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  • With this goal in mind we proceeded

    2021-10-20

    With this goal in mind, we proceeded to explore the C5-heteroaryl class of pyrazole-acids. Initial efforts, focused on a thiophene replacement, demonstrated little improvement. The 2-thiophene derivative (0.25μM and 0.24μM), a surrogate to the phenyl moiety, demonstrated only a modest boost in activity, when compared to . In addition, compound demonstrated a further reduction in affinity when assayed in the presence of human serum. Similarly, while thiophene analog (0.08μM and 0.09μM) showed improved intrinsic affinity for GPR109a, when compared with , compound also demonstrated reduced in vitro activity when assayed in the presence of human serum. We proceeded to explore the C5 -methyl pyrazole derivatives. While the 4--methyl pyrazole derivative, (1.6μM and 2.1μM), showed only modest intrinsic affinity for the niacin receptor, more intriguing was the limited effect serum had on the compound’s intrinsic affinity. Even more promising was the 5--methyl pyrazole-acid (0.45μM and 0.39μM) which showed good intrinsic affinity and nearly comparable activity in the presence of serum. Finally, the C-5--pyrazole and -triazole derivatives (3.4μM and 1.9μM) and (5.2μM and 4.0μM) demonstrated only modest affinity for the receptor, despite a minimal serum shift effect. In light of the promising in vitro activity for the series, we proceeded to investigate the ADME properties of select members of the class. In this regard, the mouse pharmacokinetic (mPK) profiles of lead candidates , a compound with excellent intrinsic affinity but an eightfold serum shift effect and compound , a compound with good intrinsic affinity and minimal serum-effect, were studied. As illustrated in , both and showed mPK profiles that compared favorably with niacin and pyrazole-tetrazole . The high affinity agonist demonstrated good bioavailability and low clearance when compared to niacin. Similarly, agonist with a promising in vitro profile and low-serum shift effect, showed modest results across all parameters. In an effort to understand the effect this serum shift might be having on the in vivo efficacy, we performed a head-to-head comparison of compounds and in our mouse PD assay. In this regard, we dosed compound in our mouse plasma free fatty AS-703026 australia assay (pFFA) and our mouse vasodilation assay (mVD). As illustrated in , six male C57 B1/6 mice were each dosed at 10mpk (IP) for 15min with and compared to mice dosed, 10mpk (IP) of , and 100mpk (IP) with niacin and the characteristic reduction in plasma free fatty acids was measured. In the case of compound , the mice that were treated showed a 41% reduction in plasma free fatty acids at 10mpk, compared to a 21% reduction in plasma free fatty acid upon administration of and a 38% reduction with niacin. Having demonstrated the ability of agonist to effectively lower plasma free fatty acids in our mouse PD model, further investigations hinged on whether or not this class of agonists would elicit a flushing response in our mouse vasodilation assay. With this goal in mind, compound was administered to eight mice at 30mpk (IP) for 15min, three times the dose for FFA reduction. As illustrated in , niacin administered in 13 mice at 30mpk (IP) showed an 80% change in perfusion, characteristic of a flushing response in the mouse. In contrast, compound showed no change in perfusion under similar experimental conditions. In summary, we have identified a new class of pyrazole-acids that act as selective agonists of GPR109a. In particular, optimization of the pyrazole-acid series resulted in the identification of compound , a potent, low-serum shift, and flush-free agonists of GPR109a that demonstrated superior in vivo efficacy when compared to previous members of the class. Further investigations are currently underway.
    Introduction Coronary heart disease and stroke remain major causes of morbidity and mortality worldwide. Abnormally high levels of LDL-cholesterol (LDL-c) and low levels of HDL-cholesterol (HDL-c) (i.e., dyslipidemia) have long been regarded as risk factors for the development of atherosclerotic disease. Niacin (nicotinic acid; vitamin B3) has been used for more than half a century to treat dyslipidemia; in fact, niacin was the first cholesterol modulating drug shown to reduce atherosclerotic disease and associated mortalities in the Coronary Drug Project [1], [2], [3]. Niacin possesses a broad spectrum of lipid-modulating activities, including lowering LDL-c, VLDL-c, triglycerides and Lipoprotein-A as well as increasing HDL-c [1], [4]. These changes in lipid profiles are accompanied in the clinical setting by improvements in symptoms of atherosclerosis. Unfortunately, patient compliance in clinical use of niacin has been severely hampered by its main side effect of cutaneous flushing [5]. The discovery of G-protein coupled receptor GPR109A (recently renamed as hydroxyl-carboxylic acid receptor 2 or HCA2) as a molecular target for niacin stimulated significant interest in the development of novel chemical entities retaining the lipid-modulating properties of niacin, but perhaps devoid of its flushing side effect [6]. GPR109A is expressed in multiple tissues, namely adipocytes, cells of immune origin, keratinocytes and hepatocytes. The lipid-modifying properties of niacin were until very recently believed to be mediated mostly by its anti-lipolytic activity exerted through inhibition of cAMP signaling in adipocytes via activation of GPR109A [4]. The flushing side effect of niacin has been attributed to the release of prostaglandins upon activation of GPR109A expressed in skin Langerhans cells as well as its action on keratinocytes [7], [8], [9].