AC 265347 - CAS 1253901-26-6
Category: Inhibitor
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Molecular Weight:
AC 265347 is a CaSR biased allosteric modulator (pEC50 = 7.8-8.1) that bias signaling towards the accumulation of PERK1/2 and IP1. AC 265347 stimulates CaSR signaling in cellular proliferation and phosphatidyl inositol (PI) hydrolysis assays. It significantly activates human GABAB or type I PTH receptors.
Brife Description:
CaSR agonist
≥99% by HPLC
α-(2,4-Dimethylphenyl)-α-methyl-2-benzothiazolemethanol; 1-(1,3-benzothiazol-2-yl)-1-(2,4-dimethylphenyl)ethanol
Canonical SMILES:
1.Identification of Global and Ligand-Specific Calcium Sensing Receptor Activation Mechanisms.
Keller AN;Kufareva I;Josephs TM;Diao J;Mai VT;Conigrave AD;Christopoulos A;Gregory KJ;Leach K Mol Pharmacol. 2018 Jun;93(6):619-630. doi: 10.1124/mol.118.112086. Epub 2018 Apr 10.
Calcium sensing receptor (CaSR) positive allosteric modulators (PAMs) are therapeutically important. However, few are approved for clinical use, in part due to complexities in assessing allostery at a receptor where the endogenous agonist (extracellular calcium) is present in all biologic fluids. Such complexity impedes efforts to quantify and optimize allosteric drug parameters (affinity, cooperativity, and efficacy) that dictate PAM structure-activity relationships (SARs). Furthermore, an underappreciation of the structural mechanisms underlying CaSR activation hinders predictions of how PAM SAR relates to in vitro and in vivo activity. Herein, we combined site-directed mutagenesis and calcium mobilization assays with analytical pharmacology to compare modes of PAM binding, positive modulation, and agonism. We demonstrate that 3-(2-chlorophenyl)-;N;-((1;R;)-1-(3-methoxyphenyl)ethyl)-1-propanamine (NPS R568) binds to a 7 transmembrane domain (7TM) cavity common to class C G protein-coupled receptors and used by (;αR;)-(-)-;α;-methyl-;N;-[3-[3-[trifluoromethylphenyl]propyl]-1-napthalenemethanamine (cinacalcet) and 1-benzothiazol-2-yl-1-(2,4-dimethylphenyl)-ethanol (AC265347); however, there are subtle distinctions in the contribution of select residues to the binding and transmission of cooperativity by PAMs.
2.Divergent effects of strontium and calcium-sensing receptor positive allosteric modulators (calcimimetics) on human osteoclast activity.
Diepenhorst NA;Leach K;Keller AN;Rueda P;Cook AE;Pierce TL;Nowell C;Pastoureau P;Sabatini M;Summers RJ;Charman WN;Sexton PM;Christopoulos A;Langmead CJ Br J Pharmacol. 2018 May 1. doi: 10.1111/bph.14344. [Epub ahead of print]
BACKGROUND AND PURPOSE: ;Strontium ranelate, a drug approved and until recently used for the treatment of osteoporosis, mediates its effects on bone at least in part via the calcium-sensing (CaS) receptor. However, it is not known whether bone-targeted CaS receptor positive allosteric modulators (PAMs; calcimimetics) represent an alternative (or adjunctive) therapy to strontium (Sr;2+;o; ).;EXPERIMENTAL APPROACH: ;We assessed three structurally distinct calcimimetics [cinacalcet, AC-265347 and a benzothiazole tri-substituted urea (BTU-compound 13)], alone and in combination with extracellular calcium (Ca;2+;o; ) or Sr;2+;o; , in G protein-dependent signalling assays and trafficking experiments in HEK293 cells and their effects on cell differentiation, tartrate-resistant acid phosphatase (TRAP) activity and hydroxyapatite resorption assays in human blood-derived osteoclasts.;KEY RESULTS: ;Sr;2+;o; activated CaS receptor-dependent signalling in HEK293 cells in a similar manner to Ca;2+;o; , and inhibited the maturation, TRAP expression and hydroxyapatite resorption capacity of human osteoclasts. Calcimimetics potentiated Ca;2+;o; - and Sr;2+;o; -mediated CaS receptor signalling in HEK293 cells with distinct biased profiles, and only cinacalcet chaperoned an endoplasmic reticulum-retained CaS mutant receptor to the cell surface in HEK293 cells, indicative of a conformational state different from that engendered by AC-265347 and BTU-compound 13.
3.Biased allosteric modulation at the CaS receptor engendered by structurally diverse calcimimetics.
Cook AE;Mistry SN;Gregory KJ;Furness SG;Sexton PM;Scammells PJ;Conigrave AD;Christopoulos A;Leach K Br J Pharmacol. 2015 Jan;172(1):185-200. doi: 10.1111/bph.12937. Epub 2014 Dec 1.
BACKGROUND AND PURPOSE: ;Clinical use of cinacalcet in hyperparathyroidism is complicated by its tendency to induce hypocalcaemia, arising partly from activation of calcium-sensing receptors (CaS receptors) in the thyroid and stimulation of calcitonin release. CaS receptor allosteric modulators that selectively bias signalling towards pathways that mediate desired effects [e.g. parathyroid hormone (PTH) suppression] rather than those mediating undesirable effects (e.g. elevated serum calcitonin), may offer better therapies.;EXPERIMENTAL APPROACH: ;We characterized the ligand-biased profile of novel calcimimetics in HEK293 cells stably expressing human CaS receptors, by monitoring intracellular calcium (Ca(2+) i ) mobilization, inositol phosphate (IP)1 accumulation, ERK1/2 phosphorylation (pERK1/2) and receptor expression.;KEY RESULTS: ;Phenylalkylamine calcimimetics were biased towards allosteric modulation of Ca(2+) i mobilization and IP1 accumulation. S,R-calcimimetic B was biased only towards IP1 accumulation. R,R-calcimimetic B and AC-265347 were biased towards IP1 accumulation and pERK1/2. Nor-calcimimetic B was unbiased. In contrast to phenylalkylamines and calcimimetic B analogues, AC-265347 did not promote trafficking of a loss-of-expression, naturally occurring, CaS receptor mutation (G(670) E).
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CAS 1253901-26-6 AC 265347

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