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1Dual Metalloprotease Inhibitors. 6. Incorporation of Bicyclic and Substituted Monocyclic Azepinones As Dipeptide Surrogates in Angiotensin-Converting Enzyme/neutral Endopeptidase Inhibitors.

JA Robl,MP Cimarusti,LM Simpkins,B Brown,DE Ryono,JE Bird,MM Asaad,TR Schaeffer,NC Trippodo

A series of substituted monocyclic and bicyclic azepinones were incorporated as dipeptide surrogates in mercaptoacetyl dipeptides with the desire to generate a single compound which would potently inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). Many of these compounds displayed excellent potency against both enzymes. Two of the most potent compounds, monocyclic azepinone 2n and bicyclic azepinone 3q, demonstrated a high level of activity versus ACE and NEP both in vitro and in vivo.

1996Journal of Medicinal Chemistry（1996）引用：86

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2ChemInform Abstract: Dual Metalloprotease Inhibitors. Part 6. Incorporation of Bicyclic and Substituted Monocyclic Azepinones As Dipeptide Surrogates in Angiotensin‐Converting Enzyme (ace)/neutral Endopeptidase (NEP) Inhibitors.

J. A. ROBL,M. P. CIMARUSTI,L. M. SIMPKINS,B. BROWN,D. E. RYONO,J. E. BIRD,M. M. ASAAD,T. R. SCHAEFFER,N. C. TRIPPODO

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

1996ChemInform（1996）引用：13

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3Argatroban Analogs: Synthesis, Thrombin Inhibitory Activity and Cell Permeability of Aminoheterocyclic Guanidine Surrogates

RN MISRA,YF KELLY,BR BROWN, DGM ROBERTS, SH CHONG,SM SEILER

A series of Argatroban analogs, 3–6, in which the guanidino group was replaced by amino-substituted heterocycles of decreasing basicity were prepared and evaluated for their ability to inhibit human α-thrombin. Basicity was found to be important in determining inhibitory potency. Aminopyridine analog 3b (pKa∼7) afforded the most potent inhibition (I50=0.47 μM) and exhibited enhanced Caco-2 cell permeability.

1995ChemInform引用：37

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4Dual Metalloprotease Inhibitors. IV. Utilization of Thiazepines and Thiazines As Constrained Peptidomimetic Surrogates in Mercaptoacyl Dipeptides

J DAS,JA ROBL,JA REID,CQ SUN,RN MISRA,BR BROWN,DE RYONO,MM ASAAD,JE BIRD,NC TRIPPODO,EW PETRILLO,DS KARANEWSKY

A structure-activity study of the dual acting ACE/NEP inhibitors related to 1a and 1b was undertaken to determine the parameters critical for activity versus ACE and NEP in vitro.

1994BIOORGANIC & MEDICINAL CHEMISTRY LETTERS（1994）引用：36

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5Interphenylene 7-Oxabicyclo[2.2.1]heptane Oxazoles - Highly Potent, Selective, and Long-Acting Thromboxane A(2)-Receptor Antagonists

R N Misra,B R Brown,P M Sher, M,S E Hall,W C Han,J C Barrish,O Kocy,D N Harris,H J Goldenberg

A series of interphenylene 7-oxabicyclo[2.2.1]heptane oxazoles (2) were prepared and evaluated for their thromboxane (TxA2) antagonistic activity in vitro and duration of action in vivo. Examination of the carboxyl side chain indicated that the interphenylene ring substitution pattern and, to a lesser extent, chain length were important factors in determining TxA2 antagonistic potency. For the carboxyl side chain, ortho substitution, a single methylene spacer between the interphenylene and oxabicycloheptane rings, and a propionic acid side-chain length were determined to be optimal. With respect to the oxazole side chain a wide range of amide substituents with diverse structures and lipophilicities were compatible with potent antagonistic activity. Finally, an acidic functional group on the alpha-chain and a hydrogen bond acceptor on the 4-position of the oxazole ring were critical for potent activity. From the analogs prepared 42 (BMS-180,291: [(+)-1S-(1 alpha, 2 alpha, 3 alpha, 4 alpha)-2-[[3-[4-[(n- pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2- yl]methyl]benzenepropanoic acid) was found to be a potent, selective, and orally-active TxA2 antagonist with a long duration of action and has been selected as a candidate for clinical development. In human platelet-rich plasma, 42 inhibited arachidonic acid (800 microM) and U-46,-619 (10 microM) induced aggregation with I50 values of 7 and 21 nM, respectively. Radioligand binding studies of 42 with [3H]-SQ 29,548 showed a Kd value of 4.0 +/- 1.0 nM in human platelet membranes. Both in vitro and in vivo studies indicated 42 was devoid of direct agonistic activity. In vivo 42 (0.2 mg/kg, po) showed extended protection (T50 = 14.4 h) from U-46,619 (2 mg/kg, iv) induced death in mice, and a single oral dose of 42 (3 mg/kg) abolished U46,619-induced platelet aggregation ex vivo in African green monkeys for > 24 h.

