Structure Determination and Comparison of BM567, a Sulfonylurea, with Terbogrel, Two Compounds with Dual Action, Thromboxane Receptor Antagonism and Thromboxane Synthase Inhibition CatherineMichaux, a, *Ste´phanieRolin, b Jean-MichelDogne´, c Franc¸oisDurant, a BernardMasereel, b JacquesDelarge c andJohanWouters a a Lab. Chimie Mole ´culaire Structurale, Faculte ´s Universitaires N.-D. de la Paix, 61 rue de Bruxelles, B-5000 Namur, Belgium b De ´partement de Pharmacie, Faculte ´s Universitaires N.-D. de la Paix, 61 rue de Bruxelles, B-5000 Namur, Belgium c Service de Chimie Pharmaceutique, 1 avenue de l’ho ˆpital, B-4000 Lie `ge, Belgium Received17November2000;revised16January2001;accepted16February2001 Abstract—BM567, a sulfonylurea compound—whose crystal structure is here discussed—and terbogrel, are both thromboxane receptorantagonistsandthromboxanesynthaseinhibitors.Inthispaper,theircrystallographicandelectronicstructuresarecom- paredandleadtonewsynthesisprospectsamongthesulfonylureaseries. # 2001ElsevierScienceLtd.Allrightsreserved. Thromboxane A 2 (TXA 2 ), an unstable endogenous arachidonic acid metabolite, plays a role in platelet aggregation, and broncho- and vasoconstriction. 1 Itis implicated in cardiovascular, renal and pulmonary dis- eases. Thromboxane synthase inhibitors (TXSIs) and thromboxane receptor antagonists (TXRAs) have been developed to treat these disorders. 2,3 However, TXSIs havenotshownclinicalefficacyduetotheaccumulation of PGH 2 , 4 a thromboxane receptor agonist. The com- binationofTXSIandTXRAactivitywasprovedtobe betterthanthatofselectivecompounds 5,6 anddifferent series of compounds with this dual action have been developed. 7 10 In our laboratory, a series of sulfonylureas, including BM567 (1), has been designed and were found to be bothTXSIsandTXRAs(Table1). 11 Sotheyrepresenta novelchemicalfamilyoftherapeuticagents. Here we report the structure determination of BM567 (1)anditsstructuralcomparisonwithterbogrel(2)with dualaction(Table1). 12 The molecular electrostatic potential (MEP) has been calculated on both compounds and pK a of BM567 measured leading to a pharmacophore that provides ideastoimprovedualactionofBM567. Crystal Structure of BM567 CrystalstructureofBM567(1)wasfirstrefinedagainst room temperature data. 13 The pentyl chain was dis- ordered and electron density not well defined, so low temperaturedata(80  C)werecollected.Thestructure refinedwiththisprocedurehasalower R factor(6.57%) and therefore coordinates corresponding to this model wereretainedinthiswork. Although reduced in the low temperature structure, thermalmotiononthepentylchainwasstilltoohighto allowreasonableanisotropicrefinementofthischainor clear introduction of disorder. The great flexibility of pentyl is possibly due to its poor stabilisation in the crystalpacking. Based on the torsion angles along the sulfonylurea group(f1, f2, f3and f4),bothmolecules(aandb)in the asymmetric unit adopt two distinct conformations (Table 2). Previously, four conformations have been 0960-894X/01/$-seefrontmatter # 2001ElsevierScienceLtd.Allrightsreserved. PII:S0960-894X(01)00114-7 Bioorganic&MedicinalChemistryLetters11(2001)1019–1022 *Correspondingauthor.Tel.:+32-08172-4555;fax:+32-08172-4530; e-mail:catherine.michaux@scf.fundp.ac.be