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Woburn, MA, United States

Carter P.H.,Bristol Myers Squibb | Dean T.,Harvard University | Bhayana B.,Harvard University | Khatri A.,Harvard University | And 2 more authors.
Molecular Endocrinology | Year: 2015

The parathyroid hormone receptor-1 (PTHR1) plays critical roles in regulating blood calcium levels and bone metabolism and is thus of interest for small-molecule ligand development. Of the few small-molecule ligands reported for the PTHR1, most are of low affinity, and none has a welldefined mechanism of action. Here, we show that SW106 and AH-3960, compounds previously identified to act as an antagonist and agonist, respectively, on the PTHR1, each bind to PTHR1- delNT, a PTHR1 construct that lacks the large amino-terminal extracellular domain used for binding endogenous PTH peptide ligands, with the same micromolar affinity with which it binds to the intact PTHR1. SW106 antagonized PTHR1-mediated cAMP signaling induced by the peptide analog, M-PTH(1–11), as well as by the native PTH(1–9) sequence, as tethered to the extracellular end of transmembrane domain (TMD) helix-1 of the receptor. SW106, however, did not function as an inverse agonist on either PTHR1-H223R or PTHR1-T410P, which have activating mutations at the cytoplasmic ends of TMD helices 2 and 6, respectively. The overall data indicate that SW106 and AH-3960 each bind to the PTHR1 TMD region and likely to within an extracellularly exposed area that is occupied by the N-terminal residues of PTH peptides. Additionally, they suggest that the inhibitory effects of SW106 are limited to the extracellular portions of the TMD region that mediate interactions with agonist ligands but do not extend to receptor-activation determinants situated more deeply in the helical bundle. The study helps to elucidate potential mechanisms of small-molecule binding at the PTHR1. © 2015 by the Endocrine Society.

Williams J.D.,Microbiotix, Inc | Ding X.,Microbiotix, Inc | Nguyen S.,Microbiotix, Inc | Vines K.K.,CreaGen Biosciences Inc | Peet N.P.,Microbiotix, Inc
Synthetic Communications | Year: 2013

6-Cyanobenzo[b]furan-2-boronic acid pinacol ester (10) is a potentially useful two-point scaffold for the construction of specific compounds or compound libraries with benzofuran cores. Using a per-iodination/de-iodination strategy coupled with Sonogashira alkynylation and Cu-catalyzed heteroannulation, we have developed a procedure that allows the preparation of benzo[b]furan-6- carbonitrile (9) and 6-cyanobenzo[b]furan-2-boronic acid pinacol ester (10) in gram quantities. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file. © 2013 Taylor and Francis Group, LLC.

Nguyen S.T.,Microbiotix, Inc | Williams J.D.,Microbiotix, Inc | Butler M.M.,Microbiotix, Inc | Ding X.,Microbiotix, Inc | And 9 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

Herein we describe the synthesis and antibacterial evaluation of a new, unsymmetrical triaryl bisamidine compound series, [Am]-[indole]-[linker]-[HetAr/ Ar]-[Am], in which [Am] is an amidine or amino group, [linker] is a benzene, thiophene or pyridine ring, and [HetAr/Ar] is a benzimidazole, imidazopyridine, benzofuran, benzothiophene, pyrimidine or benzene ring. When the [HetAr/Ar] unit is a 5,6-bicyclic heterocycle, it is oriented such that the 5-membered ring portion is connected to the [linker] unit and the 6-membered ring portion is connected to the [Am] unit. Among the 34 compounds in this series, compounds with benzofuran as the [HetAr/Ar] unit showed the highest potencies. Introduction of a fluorine atom or a methyl group to the triaryl core led to the more potent analogs. Bisamidines are more active toward bacteria while the monoamidines are more active toward mammalian cells (as indicated by low CC 50 values). Importantly, we identified compound P12a (MBX 1887) with a relatively narrow spectrum against bacteria and a very high CC50 value. Compound P12a has been scaled up and is currently undergoing further evaluations for therapeutic applications. © 2014 Elsevier Ltd. All rights reserved.

Nguyen S.T.,Microbiotix, Inc | Williams J.D.,Microbiotix, Inc | Majgier-Baranowska H.,Microbiotix, Inc | Li B.,Microbiotix, Inc | And 3 more authors.
Synthetic Communications | Year: 2014

A new three-step synthesis of 6-cyanobenzo[b]furan (6) was developed, starting from commercially available 6-hydroxybenzo[b]furan-3-one (18). Key steps in this process were the first step, which was the reductive dehydration of 18 to produce 6-hydroxybenzo[b]furan (19), and the last step, which converted the aryl triflate 20 to the aryl cyanide 6 in a palladium-catalyzed cross-coupling protocol. Overall yield for this new synthesis was 49%. © 2014 Copyright Taylor & Francis Group, LLC.

Lee J.,CreaGen Biosciences Inc | Khanapure S.P.,CreaGen Biosciences Inc | Kim H.-O.,CreaGen Biosciences Inc | Rajur R.S.B.,CreaGen Biosciences Inc | And 5 more authors.
Synthetic Communications | Year: 2010

Unexpected difficulty in the conversion of a bromobenzofuran to the corresponding formylbenzofuran led us to develop a new synthesis for 5-formylbenzo[b]furan-2-carbonitrile (1). Copyright © 2010 Taylor and Francis Group, LLC.

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