1993Journal of medicinal chemistry（1993）引用：40

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6Thromboxane Receptor Antagonist BMS-180291: A New Pre-Clinical Lead

RN MISRA,BR BROWN,PM SHER,MM PATEL,SE HALL,WC HAN,JC BARRISH,DM FLOYD,PW SPRAGUE,RA MORRISON, RE RIDGEWELL,RE WHITE,

The synthesis and initial pharmacology of interphenylene 7-oxabicyclo[2.2.1]heptane oxazole thromboxane (TxA2) receptor antagonist BMS-180291 is described. BMS-180291 has been characterized as an orally bioavailable, potent and selective TxA2 antagonist with a long duration of action.

1992BIOORGANIC & MEDICINAL CHEMISTRY LETTERS（1992）引用：32

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7Interphenylene Phenyl Oxazoles - Novel, Potent Thromboxane Receptor Antagonists

RN MISRA,DN HARRIS,IM MICHEL,HJ GOLDENBERG,ML WEBB,BR BROWN

The synthesis and in vitro evaluation of a novel series of structurally simple interphenylene phenyl oxazoles 2 is described. The optimal interphenylene substitution pattern and carboxyl side chain length were determined and from this series 2b (SQ 34,942) was identified as a potent TxA2 antagonist (AAIPA I50=31 nM, K(d)=19 nM).

1992Bioorganic & medicinal chemistry letters（1992）引用：1

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8Conformationally-restricted Analogs of TXA2 Antagonist SQ 33,961: Receptor Binding Conformation of the Carboxyl Sidechain

RN MISRA,BR BROWN,DN HARRIS,AT PUDZIANOWSKI

Two distinct conformational families, exemplified by 1 and 2, of thromboxane A2 (TxA2 receptor antagonist SQ 33,961 have been determined by molecular modeling. Synthesis and biological evaluation of confromationally-restricted mimic 3Z suggested that the hairpin conformer, 1, is the bioactive conformation.

1991Bioorganic & Medicinal Chemistry Letters（1991）引用：2

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9Interphenylene 7-Oxabicycloheptane Txa2 Antagonists - Bms-180,291a - A New Clinical Candidate

Rn Misra,Br Brown,Pm Sher,Mm Patel,Wc Han,Se Hall,Dm Floyd,Dn Harris,A Hedberg,Ml Ogletree,Wa Schumacher,Ml Webb

1991ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY（1991）

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10Interphenylene 7-Oxabicycloheptanes-2 Sq-33,961 - A New Potent, Selective, Long-Acting Txa2 Antagonist

Rn Misra,Br Brown,Pm Sher,Mm Patel,Wc Han,Jc Barrish,Se Hall,Dn Harris

1991ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY（1991）

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11Interphenylene 7-Oxabicyclo[2.2.1]heptanes. SQ33,961: a New Potent, Long-Acting Thromboxane Antagonist

RN MISRA,BR BROWN,PM SHER,MM PATEL,HJ GOLDENBERG,IM MICHEL,DN HARRIS

The synthesis and initial biological evaluation of a novel series of chiral interphenylene 7-oxabicyclo-[2.2.1]heptane TxA2 antagonists with 4-amido oxazole omega chains is described. Within this series SQ 33,961 has been identified as a highly potent TxA2 antagonist with an exceptionally long in vivo duration of action.

1991BIOORGANIC & MEDICINAL CHEMISTRY LETTERS（1991）引用：11

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