Molecular Characteristics of Good Drugs PDF

Molecular Characteristics of Good Drugs Dr Graeme Kay [email protected] 01224 262548  Serendipity Serendipity is the effect by which one accidentally discovers something fortunate, especially while looking for something else entirely. The word derives from an old Persian fa...

Molecular Characteristics of Good Drugs Dr Graeme Kay [email protected] 01224 262548  Serendipity Serendipity is the effect by which one accidentally discovers something fortunate, especially while looking for something else entirely. The word derives from an old Persian fairy tale and was coined by Horace Walpole on 28 January 1754. The Three Princes of Serendip is an old Persian fairy tale about three men who were on a mission but they always found something that was irrelevant but needed in reality.  Serendipity and the Prepared Mind The French scientist Louis Pasteur said that "in the field of observation, chance favours only the prepared mind." Albert Hofmann, the Swiss chemist who discovered LSD’s properties by accidentally ingesting it at his lab, wrote: "It is true that my discovery of LSD was a chance discovery, but it was the outcome of planned experiments and these experiments took place in the framework of systematic pharmaceutical, chemical research. It could better be described as serendipity."  Examples Mustard Gas Ship exploded in Italian harbour carrying mustard gas. Survivors lost their natural defence against microbes. White blood cells destroyed. Leukaemia excess proliferation of white blood cells – selective cell kill potential.  Examples Disulfiram is a drug used to support the treatment of chronic alcoholism by producing an acute sensitivity to alcohol.. Workers in rubber industry found that they often acquired a distaste for alcohol. This was caused by an antioxidant used finding its way into their bodies.  Examples Clonidine Originally designed to be a nasal vasoconstrictor, to be used in nasal drops and shaving soaps. Clinical trials revealed that it caused a marked fall in blood pressure – it went on to become an important antihypertensive!  Sildenafil Vasodilator – heart treatment. Anti-impotence. Molecular Characteristics of Good Drugs BARBER, J. and ROSTON, C. Pharmaceutical Chemistry. Current Edition. Oxford University Press. Chapter 12, pp 327-340. ning Objectives: Have an understanding of Lipinski’s rule of five and its exceptions Have an understanding of the fundamental principles of structure-activ relationships. Lipinski’s Rule of Five Lipinski’s Rule of Five Database of 2500 drug-like compounds All had entered Phase II clinical trials, i.e. not shown early toxicity. Candidates likely to be administered via injection ignored. Orally-active drugs. What are the problems to overcome? 1. Has to pass through the lumen of the gut, through the gut wall and beyond into the bloodstream (aqueous). For this to be achieved, what do we have to consider?  Important Factors Size? Solubility? Hydrogen Bonding? hin their database only 11% of their compound molecular weight greater than 500. gs that are successful for oral delivery tend to ll, i.e. they can cross membranes better.  OH OH O O O N O- NH OH ibuprofen F MWT 206 O Atorvastatin MWT 577 N+ O- N N OH metronidazole MWT 171 bility compound to cross a membrane it must be soluble in water and also lipid. rtant: Not too soluble in either!  Log P P is the usual parameter used to articulate solubilit P = COCTANOL / CWATER P is the partition coefficient. Lipinski and co-workers found within their database only 10% of their compounds had log P values greater than 5. Compounds with a log P values above 5 are very hydrophobic – stick in membranes. Hydrogen Bonding https://chemdictionary.org/wp-content/uploads/2017/10/H-bon-3-300x179.jpg rogen Bonding drogen bond donor and acceptor are required. donor in a hydrogen bond is the atom to which the ogen atom participating in the hydrogen bond is lently bonded, and is usually a strongly tronegative atom such as N, O, or F. The hydrogen ptor is the neighbouring electronegative ion or mole must posses a lone electron pair in order to form a ogen bond. Lipinski and co-workers suggested to count only OH and NH groups with: OH and NH groups acting H-bond donors and O and N as H-bond acceptors. Lipinski and co-workers found within their database only 12% of their compounds had more than 10 H- bonds and only 8% had more than 5 H-bonds. Note: if a drug bonds too strongly to itself, it can’t pass lipid membranes.  