BMS 195614

BMS 195614 is a selective RARα antagonist [1]. It can bind to the RARα subunit [5].

BMS195614,4[[[[5,6-Dihydro-5,5-dimethyl-8-(3-quinolinyl)]-2-naphthalenyl] carbonyl]amino]benzoic acid [2], was considered to be retinoid antagonists as it inhibited all-transretinoic acid-induced (ATRA-induced) retinoic acid response elements-chloramphenicol acetyltransferase (RARE-CAT) reporter expression via concomitantly transfected retinoic acid receptors (RARs) [3][4].

Retinoic acids (RAs) are the most notably biologically active derivatives (collectively referred to as retinoids) of vitamin A (retinol). Retinoic acids exert a wide variety of profound effects on cellular differentiation, vertebrate development and homeostasis [6].

BMS 195614 reversed the induction effect of selective RARα agonists, AM580, AM80 and BMS 194753 on differentiation of the acute promyelocytic leukemia cell lines, NB4 and HL60 [1]. Treatment with retinoic acid (RA) (10-6 M) for 72 hrs significantly reduced T47D breast cancer cells migration. But RA in combination with BMS 195614 did not affect the cell movement [7]. In cells of a bovine stromal-vascular fraction from intramuscular fat, BMS 195614 significantly diminished the anti-adipogenic effect of ATRA [8].

BMS 195614 displayed poor in vivo activity in mice when administered orally. Treatment with BMS 195614 at oral doses for 1 month showed no inhibition to spermatogenesis [3]. Oral administration of BMS 195614 did not suppress spermatogenesis in mice [9].

References:
[1].  F. Christopher Zusi, Matthew V. Lorenzi and Valerie Vivat-Hannah. Selective retinoids and rexinoids in cancer therapy and chemoprevention. Drug Discovery Today, 2002, 7(23):1165-1174.
[2].  John E. Starrett, Jr., David R. Tortolani, Muzammil M. Mansuri, et al. Bristol-Myers Squibb Co. Retinoid-like Heterocycles. US patent 5,559,248. 1996 Sep. 24.
[3].  Sanny S. W. Chung, Rebecca A. D. Cuellar, Xiangyuan Wang, et al. Pharmacological Activity of Retinoic Acid Receptor Alpha-Selective Antagonists in Vitro and in Vivo. ACS Med. Chem. Lett., 2013, 4: 446-450.
[4].  Eun Young Park, Alice Dillard, Elizabeth A. Williams, et al. Retinol Inhibits the Growth of All-Trans-Retinoic Acid–Sensitive and All-Trans-Retinoic Acid–Resistant Colon Cancer Cells through a Retinoic Acid Receptor–Independent Mechanism. Cancer Res., 2005, 65(21):9923-9934.
[5].  Dongchun Liang, Aijun Zuo, Hui Shao, et al. Retinoic Acid Inhibits CD25þ Dendritic Cell Expansion and cd T-Cell Activation in Experimental Autoimmune Uveitis. Invest Ophthalmol Vis Sci., 2013, 54:3493-3503.
[6].  Pierre Chamban. A decade of molecular biology of retinoic acid receptors. FASEBJ., 1996, 10:940-954.
[7].  Flamini Marina Ines, Gauna Gisel Valeria, Sottile Mayra Lis, et al. Retinoic acid reduces migration of human breast cancer cells: role of retinoic acid receptor β. J. Cell. Mol. Med., 2014, 18(6): 1113-1123.
[8].  Nikolas Gunkel, Thorsten Meyer and John Michael Graettinger; N/A. Method of Modulating the Degree of Adipose Tissue Deposited Intramuscularly. US patent 20140094512A1. 2014 Apr. 3.
[9].  Fern E. Murdoch and Erwin Goldberg. Male contraception: Another holy grail. Bioorg. Med. Chem. Lett., 2014, 24:419-424.

Outcome appraisal of patients with limited brain metastases (BMs) from non small cell lung cancer (NSCLC) treated with different local therapeutic strategies: a single institute evaluation.[Pubmed:28256924]

Br J Radiol. 2017 Apr;90(1072):20170022.

