Development of potent and selective small-molecule human Urotensin-II antagonists

McAtee, John J.; Dodson, Jason W.; Dowdell, Sarah E.; Girard, G. R.; Goodman, Krista B.; Hilfiker, Mark A.; Sehon, Clark A.; Sha, Deyou; Wang, Gren Z.; Wang, Ning; Viet, Andrew Q.; Zhang, Dao Hua; Aiyar, Nambi; Behm, David J.; Carballo, Luz H.; Evans, Christopher A.; Fries, Harvey E.; Nagilla, Rakesh; Roethke, Theresa J.; Xu, Xiaoping; Yuan, Catherine C.K.; Douglas, Stephen A.; Neeb, Michael J.

doi:10.1016/j.bmcl.2008.05.027

Cited by 9 publications

(2 citation statements)

References 33 publications

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“…The first section provides an overview of reports where the authors have successfully minimized CYP2D6 inhibition during LO and reported significant structure activity relationships (SAR) at CYP2D6. These articles cover a wide range of therapeutic targets including dipeptidyl peptidase IV (DPP-4) inhibitors [68], CXC chemokine receptor 3 (CXCR3) antagonists [69], human urotensin-II (hU-II) antagonists [70], CC chemokine receptor 3 (CCR3) antagonists [71][72][73], monoamine reuptake inhibitors [74][75][76][77], kappa opioid receptor agonists [78,79], sodium channel blockers [80], 20-HETE synthase inhibitors [81,82], CB2 receptor agonists [83], H3 receptor antagonists [84], melanin-concentrating hormone receptor-1 (MCH-R1) antagonists [85], and chemokine CCR5 receptor antagonists [86].…”

Section: Survey Of Medicinal Chemistry Tactics Used To Reduce Cyp2d6 mentioning

confidence: 99%

“…Researchers at GlaxoSmithKline previously identified, by high throughput screening and HtL optimization, compound 10 as a potent UT-II receptor antagonist (10: UT-II K i = 16 nM) ( Fig. (5)) [70]. This antagonist could not be further developed due to its high intrinsic clearance, poor bioavailability and significant CYP2D6 and CYP3A4 inhibitory activity (CYP2D6 IC 50 = 750 nM; CYP3A4 IC 50 = 1,400 nM).…”

Section: Human Urotensin-ii (Hu-ii) Antagonistsmentioning

confidence: 99%

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Medicinal Chemistry Strategies to Reduce CYP2D6 Inhibitory Activity of Lead Candidates

Bourdonnec¹,

Leister²

2009

CMC

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Among the various human cytochrome P450s (CYP450s) that catalyze the biotransformation of xenobiotics, CYP450 2D6 (CYP2D6) is one of the most important based on the number and wide variety of its drug substrates. CYP2D6 shows a high degree of interindividual variability, which is primarily due to the extensive genetic polymorphism that influences its expression and function. A number of drugs have been clinically implicated in major drug-drug interactions (DDI) via CYP2D6 inhibition. In order to avoid or minimize issues related to CYP2D6-mediated DDIs, pharmaceutical companies routinely screen for potential CYP2D6 liability of lead candidates in the early stage of the drug discovery process. This review summarizes the medicinal chemistry tactics employed to mitigate inhibitory activity at CYP2D6, identified through an extensive literature survey covering the 1998-2008 period.

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