Polypharmacology by Design: A Medicinal Chemist’s Perspective on Multitargeting Compounds

Abstract

Multitargeting compounds comprising activity on more than a single biological target have gained remarkable relevance in drug discovery owing to the complexity of multifactorial diseases such as cancer, inflammation, or the metabolic syndrome. Polypharmacological drug profiles can produce additive or synergistic effects while reducing side effects and significantly contribute to the high therapeutic success of indispensable drugs such as aspirin. While their identification has long been the result of serendipity, medicinal chemistry now tends to design polypharmacology. Modern in vitro pharmacological methods and chemical probes allow a systematic search for rational target combinations and recent innovations in computational technologies, crystallography, or fragment-based design equip multitarget compound development with valuable tools. In this Perspective, we analyze the relevance of multiple ligands in drug discovery and the versatile toolbox to design polypharmacology. We conclude that despite some characteristic challenges remaining unresolved, designed polypharmacology holds enormous potential to secure future therapeutic innovation.

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

“…[145] Polypharmacology represents an increasingly recognizeds trategy for the treatment of complex diseases,such as cancer or CNS diseases. [146][147][148][149][150][151] Pochetti et al reported two inhibitors of MMP-8t hat bind to an S1'*p ocket previously unobserved for humann eutrophil collagenase . [152] This extra binding region is formed through the rearrangement of the Tyr227 side chain induced by the inhibitors.…”

“…In a similar approach, the group developed a dual inhibitor for the target enzymes MMP‐7 and ‐13 . Polypharmacology represents an increasingly recognized strategy for the treatment of complex diseases, such as cancer or CNS diseases …”

A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors

“…The organic phase was evaporated under reduced pressure, and the aqueous phase was 4.1.8. N-(6-Chloro-1,2,3,4-tetrahydroacridin-9-yl)-N'- (9-fluoro-7H-5,6,8,9,10,11hexahydro-5,9:7,11-dimethanobenzo[9]annulen-7-yl)-1, 5- 4.1.9. tert-Butyl (9-fluoro-7H-5,6,8,9,10,11-hexahydro-2-nitro-5,9:7,11dimethanobenzo[9]annulen-7-yl)carbamate (15) To a mixture of amine 14 [59] (496 mg, 1.79 mmol) and 2N NaOH (1.4 mL) in THF 4.1.10. tert-Butyl (2-amino-9-fluoro-7H-5,6,8,9,10,11-hexahydro-5,9:7,11dimethanobenzo[9]annulen-7-yl)carbamate (16) A suspension of the nitro derivative 15 (583 mg, 1.54 mmol) and PtO2 (48 mg, 0.12 mmol) in EtOH (100 mL) was hydrogenated at 1 atm of H2 at room temperature for 4 h. Hz, 1H, 4-H); 13 4.1.11. N-(7-Amino-9-fluoro-7H- 5,6,8,9,10,11-hexahydro-5,9:7,11-…”

“…Multitarget treatments may involve the use of several specific drugs (drug cocktails or fixed-dose combinations) or a single drug with the ability to hit several biological targets (multitarget drugs). Even though the design and development of multitarget drugs can be very challenging [12], it has some clear advantages over multiple-medication therapies, such as simpler dose regimens and improved patient compliance, simpler pharmacokinetics and lack of drug-drug interactions, and simpler clinical development, among others [13,14]. In fact, both strategies are being currently used in AD treatment or pursued in AD drug discovery.…”

“…7.93 (d, J = 9.2 Hz, 1H, 8'-H);13 C NMR (100.6 MHz, CDCl3, this compound decomposed partially during acquisition of the spectrum, only some representative signals are given) δ 22.1 (CH2), 22.7 (CH2), 22.8 (CH2) (C3, C2', C3'), 24.7 (CH2, C1'),28.8 (CH2, C4), 30.9 (CH2, C2), 32.6 (CH2, C4'), 37.4 (CH3, OSO2CH3),48.8 (CH2, …”