OBJECTIVE: To evaluate the outcome of patients with non-small-cell lung cancer (NSCLC) with limited brain metastases (BMs) treated with local approaches omitting whole-brain radiation therapy (WBRT). METHODS: Surgery was performed in case of a single, large BM, controlled extracranial disease and Karnofsky Performance Status (KPS) 90-100; stereotactic radiosurgery (SRS) or hypofractionated stereotactic radiosurgery (HSRS) was performed in all other cases. The prescribed dose was 24 Gy/1 fraction for lesions <2.5 cm, and a median of 30 Gy (24-40 Gy) in 3-5 fractions for lesions >2.5 cm. RESULTS: 156 patients treated for 228 BMs were retrospectively evaluated. The median age was 62 years. The majority of patients had a KPS 90-100, recursive partitioning analysis Class II, diagnosis-specific graded prognostic assessment score 2.5-3 and 1-2 BMs. Surgical resection was performed in 18 cases, and SRS/HSRS was performed in 210 cases. The 1-2-year local control was 87.2 +/- 3.0% and 72.8 +/- 5.0%; the 1.2-year brain distant failure was 30.8 +/- 4.0% and 58.1 +/- 6.0%; the 1-2-year overall survival was 60.9 +/- 3.9% and 31.4 +/- 4.0%. On univariate and multivariate analysis, the following factors influenced survival: age (p = 0.01), the presence of lymph node involvement (p = 0.03), KPS (p << 0.01), the presence of extracranial metastases at the time of BM treatment (p < 0.01), the number of BMs (p = 0.02) and the treatment performed (p < 0.01). CONCLUSION: The choice of an adequate local treatment can impact on survival in patients with limited BMs from NSCLC. A careful evaluation of prognostic and predictive factors is a pivotal additional aid. Advances in knowledge: Radiosurgery or surgery followed by radiosurgery on the tumour bed in place of WBRT proved to be an effective treatment influencing outcome. Surgical resection followed by SRS on the tumour bed has to be considered for lesions >/=15 mm, in patients with good KPS, age

Safety, pharmacokinetics, and pharmacodynamics of BMS-986142, a novel reversible BTK inhibitor, in healthy participants.[Pubmed:28265691]

Eur J Clin Pharmacol. 2017 Jun;73(6):689-698.

PURPOSE: BMS-986142 is an oral, small-molecule reversible inhibitor of Bruton's tyrosine kinase. The main objectives of our phase I studies were to characterize the safety and tolerability, pharmacokinetics, and pharmacodynamics of BMS-986142 in healthy participants, and to investigate the potential for the effect of BMS-986142 on the PK of methotrexate (MTX) in combination. METHODS: In a combined single ascending dose and multiple ascending dose study, the safety, pharmacokinetics, and pharmacodynamics of BMS-986142 were assessed in healthy non-Japanese participants following administration of a single dose (5-900 mg) or multiple doses (25-350 mg, once daily for 14 days). In a drug-drug interaction study, the effect of BMS-986142 (350 mg, once daily for 5 days) on the single-dose pharmacokinetics of MTX (7.5 mg) was assessed in healthy participants. RESULTS: BMS-986142 was generally well tolerated, alone and in combination with MTX. BMS-986142 was rapidly absorbed with peak concentrations occurring within 2 h, and was eliminated with a mean half-life ranging from 7 to 11 h. Exposure of BMS-986142 appeared dose proportional within the dose ranges tested. A dose- and concentration-dependent inhibition of CD69 expression was observed following administration of BMS-986142. BMS-986142 did not affect the pharmacokinetics of MTX. CONCLUSIONS: BMS-986142 was well tolerated at the doses tested, had pharmacokinetic and pharmacodynamic profiles which support once-daily dosing, and can be coadministered with MTX without the pharmacokinetic interaction of BMS-986142 on MTX.

BMS-933043, a Selective alpha7 nAChR Partial Agonist for the Treatment of Cognitive Deficits Associated with Schizophrenia.[Pubmed:28337332]

ACS Med Chem Lett. 2017 Feb 8;8(3):366-371.

The therapeutic treatment of negative symptoms and cognitive dysfunction associated with schizophrenia is a significant unmet medical need. Preclinical literature indicates that alpha7 neuronal nicotinic acetylcholine (nACh) receptor agonists may provide an effective approach to treating cognitive dysfunction in schizophrenia. We report herein the discovery and evaluation of 1c (BMS-933043), a novel and potent alpha7 nACh receptor partial agonist with high selectivity against other nicotinic acetylcholine receptor subtypes (>100-fold) and the 5-HT3A receptor (>300-fold). In vivo activity was demonstrated in a preclinical model of cognitive impairment, mouse novel object recognition. BMS-933043 has completed Phase I clinical trials.

