Recent Advances in Retrometabolic Drug Design (RMDD) and Development
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REVIEW Center for Drug Discovery1, University of Florida, Gainesville, FL; Diabetes Research Institute2 and Department of Molecular and Cellular Pharmacology3, University of Miami, Miami, FL, USA Recent advances in retrometabolic drug design (RMDD) and development N. Bodor 1, P. Buchwald 2,3 Received January 18, 2010, accepted February 26, 2010 Prof. Nicholas Bodor, Center for Drug Discovery, University of Florida, Health Science Center, P.O. Box 100497, Gainesville, FL 32610-0497, USA [email protected] Pharmazie 65: 395–403 (2010) doi: 10.1691/ph.2010.0523R As a general review for the 7th Retrometabolism-Based Drug Design and Targeting Conference, recent developments within this field are briefly reviewed with various illustrative examples from different thera- peutic areas. Retrometabolic drug design incorporates two major systematic approaches: the design of soft drugs and of chemical delivery systems (CDS). Both aim to design new, safe drugs with an improved thera- peutic index by integrating structure-activity and structure-metabolism relationships; however, they achieve it by different means: whereas soft drugs are new, active therapeutic agents that undergo predictable metabolism to inactive metabolites after exerting their desired therapeutic effect, CDSs are biologically inert molecules that provide enhanced and targeted delivery of an active drug to a particular organ or site through a designed sequential metabolism that involves several steps. 1. Introduction etiprednol dicloacetate) (Bodor and Buchwald 2006c), soft -blockers (e.g., adaprolol) (Bodor and Buchwald 2005), and Although the drug discovery and development processes have soft anticholinergics (e.g., tematropium) (Kumar and Bodor significantly advanced by increasing insight into the molecu- 1996). Detailed quantitative structure-activity relationships lar/biochemical mechanisms of drug action and by improved were developed in these drug classes (Buchwald 2007a, 2008; and accelerated screening technologies and lead selection Buchwald and Bodor 2002, 2004, 2006) by taking into account, methods, the number of approved new chemical entities (NCE) among other things, the size-related effects through a bilinear has not increased accordingly. This lack of success underlines LinBiExp model (Buchwald 2005, 2007b). A number of soft the still limited understanding of what makes a good drug, drug approaches both by our laboratories and by many others but also the increasing developmental problems caused by already resulted in marketed drugs such as, for example, esmolol stringent regulations. There are still too many “me too” drugs and landiolol, soft -blockers containing easily hydrolyzable being developed just through limited modifications of known ester functions (Fig. 1), or remifentanil, a soft opioid analgesic drugs. Highly touted new technologies, such as combinatorial based on carfentanyl (Fig. 2). Some therapeutic compounds can chemistry and high-throughput screening (HTS), still have had also be considered as “accidental” soft drugs, i.e., drugs that no significant impact (Proudfoot 2002). Not enough emphasis is are, in fact, soft drugs even though they were not intentionally put on the safety issues. This important component is addressed designed as such. For example, methylphenidate, a methyl ester by retrometabolic drug design (RMDD) approaches, a general containing piperidine derivative that is structurally related to concept directed toward the design of improved therapeutic amphetamine (Fig. 3), which is widely used for the treatment of index (TI = TD /ED ), which is a reflection of the degree of 50 50 attention-deficit-hyperactivity disorder (ADHD). As a methyl selectivity or margin of safety. This type of design diverts the ester, it is easily hydrolyzed (Markowitz et al. 2000) to the metabolism of the drugs to novel, non-toxic pathways avoiding inactive (Patrick et al. 1981) acidic metabolite (ritalinic acid). the formation of toxic metabolites. With RMDD, metabolism Thus, methylphenidate can be considered a safe, soft drug, does not just happen, but the metabolic route is imposed on the which is why it is used extensively in pediatric patients. new drug by design. As is well known, RMDD involves two Soft drug design approaches are widely used in both industrial basic directions: soft drugs (SD) and targeted chemical delivery and academic settings. Some more interesting developments systems (CDS). include: 1. Soft estradiol analogs developed by Labaree and co-workers at Yale University (Fig. 4) (Labaree et al. 2001, 2003). These 