)a 190 1300 59 67 140 96 >10000
rat-GPR109a EC50 (nM)a 8.0 4.0 2.0 5.0 2.0 8.0 39 ± 10
m-GPR109a EC50 (nM)a 12 NDb 5.0 4.0 NDb 6.0 29 ± 5.0
dog-GPR109a EC50 (nM)a 16 NDb 3.0 NDb 1.0 5.0 31 ± 13
rat FFA reduction (1 h post 1.0 mg/kg dosing) (%) –29 –15c NDb –50 –58 –53 –80d
rat TG reduction (1 h post 1.0 mg/kg dosing) (%) –40 –16c –59 –31 –49 –53 –60d
dog FFA reduction (1 h post 1.0 mg/kg dosing) (%) –90e NDb –80c NDb –80f –50 –38c
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a

Data represent an average of multiple determinations (n ≥ 3) ± standard deviations.

b

ND, not determined.

c

3.0 mg/kg dosing.

d

10.0 mg/kg dosing.

e

0.3 mg/kg dosing.

f

2.0 mg/kg dosing.

Additionally, compound 33 was assessed for the reduction in FFA and TG in fasted rats (Table 3). Compound 33 was dosed orally in fasted rats, which demonstrated robust efficacy in vivo (rat FFA, −53%; TG, −53%, 1 h post 1.0 mg/kg po dosing) as compared to 4. Compound 33 had good plasma exposure in rat AUC0–24 h = 7.6 μM h, 5 mg/kg po dosing, and F = 76%. A head-to-head study between 33 and NA demonstrated that 33 also had improved potency as compared to NA in vitro and in vivo (see the Supporting Information). Compound 33 dose dependently reduced rat plasma FFA and TG with an ED50 of approximately 0.5 mg/kg and a maximally effective dose of 3.0 mg/kg. The ED50 for NA on plasma FFA was difficult to calculate due to its steep dose response effect in this model. The maximally effective dose for NA on plasma FFA was 10 mg/kg. A time–course study of 33 in rat at 3.0 mg/kg showed that it reduced FFA and plasma TG 0.5, 1, and 2 h after dosing but had no activity at later time points. In comparison, the duration of activity with NA at 10 mg/kg treatment did not extend beyond 2 h after dosing. Compound 33 was studied for efficacy and flushing profile in fasted male beagle dogs and exhibited dose-dependent inhibition of plasma FFA with 50% FFA reduction at 1.0 mg/kg (Figure 1). At this dose and up to 10 mg/kg, dogs had no overt signs of flushing, as determined by quantification of changes in cutaneous blood flow and/or changes in skin color and behavior (Figure 2). In contrast, NA achieved similar reduction of FFA at 30 mg/kg dose, but this dose produced a pronounced flushing response in 9 of 13 dogs, observed as an average of a 5-fold increase in cutaneous blood flow from baseline as well as behavioral responses characterized by head shaking and ear scratching. There was no incidence of nephrotoxicity with 33 in mice at 100 mg/kg po for 5 days. This compound also demonstrated a good pharmacokinetic (PK) profile in the dog (dog AUC0–24 h = 7.2 μM h, 1.0 mg/kg po dosing, and F = 40%). Compound 33 had no effect on hERG at concentrations up to 10 μM,31 representing a 1400-fold multiple of the projected free human Cmax required for efficacy, was not an inhibitor of human CYPs 1A2, 2C9, 2D6, or 3A4 (IC50 > 50 μM), and did not show induction of CYP3A4 in the human PXR assay up to 10 μM. No significant activity was observed for 33 in various counter screens. The CLint value of compound 33 in human/rat/dog/mouse is 1.6/10/<1/8.7 μL/min/106 cells.

Figure 1.

Figure 1

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Acute FFA reduction of compound 33 in dogs.

Figure 2.

Figure 2

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Peak fold increase from baseline in cutaneous blood flow in dogs dosed with compound 33 (0.3–10 mg/kg, po), NA, or vehicle (data for individual dogs).

In summary, we have identified a potent NAR agonist 33, which demonstrated excellent in vivo activity in animal models. In addition, the incidence and magnitude of cutaneous blood flow increases (flushing) observed with NA in the dog models were not observed with compound 33, suggesting that it has an improved therapeutic window to flushing as compared to NA. This compound was investigated and developed further for its clinical potential.32 Data from the phase I and phase II studies will be the subject of future publications.

Acknowledgments

We thank Drs. John Piwinski, Catherine Strader, Michael Graziano, and Jean Lachowicz for their strong support.

Glossary

Abbreviations

NA

nicotinic acid

FFA

free fatty acid

VLDL-C

very low-density lipoprotein cholesterol

LDL-C

low-density lipoprotein cholesterol

TG

triglyceride

Lp-a

lipoprotein a

HDL-C

high-density lipoprotein cholesterol

CAD

coronary artery disease

NAR

nicotinic acid receptor

GPR

G-protein coupled receptor

cAMP

3′-5′-cyclic adenosine monophosphate

PK

pharmacokinetic

CYP

cytochrome P450

BUN

blood urea nitrogen

TFA

trifluoroacetic acid

CDI

1,1′-carbonyldiimidazole

Supporting Information Available

Experimental procedures for assay protocols, in vivo studies, and synthesis and characterization of compounds 1–-36. This material is available free of charge via the Internet at http://pubs.acs.org.

The authors declare no competing financial interest.

Supplementary Material

ml200243g_si_001.pdf (3.2MB, pdf)

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Supplementary Materials

ml200243g_si_001.pdf (3.2MB, pdf)

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