The syntheses of [(13) C6 ] and [phenyl-(14) C(U)]BMS-816336, an inhibitor of 11beta-hydroxysteroid dehydrogenase type 1, for type 2 diabetes.[Pubmed:28273377]

J Labelled Comp Radiopharm. 2017 Jun 30;60(8):357-365.

Type 2 diabetes is a significant worldwide health problem. To support the development of BMS-816336 as an inhibitor of 11beta-hydroxysteroid dehydrogenase type 1 for type 2 diabetes, the synthesis of carbon-14 labeled material was required for use in metabolic profiling. [Phenyl-(14) C(U)]BMS-816336 was synthesized in 8 steps and 22% radiochemical yield from commercially available [(14) C(U)]bromobenzene. The radiochemical purity of [phenyl-(14) C(U)]BMS-816336 was 100% having a specific activity of 84.4 muCi/mg or 28.8 mCi/mmol for a total of 8.9 mCi. It was also necessary to synthesize [(13) C6 ]BMS-816336 for use as a liquid chromatography/mass spectrometry standard. [(13) C6 ]BMS-816336 was also prepared in 8 labeled steps in 26% yield from [(13) C6 ]bromobenzene.

Differential action on coregulator interaction defines inverse retinoid agonists and neutral antagonists.[Pubmed:19477412]

Chem Biol. 2009 May 29;16(5):479-89.

Retinoic acid receptors (RARs) are ligand-dependent transcription factors that control a plethora of physiological processes. RARs exert their functions by regulating gene networks controlling cell growth, differentiation, survival, and death. Uncovering the molecular details by which synthetic ligands direct specificity and functionality of nuclear receptors is key to rational drug development. Here we define the molecular basis for (E)-4-[2-[5,6-Dihydro-5,5-dimethyl-8-(2-phenylethynyl)naphthalen-2-yl]ethen-1-yl] benzoic acid (BMS204,493) acting as the inverse pan-RAR agonist and define 4-[5,6-Dihydro-5,5-dimethyl-8-(quinolin-3-yl)naphthalen-2-carboxamido]benzoic acid (BMS195,614) as the neutral RARalpha-selective antagonist. We reveal the details of the differential coregulator interactions imposed on the receptor by the ligands and show that the anchoring of H12 is fundamentally distinct in the presence of the two ligands, thus accounting for the observed effects on coactivator and corepressor interactions. These ligands will facilitate studies on the role of the constitutive activity of RARs, particularly of the tumor suppressor RARbeta, whose specific functions relative to other RARs have remained elusive.

Structural basis for engineering of retinoic acid receptor isotype-selective agonists and antagonists.[Pubmed:10421757]

Chem Biol. 1999 Aug;6(8):519-29.

BACKGROUND: Many synthetic retinoids have been generated that exhibit a distinct pattern of agonist/antagonist activities with the three retinoic acid receptors (RARalpha, RARbeta and RARgamma). Because these retinoids are selective tools with which to dissect the pleiotropic functions of the natural pan-agonist, retinoic acid, and might constitute new therapeutic drugs, we have determined the structural basis of their receptor specificity and compared their activities in animal and yeast cells. RESULTS: There are only three divergent amino acid residues in the ligand binding pockets (LBPs) of RARalpha, RARbeta and RARgamma. We demonstrate here that the ability of monospecific (class I) retinoid agonists and antagonists to bind to and induce or inhibit transactivation by a given isotype is directly linked to the nature of these residues. The agonist/antagonist potential of class II retinoids, which bind to all three RARs but depending on the RAR isotype have the potential to act as agonists or antagonists, was also largely determined by the three divergent LBP residues. These mutational studies were complemented by modelling, on the basis of the three-dimensional structures of the RAR ligand-binding domains, and a comparison of the retinoid agonist/antagonist activities in animal and yeast cells. CONCLUSIONS: Our results reveal the rational basis of RAR isotype selectivity, explain the existence of class I and II retinoids, and provide a structural concept of ligand-mediated antagonism. Interestingly, the agonist/antagonist characteristics of retinoids are not conserved in yeast cells, suggesting that yeast co-regulators interact with RARs in a different way than the animal cell homologues do.