2. Soft drug examples and recent developments compounds, while estrogenic, can be used locally for the The soft drug concept was introduced during the 1970 s (Bodor treatment of vaginal dispareunia, but are void of systemic 1977, 1982, 1984), and since then it has been applied by many estrogenic activity, due to their facile hydrolytic deactiva- research groups in a large number of therapeutic areas. Compre- tion. hensive reviews of all major aspects have been published (Bodor 2. Hydrolyzable ester containing soft cyclosporin analogs and Buchwald 2000, 2003b). Our laboratory focused mainly on (Fig. 5) explored at Enanta (Lazarova et al. 2003) for the the design of soft corticosteroids (e.g., loteprednol etabonate, treatment of autoimmune disorders. Pharmazie 65 (2010) 395 REVIEW O H O NH (S) N N O NH O NH OH OH OH O O O O O (S) O O metoprolol esmolol landiolol O (Breviblock™) (Onoact™) Fig. 1: Soft -blockers. The deactivating ester functions are structurally removed from the pharmacophore OH OH O OH O O N N O O O O HO HO HO N N O estradiol (E2) estriol estrone O soft drug carfentanyl remifentanil OH design OH (Ultiva™) O m R Fig. 2: Soft opioid analgesic, remifentanil 16 O 15 O n m O HO m = 0,1,2 HO OH OH H H N O N OH O m n 11 O O O O methylphenidate ritalinic acid 7 (Ritalin™) n (inactive) HO m O HO Fig. 3: Methylphenidate and its inactive metabolite, ritalinic acid Fig. 4: Soft estradiol analogs 3. Soft tacrolimus analogs (Fig. 6) (e.g., MLD987) investigated A similarly positioned thioester in fluticasone propionate at Novartis (Hersperger et al. 2004) for inhalation treatment undergoes oxidative and not hydrolytic ester cleavage. of asthma. 7. Soft amiodarone analogs (Fig. 10) for the treatment of atrial 4. Novel soft cytokine (Fig. 7) analogs developed at Janssen fibrillation were developed by Aryx Therapeutics (Arya et al. (Freyne et al. 2005) for inhalation therapy of asthma. 2009; Morey et al. 2001; Raatikainen et al. 2000) using the 5. Some locally acting soft benzodiazepine analogs dedicated software “Computer Assisted Soft Drug Design” (CNS7259X, CNS7056) of midazolam and bromazepam, (Bodor et al. 1998a) licensed from the University of Florida. developed at GlaxoSmithKline (Fig. 8) (Kilpatrick et al. Recent Phase II clinical studies demonstrated the superior 2007; Kilpatrick and Tilbrook 2006; Pacofsky et al 2002; safety profile of budiodarone (ATI-2042) as compared to Stafford et al. 2002). amiodarone. 6. Intended soft mometasone furoate analogs (Fig. 9) investi- 8. Soft cisapride analogs (e.g., ATI-7505) were also developed gated at Novartis (Sandham et al. 2004) that, however, did at Aryx Therapeutics (Fig. 11) and they also demonstrated not fulfill expectations as the highly hindered 17-esters did improved activity and safety in clinical trials for gastropare- not hydrolyze to the predicted inactive acidic metabolite. sis (Camilleri et al. 2007). O R O HO HO R=CH3, CH2CH 3, ± O O O O CH2CH2 , H CH OCH H N N 2 3, N N N N CH2SCH N N 3 O N O O O N O O O N O N O O NH O O NH O O H H N N N N N N O N O N H H O O cyclosporin A soft cyclosporin A analogs Fig. 5: Soft cyclosporin A analogs 396 Pharmazie 65 (2010) REVIEW HO O O O O OH OH O O O O O O N O N O O O O OH O OH O O O O O O tacrolimus (FK506) MLD987 (soft tacrolimus analog) Fig. 6: Soft tacrolimus analog MLD987 H H O N O O N O N Cl N Cl N N N N O OH S R S Cl O R=CH3 Cl O CH2CH3, (CH2)nCH3, soft cytokine inhibitors CH2CH2Ph CH2CF3, CH2CHCH2, (CH2)3OH, CH2CN, CH2COCH3, etc. Fig. 7: Soft cytokine inhibitors O H H O N N O O N Cl Cl N O OH F F CNS 7259X CNS 7261X inactive (acidic) metabolites N N O O Br N Br N O OH N N CNS 7056 CNS 7054 O H O N N N Cl N Br N Cl N F N diazepam bromazepam midazolam Fig. 8: Soft benzodiazepines, their inactive metabolites, and representative benzodiazepine structures Pharmazie 65 (2010) 397 REVIEW O O O O HO O OH O O Cl O F HO O O F O O O Cl O HO O O F Cl inactive (acidic) metabolite O F F Cl S O O O O O O HO HO O Cl F O O F mometasone furoate fluticasone propionate Fig. 9: Soft mometasone furoate analogs, their expected inactive metabolite, and related glucocorticoid structures (mometasone furoate and fluticasone propionate) R O OH O O I I O O O O N N I I O O soft amiodarone analogs R = CH3 ATI-2001 CH2CH3, ATI-2010 CH(CH3)2, ATI-2064 CH(CH3)CH2CH3, ATI-2042 ATI-2054 (CH2)4CH3 cHx, MeAda, etc. I O O N I O amiodarone Fig. 10: Soft amiodarone analogs 398 Pharmazie 65 (2010) REVIEW H2N O H2N O O O H H N (S) N (S) Cl (R) O Cl (R) O (R) O N N O N O inactive (acidic) ATI-7505 metabolite H2N O O H N Cl O N O F cisapride Fig. 11: Soft gastro-prokinetics based on cisapride O O O O O N N N O O O O OH N N N MOC-etomidate acid metabolite etomidate Fig.