Design and Synthesis of New Tetrazolyl- and Carboxy-biphenylylmethyl-quinazolin-4-one Derivatives as Angiotensin II AT 1 Receptor Antagonists Mohamed A. H. Ismail,* ,² Stewart Barker, ‡ Dalal A. Abou El Ella, ² Khaled A. M. Abouzid, ² Rabab A. Toubar, ² and Matthew H. Todd* ,§ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams UniVersity, ElKhalifa ElMaamoon St., 11566, Abbasseya, Cairo, Egypt, School of Biological and Chemical Sciences, Queen Mary, UniVersity of London, Mile End Road, London, E1 4NS, UK, and School of Chemistry, UniVersity of Sydney, NSW 2006, Australia ReceiVed March 15, 2005 A series of novel quinazolin-4-ones was designed and their molecular modeling simulation fitting to a new HipHop 3D pharmacophore model using CATALYST was examined. Several compounds showed significant high simulation fit values. The designed compounds were synthesized and eight of them were biologically evaluated in vitro using an AT 1 receptor binding assay, where compound XX competed weakly against radiolabeled Sar 1 Ile 8 -angiotensin II (Ang II) binding, compounds XIV and XXII showed moderate competition, and compound XXV showed almost equal ability to displace radiolabeled Sar 1 Ile 8 -Ang II binding to AT 1 receptors as losartan. In vivo biological evaluation study of compounds XIV, XXII, and XXV on both normotensive and hypertensive rats revealed that compound XXV demonstrated higher hypotensive and antihypertensive activity than the reference compound losartan. To obtain a highly active compound from a candidate set of only eight tested compounds illustrates the power and utility of our pharmacophore model. 1. Introduction The octapeptide angiotensin II (Ang II) produced by the renin- angiotensin system (RAS) is a potent vasoconstrictor and thus plays an integral role in the pathophysiology of hypertension. 1 This directed many researchers toward designing drugs to block the effects of Ang II either by inhibiting the angiotensin- converting enzyme (ACE) or renin or by blocking the Ang II receptors. Ang II receptor antagonists have proved to lower blood pressure effectively, 2 and they are better tolerated than other classes of drugs. 3,4 The development of non-peptide Ang II receptor antagonists was sparked by patents of Takeda Chemical Industries in Japan in 1982, when Furukawa et al. disclosed a series of imidazole-5-acetic acid derivatives. 5,6 Further optimization of these compounds 7 gave rise to the discovery of the first lead compound losartan, which was launched in 1994 to treat hypertension. Carini et al. 8 proposed a structure-activity relationship (SAR) of AT 1 receptor antagonists that suggested activity is improved by the presence of (i) a biphenyl group (The presence of a linker chain between the two phenyl moieties reduces the activity. The biphenyl moiety, which acts as a spacer connecting the acidic group with other features, could be replaced by other similar spacers. 9 ); (ii) a tetrazole group, or an acidic isostere, 10,11 at the ortho position of the biphenyl group; (iii) a heterocyclic ring, to act as an acceptor in a hydrogen-bonding interaction with the receptor; and (iv) a short alkyl chain at the 2-position of the heterocycle, for efficient binding to the receptor. It appears that all the Ang II antagonists designed to study AT 1 receptor antagonistic activity are based on the above model as all the active molecules have these pharmacophores. 11-13 Our current investigation is based on molecular modeling studies involving the synthesis of new tetrazolyl- and carboxy-biphe- nylylmethyl quinazoline derivatives by the replacement of the imidazole ring of losartan with 4-quinazolinones, a pharma- cophore that has proven to be a rich source of exceptionally potent Ang II antagonists. 13 The 4-quinazolinone ring system has the same 1,3-arrangement of nitrogens found in the imidazole ring and can accommodate the requisite lipophilic side chain at position 2. 13h Additionally, the carbonyl group of 4-quinazolinone can serve as a mimic of the hydroxymethyl group of losartan. 14 tert-Butyl ester analogues were designed as they can be considered as potential prodrugs that could be easily hydrolyzed in vivo, giving the carboxylic acid. In this project, molecular modeling simulation studies were performed in order to predict the biological activity of the proposed compounds. The hypothesis generation was performed using the HipHop module of CATALYST software. This method is applicable when the 3D structure of the receptor is unknown and a series of compounds has been identified to have similar activity with dissimilar and/or flexible structures. The main idea of this approach is to identify the ideal hypothesis, which is a template derived from the structures of these compounds and representing the geometry of the receptor sites as a collection of functional groups in space. The program gave 10 hypotheses by default as a result of each run. All the 10 generated hypotheses had all the required features and gave good fitting with losartan and the target compounds, and we chose the hypothesis ranked number one. Retrospectively, we were pleased to note that this hypothesis gave the most consistent fit values with the experimental biological results discussed below. The generated AT 1 receptor antagonists hypothesis was subjected to simulation compare/fit studies, using the best fit algorithm, with the conformational model of a test set of the proposed compounds [XI, XIV, XVII, XVIII, XX, XXI, XXII, XXIII, and XXV (Scheme 2)] in order to predict their antagonistic activity. The simulated fitting values of the best fit conformer may be a guide for estimating relative affinities of these compounds with their receptors. The designed com- * Corresponding authors. M.A.H.I.: phone, +20 24051150; fax, +20 24051107; e-mail, mhismaeel@yahoo.com. M.H.T.: phone, +61(0) 2 9351 2180; fax, +61(0) 2 9351 3329, e-mail, m.todd@chem.usyd.edu.au. ² Ain Shams University. ‡ University of London. § University of Sydney. 1526 J. Med. Chem. 2006, 49, 1526-1535 10.1021/jm050232e CCC: $33.50 © 2006 American Chemical Society Published on Web 02/10/2006