Pergamon Bioorganic & Medicinal Chemistry Letters 9 (1999) 2741-2746 BIOORGANIC & MEDICINAL CHEMISTRY LETTERS STRUCTURE--ACTIVITY RELATIONSHIPS OF BIPHENYL TETRAZOLES AS METALLO-[3-LACTAMASE INHIBITORS* Jeffrey H. Toney, ~* Kelly A. Cleary,' Gail G. Hammond, a Xiling Yuan, a Walter J. May, b Steven M. Hutchins, ° Wallace T. Ashton, ° and Dana E. Vanderwall: aDepartments of Biochemistry, bInfectious Disease Research, and CMedicinal Chemistry, Merck Research Laboratories, P. O. Box 2000, Rahway, Nd07065-0900, U.S.A. Received 26 May 1999; accepted 15 August 1999 Abstract: Resistance to carbapenem antibiotics in Gram-negative bacteria is due, in part, to expression of a wide spectrum metallo-13-1actamase, which renders the drug inactive. Biphenyl tetrazoles containing 3-n-butyl- 1-phenylpyrazole-5-carboxylates or the corresponding 5-ethyl esters were found to inhibit metaUo-13-1actamases as well as renal dehydropeptidase I to a lesser extent. © 1999 ElsevierScienceLtd. All rights reserved. Introduction: Carbapenem antibiotics such as imipenem are useful for the treatment of a variety of Gram- negative and Gram-positive infections) However, antibiotic resistance has emerged in part due to class B metallo-13-1actamases (MBLs), which hydrolyze 13-1actams, cephalosporins and carbapenems rendering them ineffective.2 One approach to this important medical problem is to combine the antibiotic with an enzyme inhibitor as was done with Augmentina~, which is comprised of the ~-lactam antibiotic amoxicillin and clavulanic acid, a "suicide" inhibitor of the class A serine 13-1actamases. 3 In a search for agents that could prevent the hydrolysis of carbapenems, biphenyl tetrazoles (BPTs) 4a were found to be inhibitors of an MBL 4b cloned from an imipenem-resistant clinical isolate of Bacteroidesfragilis (B. fragilis). Some BPTs have been reported to be potent nonpeptide antagonists of angiotensin II and have been used for the treatment of hypertensive disorders: The present paper describes emerging structure-activity relationships (SAR) of the BPT class as candidates for reversing antibiotic resistance in B. fragilis as well as in Pseudomonas aeruginosa (P. aeru.) mediated by the plasmid-bome IMP-1 enzyme. Recent reports of MBL inhibitors distinct from BPTs have appeared including thiol esters,6~b'gthiols,6~'d trifluoromethyl alcohol and ketone derivatives of L- and D- alaninere and amino acid-derived hydroxamates.6f However, only thiols have been shown to inhibit the IMP-1 enzyme present in Serratia marcescens. 6" Purified recombinant B. fragilis 4b and IMP-16g MBL was prepared as described. Activity was assessed using the chromogenic substrate nitrocefin at K~ levels in a 96-well microtiter plate as described.4b Renal *This manuscript is dedicated to the memory of Carole Lee Toney. tpresent address: Glaxo Wellcome, Department of Structural Chemistry, Five Moore Drive, Research Triangle Park, NC 27709, U.S.A. 0960-894X/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved. PII: S0960-894X(99)00458-8