Structure–Activity Relationships, Pharmacokinetics, and in Vivo Activity of CYP11B2 and CYP11B1 Inhibitors

Papillon, Julien P. N.; Adams, Christopher M.; Hu, Qiying; Lou, Changgang; Singh, Alok Kumar; Zhang, Chun; Carvalho, José Carlos Tavares; Rajan, Srinivan; Amaral, Adam; Beil, Michael E.; Fu, Fumin; Gangl, Eric; Hu, Chii-Whei; Jeng, Arco Y.; LaSala, Daniel; Liang, Guiqing; Logman, Michael; Maniara, Wieslawa; Rigel, Dean F.; Smith, Sherri; Ksander, Gary M.

doi:10.1021/acs.jmedchem.5b00407

Cited by 29 publications

(7 citation statements)

References 60 publications

(47 reference statements)

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“…Since LCI-699 (2) entered clinical studies, additional studies have reported a variety of CYP11B2 inhibitors to improve selectivity over CYP11B1. As shown in Figure 1, most of the reported inhibitors have one of two templates to coordinate the heme-iron motif: imidazole-based inhibitors 8 like FAD286 (1) and LCI-699 (2) or pyridine-based inhibitors 9 including tetrahydroisoquinoline-based inhibitors derived from substituted pyridine structures. Among a number of reported pyridine-based inhibitors, compound 3 reported by Novartis displayed high potency and selectivity over CYP11B1 and is in phase 1 clinical trials.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of Novel Pyrazole-Based Selective Aldosterone Synthase (CYP11B2) Inhibitors: A New Template to Coordinate the Heme-Iron Motif of CYP11B2

Sakakibara¹,

Sasaki²,

Onda³

et al. 2018

J. Med. Chem.

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It is necessary for aldosterone synthase (CYP11B2) inhibitors to have both high potency and high selectivity over 11β-hydroxylase (CYP11B1), a critical enzyme for cortisol synthesis. Previous studies have reported a number of CYP11B2 inhibitors, most of which have an imidazole or pyridine ring to coordinate the heme-iron motif of CYP11B2; however, highly selective inhibitors of human CYP11B2 are still needed. To expand the selectivity in humans, we explored alternative templates and found that pyrazoles were suitable templates for CYP11B2 inhibitors. Investigation of pyrazoles, especially N-alkyl pyrazoles, as a new template to coordinate the heme-iron motif led to a potent and highly selective CYP11B2 inhibitor 28 with an aldosterone-lowering effect at 1 mg/kg dosing in cynomolgus monkeys.

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Section: ■ Introductionmentioning

confidence: 99%

Discovery of Novel Pyrazole-Based Selective Aldosterone Synthase (CYP11B2) Inhibitors: A New Template to Coordinate the Heme-Iron Motif of CYP11B2

Sakakibara¹,

Sasaki²,

Onda³

et al. 2018

J. Med. Chem.

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“…Installation of a gem -dimethyl carbinol, a group frequently appearing in bioactive compounds, via nucleophilic additions to acetone is illustrated in Scheme . The quenching of the lithium anion of the benzylic carbon in 301 with acetone led to a gem -dimethyl carbinol 302 . A lithium–iodine exchange of 2-chloro-4-iodopyridine ( 303 ) using n -butyllithium followed by reaction with acetone furnished a gem -dimethyl carbinol 304 .…”

Section: Structural Role Of a Gem-dimethyl Groupmentioning

confidence: 99%

Natural-Products-Inspired Use of the gem-Dimethyl Group in Medicinal Chemistry

Talele

2017

J. Med. Chem.

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The gem-dimethyl moiety is a structural feature frequently found in many natural products of clinical interest, including, but not limited to, taxanes, epothilones, statins, retinoids, di-/triterpenes, noviose deoxysugar, and antibiotics derived from β-lactams, macrolides, and aminocoumarins. Inspired by this time-tested moiety, medicinal chemists have widely explored its use in developing bioactive molecules because of the possibility to (1) increase target engagement, potency, and selectivity through van der Waals interactions and entropically favorable restriction to a bioactive conformation, (2) mitigate toxicity, (3) obtain superior DMPK profile, (4) modulate the p K of nearby functionality, (5) induce symmetry into a monomethyl substituted chiral center, and (6) apply the Thorpe-Ingold conformational effect in an o-hydroxydihydrocinnamic acid based prodrug design. The aim of this Perspective is to illustrate how medicinal chemists have elegantly employed the gem-dimethyl group to obtain clinically useful drugs and to provide synthetic methods to install a gem-dimethyl group.

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“…To demonstrate the applicability of this reaction in the synthesis of C6-alkylated piperidin-2-one derivatives which show a wide range of biological activities, further transformation was explored (Scheme a). Hydrogenation of 3a gave the corresponding piperidin-2-one 7 in 83% yield.…”

mentioning

confidence: 99%

Rhodium(III)-Catalyzed Site-Selective C–H Alkylation and Arylation of Pyridones Using Organoboron Reagents

Peng

Jiang

et al. 2016

Org. Lett.

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In this study we developed a method for the pyridine-directed, rhodium-catalyzed, site-selective C-H alkylation and arylation of pyridones using commercially available trifluoroborate reagents. This simple and versatile transformation proceeded smoothly under relatively mild conditions with perfect site selectivity. The coupling groups in the boron reagents can be extended to primary alkyl, benzyl, and cycloalkyl. Moreover, direct C-H arylation products could also be obtained under similar conditions.

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Structure–Activity Relationships, Pharmacokinetics, and in Vivo Activity of CYP11B2 and CYP11B1 Inhibitors

Cited by 29 publications

References 60 publications

Discovery of Novel Pyrazole-Based Selective Aldosterone Synthase (CYP11B2) Inhibitors: A New Template to Coordinate the Heme-Iron Motif of CYP11B2

Discovery of Novel Pyrazole-Based Selective Aldosterone Synthase (CYP11B2) Inhibitors: A New Template to Coordinate the Heme-Iron Motif of CYP11B2

Natural-Products-Inspired Use of the gem-Dimethyl Group in Medicinal Chemistry

Rhodium(III)-Catalyzed Site-Selective C–H Alkylation and Arylation of Pyridones Using Organoboron Reagents

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