Lipinski’s Rule of Five (note: all parameters are multiples of 5, hence the name!) Poor absorption (or permeation) is more likely when: The molecular weight is over 500 The log P is over 5 There are more than 5 H-bond donors (expressed as the sum of OHs and NHs) There are more than 10 H-bond acceptors (expressed as the sum of Ns and Os).  Exceptions Drugs for delivery via non-oral routes. Drugs to treat disorders of the gut. Antibiotics, antifungals, vitamins and cardiac glycos  Structure Activity Relationships (SAR)  Structure Activity Relationships (SAR) ‘Father of Chemotherapy’. ‘Magic bullet’ – selectivity. First effective medicinal treatment for syphilis. Paul Ehrlich Drug design and in particular SAR. By Harris & Ewing - This image is available from the United States Library of Congress's Prints and Photographs division under the digital ID hec.04709. https://en.wikipedia.org/wiki/Paul_Ehrlich#/media/File:Paul_Ehrlich_1915.jpg  Structure Activity Relationships (SAR) Structure Activity Relationships (SAR): The relationship between a molecule and its biological activity. https://image.slidesharecdn.com/sar-130222071953-phpapp02/95/structure-activity- relationships-antipsychotics-6-638.jpg?cb=1361517652  Structure Activity Relationships (SAR) aration of analogues in a logical, systemic way. ider you want to design a more polar version of butylbenzen butylbenzene Log P 3.8 cally, you would consider shortening the alkyl chain or, perha ng a methoxy (-OCH3) to the para position of the ring. rom: BARBER, J. and ROSTON, C. Pharmaceutical Chemistry. Current Edition. Oxford University Press.  O propylbenzene 1-butyl-4-methoxybenzene Log P 3.2 Log P 3.9 ethylbenzene Log P 2.8  Structure Activity Relationships (SAR) H Specific example: H2N S N O OH O 6-aminopenicillanic acid Very little antibacterial activity  H H N S O N O OH O Benzylpenicillin  NH2 H H N S HO O N O NH2 OH O H H amoxicillin N S O N O OH O Ampicillin  Development of Pharmacophore The IUPAC definition of a pharmacophore is "an ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response”. QSAR Quantitative structure-activity relationship (QSAR) is the process by which chemical structure is quantitatively correlated with a well defined process, such as biological activity or chemical reactivity.  Lead Optimisation Medicinal chemists improve drug efficacy, particularly with respect to stability and bioavailability, e.g. developing mechanism-based pro-drugs. Pro-drugs are engineered in such a way that they undergo chemical transformation either in the bloodstream or specific tissues such as the liver. Upon transformation, biologically active metabolites are released, which are the actual drugs... vailability of Sites for Chemical Derivatisation Electron releasing or donating substituents Exo Methylation NH Salt formation? Substituents N N Further hetero atoms Example: Imidazo[1-5a]Pyridines  Chemical Manipulation Once the pharmacaphore has been established it is possible to make further analogues. Why? Very few lead compounds are ideal. Most are likely to have low activity, poor selectivity, and significant side effects. Furthermore, bench to plant is a big ask!  Variation of Substituents Alkyl substituents kyl groups are interacting with a hydrophobic pocket in a binding site, then by ying length and bulky will enable you to probe the depth and width of the pocket DRUG DRUG CH3 CH2 CH2 CH3 Hydrophobic Pocket DRUG DRUG CH3 H3C CH 3 CH 3 Hydrophobic Pocket  Variation of Substituents Aromatic Substituents Variation of substituents around a ring system can alter the basicity, acidity of the that part of the molecule. Also the position of hydrogen bonding groups on a ring can be altered and may increase potency. Weak H Bond Strong H Bond H O O H  Summary portance of considering Lipinski's Rule of Five in drug design. R – Small, iterative changes in drug structure are made and the effect of biologic ity evaluated. olecules can be optimised for effectiveness, safety, solubility, spectrum of activit lity, selectivity, etc  Lipinski - Examples Using Lipinski and co-workers Rule of Five, decide if Salbutamol has good molecular drug characteristics. NOTE: calculated log P ~0.97 HO HO N H OH salbutamol SAR - Examples O N H OH NH2